Small molecule inhibitors in acute myeloid leukemia: from the bench to the clinic

References

• Litzow MR. Progress and strategies for patients with relapsed and refractory acute myeloid leukemia. Curr Opin Hematol 2007;14:130-7
   PubMed Web of Science ®Google Scholar
• Luger SM. Treating the elderly patient with acute myelogenous leukemia. Hematology Am Soc Hematol Educ Program 2010;2010:62-9
   PubMedGoogle Scholar
• Burnett A, Wetzler M, Lowenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol 2011;29:487-94
   PubMed Web of Science ®Google Scholar
• Wingard JR, Majhail NS, Brazauskas R, et al. Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. J Clin Oncol 2011;29:2230-9
   PubMed Web of Science ®Google Scholar
• Ungewickell A, Medeiros BC. Novel agents in acute myeloid leukemia. Int J Hematol 2012;96:178-85
   PubMed Web of Science ®Google Scholar
• Sekeres MA. Treatment of older adults with acute myeloid leukemia: state of the art and current perspectives. Haematologica 2008;93:1769-72
   PubMed Web of Science ®Google Scholar
• Popplewell LL, Forman SJ. Is there an upper age limit for bone marrow transplantation? Bone Marrow Transplant 2002;29:277-84
   PubMedGoogle Scholar
• Leith CP, Kopecky KJ, Godwin J, et al. Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group study. Blood 1997;89:3323-9
   PubMed Web of Science ®Google Scholar
• Mrozek K, Bloomfield CD. Chromosome aberrations, gene mutations and expression changes, and prognosis in adult acute myeloid leukemia. Hematology Am Soc Hematol Educ Program 2006;169-77
   PubMedGoogle Scholar
• O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348:994-1004
   PubMed Web of Science ®Google Scholar
• Huang ME, Ye YC, Chen SR, et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988;72:567-72
   PubMed Web of Science ®Google Scholar
• Castaigne S, Chomienne C, Daniel MT, et al. All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results. Blood 1990;76:1704-9
   PubMed Web of Science ®Google Scholar
• Grisendi S, Mecucci C, Falini B, Pandolfi PP. Nucleophosmin and cancer. Nat Rev Cancer 2006;6:493-505
   PubMed Web of Science ®Google Scholar
• Lindstrom MS. NPM1/B23: a Multifunctional chaperone in ribosome biogenesis and chromatin remodeling. Biochem Res Int 2011;2011:195209
   PubMedGoogle Scholar
• Ruggero D, Pandolfi PP. Does the ribosome translate cancer? Nat Rev Cancer 2003;3:179-92
   PubMed Web of Science ®Google Scholar
• Nozawa Y, Van Belzen N, Van der Made AC, et al. Expression of nucleophosmin/B23 in normal and neoplastic colorectal mucosa. J Pathol 1996;178:48-52
   PubMed Web of Science ®Google Scholar
• Falini B, Mecucci C, Tiacci E, et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 2005;352:254-66
   PubMed Web of Science ®Google Scholar
• Falini B, Nicoletti I, Martelli MF, Mecucci C. Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features. Blood 2007;109:874-85
   PubMed Web of Science ®Google Scholar
• Grummitt CG, Townsley FM, Johnson CM, et al. Structural consequences of nucleophosmin mutations in acute myeloid leukemia. J Biol Chem 2008;283:23326-32
   PubMedGoogle Scholar
• Sportoletti P, Grisendi S, Majid SM, et al. Npm1 is a haploinsufficient suppressor of myeloid and lymphoid malignancies in the mouse. Blood 2008;111:3859-62
   PubMed Web of Science ®Google Scholar
• den Besten W, Kuo ML, Williams RT, Sherr CJ. Myeloid leukemia-associated nucleophosmin mutants perturb p53-dependent and independent activities of the Arf tumor suppressor protein. Cell Cycle 2005;4:1593-8
   PubMed Web of Science ®Google Scholar
• Colombo E, Martinelli P, Zamponi R, et al. Delocalization and destabilization of the Arf tumor suppressor by the leukemia-associated NPM mutant. Cancer Res 2006;66:3044-50
   PubMed Web of Science ®Google Scholar
• Falini B, Bolli N, Liso A, et al. Altered nucleophosmin transport in acute myeloid leukaemia with mutated NPM1: molecular basis and clinical implications. Leukemia 2009;23:1731-43
   PubMed Web of Science ®Google Scholar
• Huang S, DeGuzman A, Bucana CD, Fidler IJ. Nuclear factor-kappaB activity correlates with growth, angiogenesis, and metastasis of human melanoma cells in nude mice. Clin Cancer Res 2000;6:2573-81
   PubMed Web of Science ®Google Scholar
• Li B, Li YY, Tsao SW, Cheung AL. Targeting NF-kappaB signaling pathway suppresses tumor growth, angiogenesis, and metastasis of human esophageal cancer. Mol Cancer Ther 2009;8:2635-44
   PubMed Web of Science ®Google Scholar
• Guzman ML, Neering SJ, Upchurch D, et al. Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood 2001;98:2301-7
   PubMed Web of Science ®Google Scholar
• Grandage VL, Gale RE, Linch DC, Khwaja A. PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-kappaB, Mapkinase and p53 pathways. Leukemia 2005;19:586-94
   PubMed Web of Science ®Google Scholar
• Cilloni D, Messa F, Rosso V, et al. Increase sensitivity to chemotherapeutical agents and cytoplasmatic interaction between NPM leukemic mutant and NF-kappaB in AML carrying NPM1 mutations. Leukemia 2008;22:1234-40
   PubMed Web of Science ®Google Scholar
• Freedman DA, Levine AJ. Nuclear export is required for degradation of endogenous p53 by MDM2 and human papillomavirus E6. Mol Cell Biol 1998;18:7288-93
   PubMed Web of Science ®Google Scholar
• Hietanen S, Lain S, Krausz E, et al. Activation of p53 in cervical carcinoma cells by small molecules. Proc Natl Acad Sci U S A 2000;97:8501-6
   PubMed Web of Science ®Google Scholar
• Pathria G, Wagner C, Wagner SN. Inhibition of CRM1-mediated nucleocytoplasmic transport: triggering human melanoma cell apoptosis by perturbing multiple cellular pathways. J Invest Dermatol 2012;132:2780-90
   PubMedGoogle Scholar
• Newlands ES, Rustin GJ, Brampton MH. Phase I trial of elactocin. Br J Cancer 1996;74:648-9
   PubMed Web of Science ®Google Scholar
• Mutka SC, Yang WQ, Dong SD, et al. Identification of nuclear export inhibitors with potent anticancer activity in vivo. Cancer Res 2009;69:510-17
   PubMed Web of Science ®Google Scholar
• Sakakibara K, Saito N, Sato T, et al. CBS9106 is a novel reversible oral CRM1 inhibitor with CRM1 degrading activity. Blood 2011;118:3922-31
   PubMed Web of Science ®Google Scholar
• Ranganathan P, Yu X, Na C, et al. Preclinical activity of a novel CRM1 inhibitor in acute myeloid leukemia. Blood 2012;120:1765-73
   PubMed Web of Science ®Google Scholar
• Kojima K, Kornblau SM, Ruvolo V, et al. Prognostic impact and targeting of CRM1 in acute myeloid leukemia. Blood 2013;121:4166-74
   PubMed Web of Science ®Google Scholar
• Savona M GR, Brown DP, et al. Phase I trial of selinexor (KPT-330), a first-In-class oral selective inhibitor of nuclear export (SINE) in patients (pts) with advanced acute myelogenous leukemia (AML). In: 55th ASH 2013; 2013
   Google Scholar
• Rettig M HM, Prior J, et al. Inhibition of nuclear transport modulator Xpo1/CRM1 for the treatment of acute myeloid leukemia (AML). In: 55th ASH Annual Meeting; 2013
   Google Scholar
• Fiskus W BR, Karissa P, et al. Co-treatment with NPM1 antagonist and FLT3 inhibitor or pan-histone deacetylase inhibitor exerts superior efficacy against cultured and primary human AML cells co-expressing mutant NPM1 and FLT3-ITD. In: AACR 104th Annual Meeting 2013; 2013
   Google Scholar
• Gurumurthy M, Tan CH, Ng R, et al. Nucleophosmin interacts with HEXIM1 and regulates RNA polymerase II transcription. J Mol Biol 2008;378:302-17
   PubMedGoogle Scholar
• Benson C, White J, De Bono J, et al. A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days. Br J Cancer 2007;96:29-37
   PubMed Web of Science ®Google Scholar
• Falini B, Bolli N, Shan J, et al. Both carboxy-terminus NES motif and mutated tryptophan(s) are crucial for aberrant nuclear export of nucleophosmin leukemic mutants in NPMc+ AML. Blood 2006;107:4514-23
   PubMed Web of Science ®Google Scholar
• Vousden KH, Prives C. Blinded by the light: the growing complexity of p53. Cell 2009;137:413-31
   PubMed Web of Science ®Google Scholar
• Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science 1991;253:49-53
   PubMed Web of Science ®Google Scholar
• Muller PA, Vousden KH. p53 mutations in cancer. Nat Cell Biol 2013;15:2-8
   PubMed Web of Science ®Google Scholar
• Levine AJ. p53, the cellular gatekeeper for growth and division. Cell 1997;88:323-31
   PubMed Web of Science ®Google Scholar
• Schottelius A, Brennscheidt U, Ludwig WD, et al. Mechanisms of p53 alteration in acute leukemias. Leukemia 1994;8:1673-81
   PubMed Web of Science ®Google Scholar
• Bueso-Ramos CE, Yang Y, deLeon E, et al. The human MDM-2 oncogene is overexpressed in leukemias. Blood 1993;82:2617-23
   PubMed Web of Science ®Google Scholar
• Wu X, Bayle JH, Olson D, Levine AJ. The p53-mdm-2 autoregulatory feedback loop. Genes Dev 1993;7:1126-32
   PubMed Web of Science ®Google Scholar
• Freedman DA, Wu L, Levine AJ. Functions of the MDM2 oncoprotein. Cell Mol Life Sci 199;55:96-107
   Google Scholar
• Zhou M, Gu L, Abshire TC, et al. Incidence and prognostic significance of MDM2 oncoprotein overexpression in relapsed childhood acute lymphoblastic leukemia. Leukemia 2000;14:61-7
   PubMed Web of Science ®Google Scholar
• Rayburn E, Zhang R, He J, Wang H. MDM2 and human malignancies: expression, clinical pathology, prognostic markers, and implications for chemotherapy. Curr Cancer Drug Targets 2005;5:27-41
   PubMed Web of Science ®Google Scholar
• Ventura A, Kirsch DG, McLaughlin ME, et al. Restoration of p53 function leads to tumour regression in vivo. Nature 2007;445:661-5
   PubMed Web of Science ®Google Scholar
• Xue W, Zender L, Miething C, et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 2007;445:656-60
   PubMed Web of Science ®Google Scholar
• Tovar C, Graves B, Packman K, et al. MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models. Cancer Res 2013;73:2587-97
   PubMed Web of Science ®Google Scholar
• Kojima K, Konopleva M, Samudio IJ, et al. MDM2 antagonists induce p53-dependent apoptosis in AML: implications for leukemia therapy. Blood 2005;106:3150-9
   PubMed Web of Science ®Google Scholar
• Lau LM, Nugent JK, Zhao X, Irwin MS. HDM2 antagonist Nutlin-3 disrupts p73-HDM2 binding and enhances p73 function. Oncogene 2008;27:997-1003
   PubMed Web of Science ®Google Scholar
• Ambrosini G, Sambol EB, Carvajal D, et al. Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1. Oncogene 2007;26:3473-81
   PubMed Web of Science ®Google Scholar
• LaRusch GA, Jackson MW, Dunbar JD, et al. Nutlin3 blocks vascular endothelial growth factor induction by preventing the interaction between hypoxia inducible factor 1alpha and Hdm2. Cancer Res 2007;67:450-4
   PubMed Web of Science ®Google Scholar
• Secchiero P, Corallini F, Gonelli A, et al. Antiangiogenic activity of the MDM2 antagonist nutlin-3. Circ Res 2007;100:61-9
   PubMed Web of Science ®Google Scholar
• Teodoro JG, Evans SK, Green MR. Inhibition of tumor angiogenesis by p53: a new role for the guardian of the genome. J Mol Med (Berl) 2007;85:1175-86
   PubMed Web of Science ®Google Scholar
• Andreeff M KK, Yee K, et al. Results of the phase 1 trial of RG7112, a small-molecule MDM2 antagonist, in Acute leukemia. In: 54th ASH Annual Meeting 2012; 2012
   Google Scholar
• Yee K MG, Assouline S, et al. Phase 1b study of the MDM2 antagonist RG7112 in combination with 2 doses/schedules of cytarabine. In: 55th ASH Annual Meeting 2013; 2013
   Google Scholar
• Long J, Parkin B, Ouillette P, et al. Multiple distinct molecular mechanisms influence sensitivity and resistance to MDM2 inhibitors in adult acute myelogenous leukemia. Blood 2010;116:71-80
   PubMed Web of Science ®Google Scholar
• Yee K MG, Assouline S, et al. Phase 1b Study Of The MDM2 Antagonist RG7112 In Combination With 2 Doses/Schedules Of Cytarabine. In: 55th ASH Annual Meeting 2013; 2013
   Google Scholar
• Ray-Coquard I, Blay JY, Italiano A, et al. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol 2012;13:1133-40
   PubMed Web of Science ®Google Scholar
• Carmena M, Earnshaw WC. The cellular geography of aurora kinases. Nat Rev Mol Cell Biol 2003;4:842-54
   PubMed Web of Science ®Google Scholar
• Fu J, Bian M, Jiang Q, Zhang C. Roles of aurora kinases in mitosis and tumorigenesis. Mol Cancer Res 2007;5:1-10
   PubMed Web of Science ®Google Scholar
• Boss DS, Beijnen JH, Schellens JH. Clinical experience with aurora kinase inhibitors: a review. Oncologist 2009;14:780-93
   PubMed Web of Science ®Google Scholar
• Kollareddy M, Zheleva D, Dzubak P, et al. Aurora kinase inhibitors: progress towards the clinic. Invest New Drugs 2012;30:2411-32
   PubMed Web of Science ®Google Scholar
• Katsha A, Soutto M, Sehdev V, et al. Aurora kinase A promotes inflammation and tumorigenesis in mice and human gastric neoplasia. Gastroenterology 2013;145:1312-22. e1-8
   PubMed Web of Science ®Google Scholar
• Sen S, Zhou H, White RA. A putative serine/threonine kinase encoding gene BTAK on chromosome 20q13 is amplified and overexpressed in human breast cancer cell lines. Oncogene 1997;14:2195-200
   PubMed Web of Science ®Google Scholar
• Marumoto T, Honda S, Hara T, et al. Aurora-A kinase maintains the fidelity of early and late mitotic events in HeLa cells. J Biol Chem 2003;278:51786-95
   PubMed Web of Science ®Google Scholar
• Carmena M, Ruchaud S, Earnshaw WC. Making the Auroras glow: regulation of Aurora A and B kinase function by interacting proteins. Curr Opin Cell Biol 2009;21:796-805
   PubMed Web of Science ®Google Scholar
• Katayama H, Sasai K, Kawai H, et al. Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53. Nat Genet 2004;36:55-62
   PubMed Web of Science ®Google Scholar
• Liu Q, Kaneko S, Yang L, et al. Aurora-A abrogation of p53 DNA binding and transactivation activity by phosphorylation of serine 215. J Biol Chem 2004;279:52175-82
   PubMed Web of Science ®Google Scholar
• Nishida N, Nagasaka T, Kashiwagi K, et al. High copy amplification of the Aurora-A gene is associated with chromosomal instability phenotype in human colorectal cancers. Cancer Biol Ther 2007;6:525-33
   PubMed Web of Science ®Google Scholar
• Reiter R, Gais P, Jutting U, et al. Aurora kinase A messenger RNA overexpression is correlated with tumor progression and shortened survival in head and neck squamous cell carcinoma. Clin Cancer Res 2006;12:5136-41
   PubMed Web of Science ®Google Scholar
• Nadler Y, Camp RL, Schwartz C, et al. Expression of aurora A (but not aurora B) is predictive of survival in breast cancer. Clin Cancer Res 2008;14:4455-62
   PubMed Web of Science ®Google Scholar
• Goos JA, Coupe VM, Diosdado B, et al. Aurora kinase A (AURKA) expression in colorectal cancer liver metastasis is associated with poor prognosis. Br J Cancer 2013;109:2445-52
   PubMed Web of Science ®Google Scholar
• Yang J, Ikezoe T, Nishioka C, et al. CD34(+)/CD38(-) acute myelogenous leukemia cells aberrantly express aurora kinase A. Int J Cancer 2013;133:2706-19
   PubMedGoogle Scholar
• Lens SM, Voest EE, Medema RH. Shared and separate functions of polo-like kinases and aurora kinases in cancer. Nat Rev Cancer 2010;10:825-41
   PubMed Web of Science ®Google Scholar
• Takeshita M, Koga T, Takayama K, et al. Aurora-B overexpression is correlated with aneuploidy and poor prognosis in non-small cell lung cancer. Lung Cancer 2013;80:85-90
   PubMed Web of Science ®Google Scholar
• Hetland TE, Nymoen DA, Holth A, et al. Aurora B expression in metastatic effusions from advanced-stage ovarian serous carcinoma is predictive of intrinsic chemotherapy resistance. Hum Pathol 2013;44:777-85
   PubMed Web of Science ®Google Scholar
• Erpolat OP, Gocun PU, Akmansu M, et al. High expression of nuclear survivin and aurora B predicts poor overall survival in patients with head and neck squamous cell cancer. Strahlenther Onkol 2012;188:248-54
   PubMedGoogle Scholar
• Pannone G, Hindi SA, Santoro A, et al. Aurora B expression as a prognostic indicator and possible therapeutic target in oral squamous cell carcinoma. Int J Immunopathol Pharmacol 2011;24:79-88
   PubMed Web of Science ®Google Scholar
• Garcia-Fernandez E, De Diego JI, Collantes-Bellido E, et al. Aurora B kinase expression in laryngeal squamous cell carcinoma and its prognostic implications. Histopathology 2011;58:368-76
   PubMedGoogle Scholar
• Vader G, Lens SM. The Aurora kinase family in cell division and cancer. Biochim Biophys Acta 2008;1786:60-72
   PubMed Web of Science ®Google Scholar
• Khan J, Ezan F, Cremet JY, et al. Overexpression of active Aurora-C kinase results in cell transformation and tumour formation. PLoS One 2011;6:e26512
   PubMed Web of Science ®Google Scholar
• Foran J, Ravandi F, Wierda W, et al. A phase I and pharmacodynamic study of AT9283, a small-molecule inhibitor of aurora kinases in patients with relapsed/refractory leukemia or myelofibrosis. Clin Lymphoma Myeloma Leuk 2014;14(3):223-30
   PubMedGoogle Scholar
• Moore AS, Blagg J, Linardopoulos S, Pearson AD. Aurora kinase inhibitors: novel small molecules with promising activity in acute myeloid and Philadelphia-positive leukemias. Leukemia 2010;24:671-8
   PubMed Web of Science ®Google Scholar
• Schwartz GK, Carvajal RD, Midgley R, et al. Phase I study of barasertib (AZD1152), a selective inhibitor of Aurora B kinase, in patients with advanced solid tumors. Invest New Drugs 2013;31:370-80
   PubMed Web of Science ®Google Scholar
• Lowenberg B, Muus P, Ossenkoppele G, et al. Phase 1/2 study to assess the safety, efficacy, and pharmacokinetics of barasertib (AZD1152) in patients with advanced acute myeloid leukemia. Blood 2011;118:6030-6
   PubMed Web of Science ®Google Scholar
• Kantarjian HM, Martinelli G, Jabbour EJ, et al. Stage I of a phase 2 study assessing the efficacy, safety, and tolerability of barasertib (AZD1152) versus low-dose cytosine arabinoside in elderly patients with acute myeloid leukemia. Cancer 2013;119:2611-19
   PubMed Web of Science ®Google Scholar
• Curry J, Angove H, Fazal L, et al. Aurora B kinase inhibition in mitosis: strategies for optimising the use of aurora kinase inhibitors such as AT9283. Cell Cycle 2009;8:1921-9
   PubMedGoogle Scholar
• Manfredi MG, Ecsedy JA, Meetze KA, et al. Antitumor activity of MLN8054, an orally active small-molecule inhibitor of Aurora A kinase. Proc Natl Acad Sci USA 2007;104:4106-11
   PubMed Web of Science ®Google Scholar
• Taga M, Hirooka E, Ouchi T. Essential roles of mTOR/Akt pathway in Aurora-A cell transformation. Int J Biol Sci 2009;5:444-50
   PubMed Web of Science ®Google Scholar
• Scharer CD, Laycock N, Osunkoya AO, et al. Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells. J Transl Med 2008;6:79
   PubMedGoogle Scholar
• VanderPorten EC, Taverna P, Hogan JN, et al. The Aurora kinase inhibitor SNS-314 shows broad therapeutic potential with chemotherapeutics and synergy with microtubule-targeted agents in a colon carcinoma model. Mol Cancer Ther 2009;8:930-9
   PubMed Web of Science ®Google Scholar
• Chang F, Steelman LS, Lee JT, et al. Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention. Leukemia 2003;17:1263-93
   PubMed Web of Science ®Google Scholar
• Radich JP, Kopecky KJ, Willman CL, et al. N-ras mutations in adult de novo acute myelogenous leukemia: prevalence and clinical significance. Blood 1990;76:801-7
   PubMed Web of Science ®Google Scholar
• Coghlan DW, Morley AA, Matthews JP, Bishop JF. The incidence and prognostic significance of mutations in codon 13 of the N-ras gene in acute myeloid leukemia. Leukemia 1994;8:1682-7
   PubMed Web of Science ®Google Scholar
• Neubauer A, Dodge RK, George SL, et al. Prognostic importance of mutations in the ras proto-oncogenes in de novo acute myeloid leukemia. Blood 1994;83:1603-11
   PubMed Web of Science ®Google Scholar
• De Melo MB, Lorand-Metze I, Lima CS, et al. N-ras gene point mutations in Brazilian acute myelogenous leukemia patients correlate with a poor prognosis. Leuk Lymphoma 1997;24:309-17
   PubMed Web of Science ®Google Scholar
• Kiyoi H, Naoe T, Nakano Y, et al. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood 1999;93:3074-80
   PubMed Web of Science ®Google Scholar
• Meshinchi S, Stirewalt DL, Alonzo TA, et al. Activating mutations of RTK/ras signal transduction pathway in pediatric acute myeloid leukemia. Blood 2003;102:1474-9
   PubMed Web of Science ®Google Scholar
• Ritter M, Kim TD, Lisske P, et al. Prognostic significance of N-RAS and K-RAS mutations in 232 patients with acute myeloid leukemia. Haematologica 2004;89:1397-9
   PubMed Web of Science ®Google Scholar
• Illmer T, Thiede C, Fredersdorf A, et al. Activation of the RAS pathway is predictive for a chemosensitive phenotype of acute myelogenous leukemia blasts. Clin Cancer Res 2005;11:3217-24
   PubMed Web of Science ®Google Scholar
• Gougopoulou DM, Kiaris H, Ergazaki M, et al. Mutations and expression of the ras family genes in leukemias. Stem Cells 1996;14:725-9
   PubMedGoogle Scholar
• Jiang K, Coppola D, Crespo NC, et al. The phosphoinositide 3-OH kinase/AKT2 pathway as a critical target for farnesyltransferase inhibitor-induced apoptosis. Mol Cell Biol 2000;20:139-48
   PubMed Web of Science ®Google Scholar
• Niessner H, Beck D, Sinnberg T, et al. The farnesyl transferase inhibitor lonafarnib inhibits mTOR signaling and enforces sorafenib-induced apoptosis in melanoma cells. J Invest Dermatol 2011;131:468-79
   PubMed Web of Science ®Google Scholar
• Ding H, Hackbarth J, Schneider PA, et al. Cytotoxicity of farnesyltransferase inhibitors in lymphoid cells mediated by MAPK pathway inhibition and Bim up-regulation. Blood 2011;118:4872-81
   PubMedGoogle Scholar
• Chun KH, Lee HY, Hassan K, et al. Implication of protein kinase B/Akt and Bcl-2/Bcl-XL suppression by the farnesyl transferase inhibitor SCH66336 in apoptosis induction in squamous carcinoma cells. Cancer Res 2003;63:4796-800
   PubMed Web of Science ®Google Scholar
• Sepp-Lorenzino L, Ma Z, Rands E, et al. A peptidomimetic inhibitor of farnesyl:protein transferase blocks the anchorage-dependent and -independent growth of human tumor cell lines. Cancer Res 1995;55:5302-9
   PubMed Web of Science ®Google Scholar
• Feldkamp MM, Lau N, Guha A. Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro-apoptotic and anti-angiogenic effects. Oncogene 1999;18:7514-26
   PubMed Web of Science ®Google Scholar
• Gomez-Benito M, Marzo I, Anel A, Naval J. Farnesyltransferase inhibitor BMS-214662 induces apoptosis in myeloma cells through PUMA up-regulation, Bax and Bak activation, and Mcl-1 elimination. Mol Pharmacol 2005;67:1991-8
   PubMed Web of Science ®Google Scholar
• Ravoet C, Mineur P, Robin V, et al. Farnesyl transferase inhibitor (lonafarnib) in patients with myelodysplastic syndrome or secondary acute myeloid leukaemia: a phase II study. Ann Hematol 2008;87:881-5
   PubMed Web of Science ®Google Scholar
• Lancet JE, Gojo I, Gotlib J, et al. A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia. Blood 2007;109:1387-94
   PubMed Web of Science ®Google Scholar
• Harousseau JL, Martinelli G, Jedrzejczak WW, et al. A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older. Blood 2009;114:1166-73
   PubMed Web of Science ®Google Scholar
• Burnett AK, Russell NH, Culligan D, et al. The addition of the farnesyl transferase inhibitor, tipifarnib, to low dose cytarabine does not improve outcome for older patients with AML. Br J Haematol 2012;158:519-22
   PubMed Web of Science ®Google Scholar
• Jabbour E, Kantarjian H, Ravandi F, et al. A phase 1-2 study of a farnesyltransferase inhibitor, tipifarnib, combined with idarubicin and cytarabine for patients with newly diagnosed acute myeloid leukemia and high-risk myelodysplastic syndrome. Cancer 2011;117:1236-44
   PubMed Web of Science ®Google Scholar
• Brandwein JM, Leber BF, Howson-Jan K, et al. A phase I study of tipifarnib combined with conventional induction and consolidation therapy for previously untreated patients with acute myeloid leukemia aged 60 years and over. Leukemia 2009;23:631-4
   PubMed Web of Science ®Google Scholar
• Whyte DB, Kirschmeier P, Hockenberry TN, et al. K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J Biol Chem 1997;272:14459-64
   PubMed Web of Science ®Google Scholar
• Morgan MA, Wegner J, Aydilek E, et al. Synergistic cytotoxic effects in myeloid leukemia cells upon cotreatment with farnesyltransferase and geranylgeranyl transferase-I inhibitors. Leukemia 2003;17:1508-20
   PubMedGoogle Scholar
• End DW, Smets G, Todd AV, et al. Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res 2001;61:131-7
   PubMed Web of Science ®Google Scholar
• Lubet RA, Christov K, You M, et al. Effects of the farnesyl transferase inhibitor R115777 (Zarnestra) on mammary carcinogenesis: prevention, therapy, and role of HaRas mutations. Mol Cancer Ther 2006;5:1073-8
   PubMedGoogle Scholar
• Sun J, Blaskovich MA, Knowles D, et al. Antitumor efficacy of a novel class of non-thiol-containing peptidomimetic inhibitors of farnesyltransferase and geranylgeranyltransferase I: combination therapy with the cytotoxic agents cisplatin, Taxol, and gemcitabine. Cancer Res 1999;59:4919-26
   PubMed Web of Science ®Google Scholar
• Lobell RB, Omer CA, Abrams MT, et al. Evaluation of farnesyl:protein transferase and geranylgeranyl:protein transferase inhibitor combinations in preclinical models. Cancer Res 2001;61:8758-68
   PubMed Web of Science ®Google Scholar
• Lobell RB, Liu D, Buser CA, et al. Preclinical and clinical pharmacodynamic assessment of L-778,123, a dual inhibitor of farnesyl:protein transferase and geranylgeranyl:protein transferase type-I. Mol Cancer Ther 2002;1:747-58
   PubMed Web of Science ®Google Scholar
• Appels NM, Bolijn MJ, Chan K, et al. Phase I pharmacokinetic and pharmacodynamic study of the prenyl transferase inhibitor AZD3409 in patients with advanced cancer. Br J Cancer 2008;98:1951-8
   PubMed Web of Science ®Google Scholar
• Felsenfeld G, Groudine M. Controlling the double helix. Nature 2003;421:448-53
   PubMed Web of Science ®Google Scholar
• Holdenrieder S, Nagel D, Schalhorn A, et al. Clinical relevance of circulating nucleosomes in cancer. Ann N Y Acad Sci 2008;1137:180-9
   PubMed Web of Science ®Google Scholar
• Quintas-Cardama A, Santos FP, Garcia-Manero G. Histone deacetylase inhibitors for the treatment of myelodysplastic syndrome and acute myeloid leukemia. Leukemia 2011;25:226-35
   PubMed Web of Science ®Google Scholar
• Olsen EA, Kim YH, Kuzel TM, et al. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 2007;25:3109-15
   PubMed Web of Science ®Google Scholar
• Whittaker SJ, Demierre MF, Kim EJ, et al. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol 2010;28:4485-91
   PubMed Web of Science ®Google Scholar
• Kuendgen A, Knipp S, Fox F, et al. Results of a phase 2 study of valproic acid alone or in combination with all-trans retinoic acid in 75 patients with myelodysplastic syndrome and relapsed or refractory acute myeloid leukemia. Ann Hematol 2005;84(Suppl 1):61-6
   PubMed Web of Science ®Google Scholar
• Garcia-Manero G, Yang H, Bueso-Ramos C, et al. Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Blood 2008;111:1060-6
   PubMed Web of Science ®Google Scholar
• Bug G, Ritter M, Wassmann B, et al. Clinical trial of valproic acid and all-trans retinoic acid in patients with poor-risk acute myeloid leukemia. Cancer 2005;104:2717-25
   PubMed Web of Science ®Google Scholar
• Raffoux E, Chaibi P, Dombret H, Degos L. Valproic acid and all-trans retinoic acid for the treatment of elderly patients with acute myeloid leukemia. Haematologica 2005;90:986-8
   PubMed Web of Science ®Google Scholar
• Khanim FL, Bradbury CA, Arrazi J, et al. Elevated FOSB-expression; a potential marker of valproate sensitivity in AML. Br J Haematol 2009;144:332-41
   PubMed Web of Science ®Google Scholar
• Fredly H, Stapnes Bjornsen C, Gjertsen BT, Bruserud O. Combination of the histone deacetylase inhibitor valproic acid with oral hydroxyurea or 6-mercaptopurin can be safe and effective in patients with advanced acute myeloid leukaemia – a report of five cases. Hematology (Am Soc Hematol Educ Program) 2010;15:338-43
   Google Scholar
• Fredly H, Ersvaer E, Kittang AO, et al. The combination of valproic acid, all-trans retinoic acid and low-dose cytarabine as disease-stabilizing treatment in acute myeloid leukemia. Clin Epigenetics 2013;5:13
   PubMed Web of Science ®Google Scholar
• Burnett AK, Milligan D, Prentice AG, et al. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer 2007;109:1114-24
   PubMed Web of Science ®Google Scholar
• Kantarjian HM, Thomas XG, Dmoszynska A, et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol 2012;30:2670-7
   PubMed Web of Science ®Google Scholar
• Fredly H, Gjertsen BT, Bruserud O. Histone deacetylase inhibition in the treatment of acute myeloid leukemia: the effects of valproic acid on leukemic cells, and the clinical and experimental evidence for combining valproic acid with other antileukemic agents. Clin Epigenetics 2013;5:12
   PubMed Web of Science ®Google Scholar
• Byrd JC, Marcucci G, Parthun MR, et al. A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia. Blood 2005;105:959-67
   PubMed Web of Science ®Google Scholar
• Garcia-Manero G, Assouline S, Cortes J, et al. Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia. Blood 2008;112:981-9
   PubMed Web of Science ®Google Scholar
• Jones PA, Baylin SB. The epigenomics of cancer. Cell 2007;128:683-92
   PubMed Web of Science ®Google Scholar
• Bhaumik SR, Smith E, Shilatifard A. Covalent modifications of histones during development and disease pathogenesis. Nat Struct Mol Biol 2007;14:1008-16
   PubMed Web of Science ®Google Scholar
• Prebet T, Sun Z, Figueroa ME, et al. Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes: results of the US leukemia intergroup trial E1905. J Clin Oncol 2014;32:1242-8
   PubMed Web of Science ®Google Scholar
• Soriano AO, Yang H, Faderl S, et al. Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood 2007;110:2302-8
   PubMed Web of Science ®Google Scholar
• Raffoux E, Cras A, Recher C, et al. Phase 2 clinical trial of 5-azacitidine, valproic acid, and all-trans retinoic acid in patients with high-risk acute myeloid leukemia or myelodysplastic syndrome. Oncotarget 2010;1:34-42
   PubMed Web of Science ®Google Scholar
• Blum W, Klisovic RB, Hackanson B, et al. Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J Clin Oncol 2007;25:3884-91
   PubMed Web of Science ®Google Scholar
• Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, et al. Phase 1/2 study of the combination of 5-aza-2’-deoxycytidine with valproic acid in patients with leukemia. Blood 2006;108:3271-9
   PubMed Web of Science ®Google Scholar
• Garcia-Manero G, Tambaro FP, Bekele NB, et al. Phase II trial of vorinostat with idarubicin and cytarabine for patients with newly diagnosed acute myelogenous leukemia or myelodysplastic syndrome. J Clin Oncol 2012;30:2204-10
   PubMed Web of Science ®Google Scholar
• Gojo I, Tan M, Fang HB, et al. Translational phase I trial of vorinostat (suberoylanilide hydroxamic acid) combined with cytarabine and etoposide in patients with relapsed, refractory, or high-risk acute myeloid leukemia. Clin Cancer Res 2013;19:1838-51
   PubMed Web of Science ®Google Scholar
• Giles F, Fischer T, Cortes J, et al. A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies. Clin Cancer Res 2006;12:4628-35
   PubMed Web of Science ®Google Scholar
• Tan P, Wei A, Mithraprabhu S, et al. Dual epigenetic targeting with panobinostat and azacitidine in acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood Cancer J 2014;4:e170
   PubMed Web of Science ®Google Scholar
• Panobinostat in treating patients with relapsed or refractory acute lymphoblastic leukemia or acute myeloid leukemia. Available from: http://clinicaltrials.gov/show/NCT00723203
   Google Scholar
• Safety and efficacy study of pracinostat with azacitadine in elderly patients with newly diagnosed acute myeloid leukemia (AML). Available from: http://clinicaltrials.gov/ct2/show/NCT01912274
   Google Scholar
• Novotny-Diermayr V, Hart S, Goh KC, et al. The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML. Blood Cancer J 2012;2:e69
   PubMed Web of Science ®Google Scholar
• McCormack E, Haaland I, Venas G, et al. Synergistic induction of p53 mediated apoptosis by valproic acid and nutlin-3 in acute myeloid leukemia. Leukemia 2012;26:910-17
   PubMed Web of Science ®Google Scholar
• Yaseen A, Chen S, Hock S, et al. Resveratrol sensitizes acute myelogenous leukemia cells to histone deacetylase inhibitors through reactive oxygen species-mediated activation of the extrinsic apoptotic pathway. Mol Pharmacol 2012;82:1030-41
   PubMed Web of Science ®Google Scholar
• Shao Y, Gao Z, Marks PA, Jiang X. Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc Natl Acad Sci USA 2004;101:18030-5
   PubMed Web of Science ®Google Scholar
• Cai D, Wang Y, Ottmann OG, et al. FLT3-ITD-, but not BCR/ABL-transformed cells require concurrent Akt/mTor blockage to undergo apoptosis after histone deacetylase inhibitor treatment. Blood 2006;107:2094-7
   PubMed Web of Science ®Google Scholar
• Gammoh N, Lam D, Puente C, et al. Role of autophagy in histone deacetylase inhibitor-induced apoptotic and nonapoptotic cell death. Proc Natl Acad Sci USA 2012;109:6561-5
   PubMed Web of Science ®Google Scholar
• Degtyarev M, De Maziere A, Orr C, et al. Akt inhibition promotes autophagy and sensitizes PTEN-null tumors to lysosomotropic agents. J Cell Biol 2008;183:101-16
   PubMed Web of Science ®Google Scholar
• Koren I, Kimchi A. Cell biology. Promoting tumorigenesis by suppressing autophagy. Science 2012;338:889-90
   Google Scholar
• Wei Y, Kadia T, Tong W, et al. The combination of a histone deacetylase inhibitor with the Bcl-2 homology domain-3 mimetic GX15-070 has synergistic antileukemia activity by activating both apoptosis and autophagy. Clin Cancer Res 2010;16:3923-32
   PubMed Web of Science ®Google Scholar
• Chen CS, Weng SC, Tseng PH, Lin HP. Histone acetylation-independent effect of histone deacetylase inhibitors on Akt through the reshuffling of protein phosphatase 1 complexes. J Biol Chem 2005;280:38879-87
   PubMed Web of Science ®Google Scholar
• Kawamata N, Chen J, Koeffler HP. Suberoylanilide hydroxamic acid (SAHA; vorinostat) suppresses translation of cyclin D1 in mantle cell lymphoma cells. Blood 2007;110:2667-73
   PubMed Web of Science ®Google Scholar
• Nishioka C, Ikezoe T, Yang J, et al. Blockade of mTOR signaling potentiates the ability of histone deacetylase inhibitor to induce growth arrest and differentiation of acute myelogenous leukemia cells. Leukemia 2008;22:2159-68
   PubMed Web of Science ®Google Scholar
• Sandilya V GV, Sharma K, et al. Combination HDACi and mTOR inhibitor therapy in poor-risk de novo and refractory patients with AML. In: ASCO Annual Meeting 2013; 2013
   Google Scholar
• Bruserud O, Stapnes C, Ersvaer E, et al. Histone deacetylase inhibitors in cancer treatment: a review of the clinical toxicity and the modulation of gene expression in cancer cell. Curr Pharm Biotechnol 2007;8:388-400
   PubMed Web of Science ®Google Scholar
• Laney JD, Hochstrasser M. Substrate targeting in the ubiquitin system. Cell 1999;97:427-30
   PubMed Web of Science ®Google Scholar
• Orlowski M, Wilk S. Catalytic activities of the 20 S proteasome, a multicatalytic proteinase complex. Arch Biochem Biophys 2000;383:1-16
   PubMed Web of Science ®Google Scholar
• Pagano M, Tam SW, Theodoras AM, et al. Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science 1995;269:682-5
   PubMed Web of Science ®Google Scholar
• Maki CG, Huibregtse JM, Howley PM. In vivo ubiquitination and proteasome-mediated degradation of p53(1). Cancer Res 1996;56:2649-54
   PubMed Web of Science ®Google Scholar
• Mani A, Gelmann EP. The ubiquitin-proteasome pathway and its role in cancer. J Clin Oncol 2005;23:4776-89
   PubMed Web of Science ®Google Scholar
• Adams J. The development of proteasome inhibitors as anticancer drugs. Cancer Cell 2004;5:417-21
   PubMed Web of Science ®Google Scholar
• Mitsiades CS, Mitsiades N, Hideshima T, et al. Proteasome inhibition as a new therapeutic principle in hematological malignancies. Curr Drug Targets 2006;7:1341-7
   PubMed Web of Science ®Google Scholar
• Kane RC, Farrell AT, Sridhara R, Pazdur R. United States Food and Drug Administration approval summary: bortezomib for the treatment of progressive multiple myeloma after one prior therapy. Clin Cancer Res 2006;12:2955-60
   PubMed Web of Science ®Google Scholar
• Kane RC, Dagher R, Farrell A, et al. Bortezomib for the treatment of mantle cell lymphoma. Clin Cancer Res 2007;13:5291-4
   PubMed Web of Science ®Google Scholar
• Guzman ML, Swiderski CF, Howard DS, et al. Preferential induction of apoptosis for primary human leukemic stem cells. Proc Natl Acad Sci USA 2002;99:16220-5
   PubMed Web of Science ®Google Scholar
• Koschny R, Holland H, Sykora J, et al. Bortezomib sensitizes primary human astrocytoma cells of WHO grades I to IV for tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Clin Cancer Res 2007;13:3403-12
   PubMed Web of Science ®Google Scholar
• Dijk M, Murphy E, Morrell R, et al. The Proteasome inhibitor bortezomib sensitizes AML with myelomonocytic differentiation to TRAIL mediated apoptosis. Cancers (Basel) 2011;3:1329-50
   PubMedGoogle Scholar
• Lu G, Punj V, Chaudhary PM. Proteasome inhibitor bortezomib induces cell cycle arrest and apoptosis in cell lines derived from Ewing’s sarcoma family of tumors and synergizes with TRAIL. Cancer Biol Ther 2008;7:603-8
   PubMed Web of Science ®Google Scholar
• Cortes J, Thomas D, Koller C, et al. Phase I study of bortezomib in refractory or relapsed acute leukemias. Clin Cancer Res 2004;10:3371-6
   PubMed Web of Science ®Google Scholar
• Sarlo C, Buccisano F, Maurillo L, et al. Phase II study of bortezomib as a single agent in patients with previously untreated or relapsed/refractory acute myeloid leukemia ineligible for intensive therapy. Leuk Res Treatment 2013;2013:705714
   PubMedGoogle Scholar
• Attar EC, De Angelo DJ, Supko JG, et al. Phase I and pharmacokinetic study of bortezomib in combination with idarubicin and cytarabine in patients with acute myelogenous leukemia. Clin Cancer Res 2008;14:1446-54
   PubMed Web of Science ®Google Scholar
• Attar EC, Johnson JL, Amrein PC, et al. Bortezomib added to daunorubicin and cytarabine during induction therapy and to intermediate-dose cytarabine for consolidation in patients with previously untreated acute myeloid leukemia age 60 to 75 years: CALGB (Alliance) study 10502. J Clin Oncol 2013;31:923-9
   PubMed Web of Science ®Google Scholar
• Blum W, Schwind S, Tarighat SS, et al. Clinical and pharmacodynamic activity of bortezomib and decitabine in acute myeloid leukemia. Blood 2012;119:6025-31
   PubMed Web of Science ®Google Scholar
• Hainsworth JD, Spigel DR, Barton J, et al. Weekly treatment with bortezomib for patients with recurrent or refractory multiple myeloma: a phase 2 trial of the Minnie Pearl Cancer Research Network. Cancer 2008;113:765-71
   PubMed Web of Science ®Google Scholar
• Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol 2011;12:431-40
   PubMed Web of Science ®Google Scholar
• Dai Y, Chen S, Wang L, et al. Bortezomib interacts synergistically with belinostat in human acute myeloid leukaemia and acute lymphoblastic leukaemia cells in association with perturbations in NF-kappaB and Bim. Br J Haematol 2011;153:222-35
   PubMed Web of Science ®Google Scholar
• Nie D, Huang K, Yin S, et al. Synergistic/additive interaction of valproic acid with bortezomib on proliferation and apoptosis of acute myeloid leukemia cells. Leuk Lymphoma 2012;53:2487-95
   PubMed Web of Science ®Google Scholar
• Holkova B, Bose P, Tombes M, et al. Phase I trial of Belinostat and Bortezomib in patients with relapsed or refractory acute leukemia, myelodysplastic syndrome, or chronic myelogenous leukemia in blast crisis - one year update. In: 54th ASH Annual Meeting; 2012; 2012
   Google Scholar
• Peled A, Petit I, Kollet O, et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science 1999;283:845-8
   PubMed Web of Science ®Google Scholar
• Broxmeyer HE, Orschell CM, Clapp DW, et al. Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J Exp Med 2005;201:1307-18
   PubMed Web of Science ®Google Scholar
• Sugiyama T, Kohara H, Noda M, Nagasawa T. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 2006;25:977-88
   PubMed Web of Science ®Google Scholar
• Tavor S, Petit I, Porozov S, et al. CXCR4 regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD/SCID mice. Cancer Res 2004;64:2817-24
   PubMed Web of Science ®Google Scholar
• Teicher BA, Fricker SP. CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res 2010;16:2927-31
   PubMed Web of Science ®Google Scholar
• Spoo AC, Lubbert M, Wierda WG, Burger JA. CXCR4 is a prognostic marker in acute myelogenous leukemia. Blood 2007;109:786-91
   PubMed Web of Science ®Google Scholar
• Rombouts EJ, Pavic B, Lowenberg B, Ploemacher RE. Relation between CXCR-4 expression, Flt3 mutations, and unfavorable prognosis of adult acute myeloid leukemia. Blood 2004;104:550-7
   PubMed Web of Science ®Google Scholar
• Nervi B, Ramirez P, Rettig MP, et al. Chemosensitization of acute myeloid leukemia (AML) following mobilization by the CXCR4 antagonist AMD3100. Blood 2009;113:6206-14
   PubMed Web of Science ®Google Scholar
• Uy GL, Rettig MP, Motabi IH, et al. A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia. Blood 2012;119:3917-24
   PubMed Web of Science ®Google Scholar
• Zeng Z, Shi YX, Samudio IJ, et al. Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML. Blood 2009;113:6215-24
   PubMed Web of Science ®Google Scholar
• Andreeff M ZZ, Kelly AM, et al. Mobilization and elimination of FLT3-ITD+ acute myelogenous leukemia (AML) stem/progenitor cells by plerixafor/G-CSF/Sorafenib: results from a phase I trial in relapsed/refractory AML patients. In: 54th ASH Annual Meeting 2012; 2012
   Google Scholar
• Granulocyte-colony stimulating factor (G-CSF) and plerixafor plus sorafenib for acute myelogenous leukemia (AML) with FLT3 mutations. Available from: http://static.linkedct.org/page/trials/NCT00943943
   Google Scholar
• Sreedhar AS, Kalmar E, Csermely P, Shen YF. Hsp90 isoforms: functions, expression and clinical importance. FEBS Lett 2004;562:11-15
   PubMed Web of Science ®Google Scholar
• Stancato LF, Chow YH, Hutchison KA, et al. Raf exists in a native heterocomplex with hsp90 and p50 that can be reconstituted in a cell-free system. J Biol Chem 1993;268:21711-16
   PubMed Web of Science ®Google Scholar
• Sato S, Fujita N, Tsuruo T. Modulation of Akt kinase activity by binding to Hsp90. Proc Natl Acad Sci U S A 2000;97:10832-7
   PubMed Web of Science ®Google Scholar
• Pratt WB, Toft DO. Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery. Exp Biol Med (Maywood) 2003;228:111-33
   PubMed Web of Science ®Google Scholar
• Fujita N, Sato S, Ishida A, Tsuruo T. Involvement of Hsp90 in signaling and stability of 3-phosphoinositide-dependent kinase-1. J Biol Chem 2002;277:10346-53
   PubMed Web of Science ®Google Scholar
• Whitesell L, Bagatell R, Falsey R. The stress response: implications for the clinical development of hsp90 inhibitors. Curr Cancer Drug Targets 2003;3:349-58
   PubMedGoogle Scholar
• Workman P. Overview: translating Hsp90 biology into Hsp90 drugs. Curr Cancer Drug Targets 2003;3:297-300
   PubMed Web of Science ®Google Scholar
• Lauria A, Ippolito M, Almerico AM. Inside the Hsp90 inhibitors binding mode through induced fit docking. J Mol Graph Model 2009;27:712-22
   PubMed Web of Science ®Google Scholar
• Fumo G, Akin C, Metcalfe DD, Neckers L. 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is effective in down-regulating mutated, constitutively activated KIT protein in human mast cells. Blood 2004;103:1078-84
   PubMed Web of Science ®Google Scholar
• Xu W, Mimnaugh E, Rosser MF, et al. Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90. J Biol Chem 2001;276:3702-8
   PubMedGoogle Scholar
• Minami Y, Kiyoi H, Yamamoto Y, et al. Selective apoptosis of tandemly duplicated FLT3-transformed leukemia cells by Hsp90 inhibitors. Leukemia 2002;16:1535-40
   PubMed Web of Science ®Google Scholar
• An WG, Schulte TW, Neckers LM. The heat shock protein 90 antagonist geldanamycin alters chaperone association with p210bcr-abl and v-src proteins before their degradation by the proteasome. Cell Growth Differ 2000;11:355-60
   PubMedGoogle Scholar
• Castro JE, Prada CE, Loria O, et al. ZAP-70 is a novel conditional heat shock protein 90 (Hsp90) client: inhibition of Hsp90 leads to ZAP-70 degradation, apoptosis, and impaired signaling in chronic lymphocytic leukemia. Blood 2005;106:2506-12
   PubMed Web of Science ®Google Scholar
• Bonvini P, Gastaldi T, Falini B, Rosolen A. Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), a novel Hsp90-client tyrosine kinase: down-regulation of NPM-ALK expression and tyrosine phosphorylation in ALK(+) CD30(+) lymphoma cells by the Hsp90 antagonist 17-allylamino,17-demethoxygeldanamycin. Cancer Res 2002;62:1559-66
   PubMed Web of Science ®Google Scholar
• Schulte TW, Blagosklonny MV, Ingui C, Neckers L. Disruption of the Raf-1-Hsp90 molecular complex results in destabilization of Raf-1 and loss of Raf-1-Ras association. J Biol Chem 1995;270:24585-8
   PubMed Web of Science ®Google Scholar
• Blagosklonny MV, Toretsky J, Neckers L. Geldanamycin selectively destabilizes and conformationally alters mutated p53. Oncogene 1995;11:933-9
   PubMed Web of Science ®Google Scholar
• Ochel HJ, Gademann G. Heat-shock protein 90: potential involvement in the pathogenesis of malignancy and pharmacological intervention. Onkologie 2002;25:466-73
   PubMedGoogle Scholar
• Yufu Y, Nishimura J, Nawata H. High constitutive expression of heat shock protein 90 alpha in human acute leukemia cells. Leuk Res 1992;16:597-605
   PubMed Web of Science ®Google Scholar
• Thomas X, Campos L, Mounier C, et al. Expression of heat-shock proteins is associated with major adverse prognostic factors in acute myeloid leukemia. Leuk Res 2005;29:1049-58
   PubMed Web of Science ®Google Scholar
• Flandrin P, Guyotat D, Duval A, et al. Significance of heat-shock protein (HSP) 90 expression in acute myeloid leukemia cells. Cell Stress Chaperones 2008;13:357-64
   PubMed Web of Science ®Google Scholar
• Kamal A, Thao L, Sensintaffar J, et al. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 2003;425:407-10
   PubMed Web of Science ®Google Scholar
• Reikvam H, Hatfield KJ, Ersvaer E, et al. Expression profile of heat shock proteins in acute myeloid leukaemia patients reveals a distinct signature strongly associated with FLT3 mutation status – consequences and potentials for pharmacological intervention. Br J Haematol 2012;156:468-80
   PubMed Web of Science ®Google Scholar
• Nimmanapalli R, O’Bryan E, Kuhn D, et al. Regulation of 17-AAG-induced apoptosis: role of Bcl-2, Bcl-XL, and Bax downstream of 17-AAG-mediated down-regulation of Akt, Raf-1, and Src kinases. Blood 2003;102:269-75
   PubMed Web of Science ®Google Scholar
• Napper JM, Sollars VE. 17-N-Allylamino-17-demethoxygeldanamycin induces a diverse response in human acute myelogenous cells. Leuk Res 2010;34:1493-500
   PubMedGoogle Scholar
• Walker AR, Klisovic R, Johnston JS, et al. Pharmacokinetics and dose escalation of the heat shock protein inhibitor 17-allyamino-17-demethoxygeldanamycin in combination with bortezomib in relapsed or refractory acute myeloid leukemia. Leuk Lymphoma 2013;54:1996-2002
   PubMed Web of Science ®Google Scholar
• Richardson PG, Chanan-Khan AA, Lonial S, et al. Tanespimycin and bortezomib combination treatment in patients with relapsed or relapsed and refractory multiple myeloma: results of a phase 1/2 study. Br J Haematol 2011;153:729-40
   PubMed Web of Science ®Google Scholar
• Richardson PG, Badros AZ, Jagannath S, et al. Tanespimycin with bortezomib: activity in relapsed/refractory patients with multiple myeloma. Br J Haematol 2010;150:428-37
   PubMed Web of Science ®Google Scholar
• Lancet JE, Gojo I, Burton M, et al. Phase I study of the heat shock protein 90 inhibitor alvespimycin (KOS-1022, 17-DMAG) administered intravenously twice weekly to patients with acute myeloid leukemia. Leukemia 2010;24:699-705
   PubMed Web of Science ®Google Scholar
• Taldone T, Gozman A, Maharaj R, Chiosis G. Targeting Hsp90: small-molecule inhibitors and their clinical development. Curr Opin Pharmacol 2008;8:370-4
   PubMed Web of Science ®Google Scholar
• Mesa RA, Loegering D, Powell HL, et al. Heat shock protein 90 inhibition sensitizes acute myelogenous leukemia cells to cytarabine. Blood 2005;106:318-27
   PubMed Web of Science ®Google Scholar
• Walsby EJ, Lazenby M, Pepper CJ, et al. The HSP90 inhibitor NVP-AUY922-AG inhibits the PI3K and IKK signalling pathways and synergizes with cytarabine in acute myeloid leukaemia cells. Br J Haematol 2013;161:57-67
   PubMedGoogle Scholar
• Rao R, Fiskus W, Yang Y, et al. HDAC6 inhibition enhances 17-AAG--mediated abrogation of hsp90 chaperone function in human leukemia cells. Blood 2008;112:1886-93
   PubMed Web of Science ®Google Scholar
• George P, Bali P, Annavarapu S, et al. Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3. Blood 2005;105:1768-76
   PubMed Web of Science ®Google Scholar
• Piper WP MH. Mechanism of resistance to Hsp90 inhibitor drugs: a complex mosaic emerges. Pharmaceuticals 2011;4:1400-22
   Google Scholar
• Reikvam H, Nepstad I, Sulen A, et al. Increased antileukemic effects in human acute myeloid leukemia by combining HSP70 and HSP90 inhibitors. Expert Opin Investig Drugs 2013;22:551-63
   PubMed Web of Science ®Google Scholar
• Rosnet O, Buhring HJ, deLapeyriere O, et al. Expression and signal transduction of the FLT3 tyrosine kinase receptor. Acta Haematol 1996;95:218-23
   PubMed Web of Science ®Google Scholar
• Zhang S, Fukuda S, Lee Y, et al. Essential role of signal transducer and activator of transcription (Stat)5a but not Stat5b for Flt3-dependent signaling. J Exp Med 2000;192:719-28
   PubMed Web of Science ®Google Scholar
• Frohling S, Schlenk RF, Breitruck J, et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 2002;100:4372-80
   PubMed Web of Science ®Google Scholar
• Pratcorona M, Brunet S, Nomdedeu J, et al. Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: relevance to post-remission therapy. Blood 2013;121:2734-8
   PubMed Web of Science ®Google Scholar
• Stirewalt DL, Kopecky KJ, Meshinchi S, et al. Size of FLT3 internal tandem duplication has prognostic significance in patients with acute myeloid leukemia. Blood 2006;107:3724-6
   PubMed Web of Science ®Google Scholar
• Kusec R, Jaksic O, Ostojic S, et al. More on prognostic significance of FLT3/ITD size in acute myeloid leukemia (AML). Blood 2006;108:405-6. author reply 6
   PubMed Web of Science ®Google Scholar
• Abu-Duhier FM, Goodeve AC, Wilson GA, et al. Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia. Br J Haematol 2001;113:983-8
   PubMed Web of Science ®Google Scholar
• Yamamoto Y, Kiyoi H, Nakano Y, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 2001;97:2434-9
   PubMed Web of Science ®Google Scholar
• Thiede C, Steudel C, Mohr B, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 2002;99:4326-35
   PubMed Web of Science ®Google Scholar
• Fiedler W, Mesters R, Tinnefeld H, et al. A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia. Blood 2003;102:2763-7
   PubMed Web of Science ®Google Scholar
• Serve H, Krug U, Wagner R, et al. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol 2013;31:3110-18
   PubMed Web of Science ®Google Scholar
• Metzelder SK, Schroeder T, Finck A, et al. High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses. Leukemia 2012;26:2353-9
   PubMed Web of Science ®Google Scholar
• Sato T, Yang X, Knapper S, et al. FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo. Blood 2011;117:3286-93
   PubMed Web of Science ®Google Scholar
• Ravandi F, Alattar ML, Grunwald MR, et al. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood 2013;121:4655-62
   PubMed Web of Science ®Google Scholar
• Fiedler W, Serve H, Dohner H, et al. A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood 2005;105:986-93
   PubMed Web of Science ®Google Scholar
• Fischer T, Stone RM, Deangelo DJ, et al. Phase IIB trial of oral Midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol 2010;28:4339-45
   PubMed Web of Science ®Google Scholar
• Daunorubicin, cytarabine, and midostaurin in treating patients with newly diagnosed acute myeloid leukemia. Available from: http://clinicaltrials.gov/show/NCT00651261
   Google Scholar
• Standard of care +/- Midostaurin to prevent relapse post stem cell transplant in patients with flt3-itd mutated AML (ARMOR). Available from: http://clinicaltrials.gov/show/NCT01883362
   Google Scholar
• Cortes JE, Kantarjian H, Foran JM, et al. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol 2013;31:3681-7
   PubMed Web of Science ®Google Scholar
• Levis JM, Alexander E, Dombret H, et al. Final results of a phase 2 open-label, monotherapy efficacy and safety study of Quizartinib (AC220) in patients with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia after second-line chemotherapy or hematopoietic stem cell transplantation. In: 54th ASH annual meeting; 2012; 2012
   Google Scholar
• Cortes J, Perl AE, Dombret H, et al. Response rate and bridging to hematopoietic stem cell transplantation (HSCT) with quizartinib (AC220) in patients with FLT3-ITD positive or negative relapsed/refractory AML after second-line chemotherapy or previous bone marrow transplant. In: ASCO Annual Meeting 2013; 2013
   Google Scholar
• A study of AC220 given after transplant in subjects with acute myeloid leukemia (AML). Available from: http://clinicaltrials.gov/show/NCT01468467
   Google Scholar
• Pratz KW, Sato T, Murphy KM, et al. FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AML. Blood 2010;115:1425-32
   PubMed Web of Science ®Google Scholar
• Grundler R, Thiede C, Miething C, et al. Sensitivity toward tyrosine kinase inhibitors varies between different activating mutations of the FLT3 receptor. Blood 2003;102:646-51
   PubMed Web of Science ®Google Scholar
• Clark JJ, Cools J, Curley DP, et al. Variable sensitivity of FLT3 activation loop mutations to the small molecule tyrosine kinase inhibitor MLN518. Blood 2004;104:2867-72
   PubMed Web of Science ®Google Scholar
• Smith CC, Wang Q, Chin CS, et al. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature 2012;485:260-3
   PubMed Web of Science ®Google Scholar
• Parmar A, Marz S, Rushton S, et al. Stromal niche cells protect early leukemic FLT3-ITD+ progenitor cells against first-generation FLT3 tyrosine kinase inhibitors. Cancer Res 2011;71:4696-706
   PubMed Web of Science ®Google Scholar
• Weisberg E, Liu Q, Zhang X, et al. Selective Akt inhibitors synergize with tyrosine kinase inhibitors and effectively override stroma-associated cytoprotection of mutant FLT3-positive AML cells. PLoS One 2013;8:e56473
   Google Scholar
• Weisberg E, Liu Q, Nelson E, et al. Using combination therapy to override stromal-mediated chemoresistance in mutant FLT3-positive AML: synergism between FLT3 inhibitors, dasatinib/multi-targeted inhibitors and JAK inhibitors. Leukemia 2012;26:2233-44
   PubMed Web of Science ®Google Scholar
• Linnekin D. Early signaling pathways activated by c-Kit in hematopoietic cells. Int J Biochem Cell Biol 1999;31:1053-74
   PubMed Web of Science ®Google Scholar
• Lennartsson J, Ronnstrand L. The stem cell factor receptor/c-Kit as a drug target in cancer. Curr Cancer Drug Targets 2006;6:65-75
   Google Scholar
• Broudy VC. Stem cell factor and hematopoiesis. Blood 1997;90:1345-64
   PubMed Web of Science ®Google Scholar
• Ikeda H, Kanakura Y, Tamaki T, et al. Expression and functional role of the proto-oncogene c-kit in acute myeloblastic leukemia cells. Blood 1991;78:2962-8
   PubMed Web of Science ®Google Scholar
• Nanri T, Matsuno N, Kawakita T, et al. Mutations in the receptor tyrosine kinase pathway are associated with clinical outcome in patients with acute myeloblastic leukemia harboring t(8;21)(q22;q22). Leukemia 2005;19:1361-6
   PubMed Web of Science ®Google Scholar
• Park SH, Chi HS, Min SK, et al. Prognostic impact of c-KIT mutations in core binding factor acute myeloid leukemia. Leuk Res 2011;35:1376-83
   PubMed Web of Science ®Google Scholar
• Ashman LK, Ferrao P, Cole SR, Cambareri AC. Effects of mutant c-Kit in early myeloid cells. Leuk Lymphoma 1999;34:451-61
   PubMed Web of Science ®Google Scholar
• Ning ZQ, Li J, Arceci RJ. Activating mutations of c-kit at codon 816 confer drug resistance in human leukemia cells. Leuk Lymphoma 2001;41:513-22
   PubMed Web of Science ®Google Scholar
• Schnittger S, Kohl TM, Haferlach T, et al. KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. Blood 2006;107:1791-9
   PubMed Web of Science ®Google Scholar
• Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996;2:561-6
   PubMed Web of Science ®Google Scholar
• Kindler T, Breitenbuecher F, Marx A, et al. Efficacy and safety of imatinib in adult patients with c-kit-positive acute myeloid leukemia. Blood 2004;103:3644-54
   PubMed Web of Science ®Google Scholar
• Cortes J, Giles F, O’Brien S, et al. Results of imatinib mesylate therapy in patients with refractory or recurrent acute myeloid leukemia, high-risk myelodysplastic syndrome, and myeloproliferative disorders. Cancer 2003;97:2760-6
   PubMed Web of Science ®Google Scholar
• Heinrich MC, Griffith DJ, Druker BJ, et al. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 2000;96:925-32
   PubMed Web of Science ®Google Scholar
• Malagola M, Martinelli G, Rondoni M, et al. Imatinib mesylate in the treatment of c-kit-positive acute myeloid leukemia: is this the real target? Blood 2005;105:904; author reply 5
   PubMed Web of Science ®Google Scholar
• Frost MJ, Ferrao PT, Hughes TP, Ashman LK. Juxtamembrane mutant V560GKit is more sensitive to imatinib (STI571) compared with wild-type c-kit whereas the kinase domain mutant D816VKit is resistant. Mol Cancer Ther 2002;1:1115-24
   PubMed Web of Science ®Google Scholar
• Brandwein JM, Hedley DW, Chow S, et al. A phase I/II study of imatinib plus reinduction therapy for c-kit-positive relapsed/refractory acute myeloid leukemia: inhibition of Akt activation correlates with complete response. Leukemia 2011;25:945-52
   PubMed Web of Science ®Google Scholar
• Dos Santos C, McDonald T, Ho YW, et al. The Src and c-Kit kinase inhibitor dasatinib enhances p53-mediated targeting of human acute myeloid leukemia stem cells by chemotherapeutic agents. Blood 2013;122:1900-13
   PubMed Web of Science ®Google Scholar
• Dasatinib (Sprycel™) in patients with newly diagnosed core binding factor (CBF) acute myeloid leukemia (AML). Available from: http://clinicaltrials.gov/show/NCT00850382
   Google Scholar
• Randomized phase III study of intensive chemotherapy with or without dasatinib (sprycel™) in adult patients with newly diagnosed core-binding factor acute myeloid leukemia (CBF-AML). Available from: http://clinicaltrials.gov/show/NCT02013648
   Google Scholar
• Dasatinib, cytarabine, and idarubicin in treating patients with high-risk acute myeloid leukemia. Available from: http://clinicaltrials.gov/ct2/show/NCT01876953
   Google Scholar
• Leonard WJ, O’Shea JJ. Jaks and STATs: biological implications. Annu Rev Immunol 1998;16:293-322
   PubMed Web of Science ®Google Scholar
• Darnell JE Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 1994;264:1415-21
   PubMed Web of Science ®Google Scholar
• Levy DE, Darnell JE Jr. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 2002;3:651-62
   PubMed Web of Science ®Google Scholar
• Gouilleux-Gruart V, Gouilleux F, Desaint C, et al. STAT-related transcription factors are constitutively activated in peripheral blood cells from acute leukemia patients. Blood 1996;87:1692-7
   PubMed Web of Science ®Google Scholar
• Spiekermann K, Biethahn S, Wilde S, et al. Constitutive activation of STAT transcription factors in acute myelogenous leukemia. Eur J Haematol 2001;67:63-71
   PubMed Web of Science ®Google Scholar
• Steensma DP, McClure RF, Karp JE, et al. JAK2 V617F is a rare finding in de novo acute myeloid leukemia, but STAT3 activation is common and remains unexplained. Leukemia 2006;20:971-8
   PubMed Web of Science ®Google Scholar
• Ikezoe T, Kojima S, Furihata M, et al. Expression of p-JAK2 predicts clinical outcome and is a potential molecular target of acute myelogenous leukemia. Int J Cancer 2011;129:2512-21
   PubMed Web of Science ®Google Scholar
• Lee JW, Kim YG, Soung YH, et al. The JAK2 V617F mutation in de novo acute myelogenous leukemias. Oncogene 2006;25:1434-6
   PubMed Web of Science ®Google Scholar
• Schnittger S, Bacher U, Kern W, et al. JAK2V617F as progression marker in CMPD and as cooperative mutation in AML with trisomy 8 and t(8;21): a comparative study on 1103 CMPD and 269 AML cases. Leukemia 2007;21:1843-5
   PubMedGoogle Scholar
• Levine RL, Loriaux M, Huntly BJ, et al. The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia. Blood 2005;106:3377-9
   PubMed Web of Science ®Google Scholar
• Iwanaga E, Nanri T, Matsuno N, et al. A JAK2-V617F activating mutation in addition to KIT and FLT3 mutations is associated with clinical outcome in patients with t(8;21)(q22;q22) acute myeloid leukemia. Haematologica 2009;94:433-5
   PubMed Web of Science ®Google Scholar
• Lo MC, Peterson LF, Yan M, et al. Combined gene expression and DNA occupancy profiling identifies potential therapeutic targets of t(8;21) AML. Blood 2012;120:1473-84
   Google Scholar
• Watanabe D, Ezoe S, Fujimoto M, et al. Suppressor of cytokine signalling-1 gene silencing in acute myeloid leukaemia and human haematopoietic cell lines. Br J Haematol 2004;126:726-35
   PubMed Web of Science ®Google Scholar
• Figueroa ME, Lugthart S, Li Y, et al. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell 2010;17:13-27
   PubMed Web of Science ®Google Scholar
• Eghtedar A, Verstovsek S, Estrov Z, et al. Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia. Blood 2012;119:4614-18
   PubMed Web of Science ®Google Scholar
• Zhou J, Bi C, Janakakumara JV, et al. Enhanced activation of STAT pathways and overexpression of survivin confer resistance to FLT3 inhibitors and could be therapeutic targets in AML. Blood 2009;113:4052-62
   PubMed Web of Science ®Google Scholar
• Hart S, Goh KC, Novotny-Diermayr V, et al. Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia. Blood Cancer J 2011;1:e44
   PubMed Web of Science ®Google Scholar
• Levis M, Ravandi F, Wang ES, et al. Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood 2011;117:3294-301
   PubMed Web of Science ®Google Scholar
• A Phase 1/2 study of SB1518 for the treatment of advanced myeloid malignancies. Available from: http://clinicaltrials.gov/show/NCT00719836
   Google Scholar
• Chopra P, Sethi G, Dastidar SG, Ray A. Polo-like kinase inhibitors: an emerging opportunity for cancer therapeutics. Expert Opin Investig Drugs 2010;19:27-43
   PubMed Web of Science ®Google Scholar
• Luo J, Emanuele MJ, Li D, et al. A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 2009;137:835-48
   PubMed Web of Science ®Google Scholar
• Irvine DA, Copland M. Targeting hedgehog in hematologic malignancy. Blood 2012;119:2196-204
   PubMed Web of Science ®Google Scholar
• Lee SW, Moskowitz MA, Sims JR. Sonic hedgehog inversely regulates the expression of angiopoietin-1 and angiopoietin-2 in fibroblasts. Int J Mol Med 2007;19:445-51
   PubMed Web of Science ®Google Scholar
• Adolphe C, Hetherington R, Ellis T, Wainwright B. Patched1 functions as a gatekeeper by promoting cell cycle progression. Cancer Res 2006;66:2081-8
   PubMed Web of Science ®Google Scholar
• Athar M, Li C, Tang X, et al. Inhibition of smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through regulation of Fas expression and apoptosis. Cancer Res 2004;64:7545-52
   PubMed Web of Science ®Google Scholar
• Kobune M, Takimoto R, Murase K, et al. Drug resistance is dramatically restored by hedgehog inhibitors in CD34+ leukemic cells. Cancer Sci 2009;100:948-55
   PubMed Web of Science ®Google Scholar
• Sims-Mourtada J, Izzo JG, Ajani J, Chao KS. Sonic Hedgehog promotes multiple drug resistance by regulation of drug transport. Oncogene 2007;26:5674-9
   PubMed Web of Science ®Google Scholar
• Kobune M, Iyama S, Kikuchi S, et al. Stromal cells expressing hedgehog-interacting protein regulate the proliferation of myeloid neoplasms. Blood Cancer J 2012;2:e87
   PubMed Web of Science ®Google Scholar
• Sheikh A, Alvi AA, Aslam HM, Haseeb A. Hedgehog pathway inhibitors - current status and future prospects. Infect Agent Cancer 2012;7:29
   PubMedGoogle Scholar
• Minami Y FN, Naoe T, et al. Effect of treatment with hedgehog inhibitor PF-04449913, on leukemia-initiation potential in acute myeloid leukemia cells. In: ASCO Annual Meeting 2013; 2013
   Google Scholar
• Jamieson C, Cortes E, Oehler V, et al. Phase 1 dose-escalation study of PF-04449913, an oral hedgehog (Hh) inhibitor, in patients with select hematologic malignancies. In: 55th ASH Annual Meeting 2013; 2013
   Google Scholar
• Fukushima N, Minami Y, Hayakawa F, et al. Treatment with hedgehog inhibitor, PF-04449913, attenuates leukemia-initiation potential in acute myeloid leukemia cells. In: 55th ASH Annual Meeting 2013; 2013
   Google Scholar
• A study to evaluate PF-04449913 with chemotherapy in patients with acute myeloid leukemia or myelodysplastic syndrome. Available from: http://clinicaltrials.gov/show/NCT01546038
   Google Scholar
• Wellbrock J, Koehler JM, Wagner W, et al. Expression of hedgehog pathway mediator Gli2 represents a clinically negative prognostic marker in acute myeloid leukemia and its inhibitor GANT61 exerts anti-leukemic effects in vitro. In: 55th ASH Annual Meeting 2013; 2013
   Google Scholar
• Reya T, Duncan AW, Ailles L, et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 2003;423:409-14
   PubMed Web of Science ®Google Scholar
• Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature 2005;434:843-50
   PubMed Web of Science ®Google Scholar
• Muller T, Bain G, Wang X, Papkoff J. Regulation of epithelial cell migration and tumor formation by beta-catenin signaling. Exp Cell Res 2002;280:119-33
   PubMed Web of Science ®Google Scholar
• Zhang T, Otevrel T, Gao Z, et al. Evidence that APC regulates survivin expression: a possible mechanism contributing to the stem cell origin of colon cancer. Cancer Res 2001;61:8664-7
   PubMed Web of Science ®Google Scholar
• Shtutman M, Zhurinsky J, Simcha I, et al. The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci USA 1999;96:5522-7
   PubMed Web of Science ®Google Scholar
• He TC, Sparks AB, Rago C, et al. Identification of c-MYC as a target of the APC pathway. Science 1998;281:1509-12
   PubMed Web of Science ®Google Scholar
• Wielenga VJ, Smits R, Korinek V, et al. Expression of CD44 in Apc and Tcf mutant mice implies regulation by the WNT pathway. Am J Pathol 1999;154:515-23
   PubMed Web of Science ®Google Scholar
• Ysebaert L, Chicanne G, Demur C, et al. Expression of beta-catenin by acute myeloid leukemia cells predicts enhanced clonogenic capacities and poor prognosis. Leukemia 2006;20:1211-16
   PubMed Web of Science ®Google Scholar
• Xu J, Suzuki M, Niwa Y, et al. Clinical significance of non-phosphorylated beta-catenin in acute myeloid leukaemia and myelodysplastic syndrome. Br J Haematol 2008;140:394-401
   PubMed Web of Science ®Google Scholar
• Curtin JC, Lorenzi MV. Drug discovery approaches to target Wnt signaling in cancer stem cells. Oncotarget 2010;1:552-66
   PubMed Web of Science ®Google Scholar
• DeAlmeida VI, Miao L, Ernst JA, et al. The soluble wnt receptor Frizzled8CRD-hFc inhibits the growth of teratocarcinomas in vivo. Cancer Res 2007;67:5371-9
   PubMed Web of Science ®Google Scholar
• Mook RA Jr, Chen M, Lu J, et al. Small molecule modulators of Wnt/beta-catenin signaling. Bioorg Med Chem Lett 2013;23:2187-91
   PubMedGoogle Scholar
• Hsiao SJ, Smith S. Tankyrase function at telomeres, spindle poles, and beyond. Biochimie 2008;90:83-92
   PubMed Web of Science ®Google Scholar
• Chen B, Dodge ME, Tang W, et al. Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nat Chem Biol 2009;5:100-7
   PubMed Web of Science ®Google Scholar
• Christensen JG, Schreck R, Burrows J, et al. A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. Cancer Res 2003;63:7345-55
   PubMed Web of Science ®Google Scholar
• Grosch S, Tegeder I, Niederberger E, et al. COX-2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective COX-2 inhibitor celecoxib. FASEB J 2001;15:2742-4
   PubMed Web of Science ®Google Scholar
• Xing L, Devadas B, Devraj RV, et al. Discovery and characterization of atropisomer PH-797804, a p38 MAP kinase inhibitor, as a clinical drug candidate. ChemMedChem 2012;7:273-80
   PubMed Web of Science ®Google Scholar
• Emami KH, Nguyen C, Ma H, et al. A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected]. Proc Natl Acad Sci USA 2004;101:12682-7
   PubMed Web of Science ®Google Scholar
• Lepourcelet M, Chen YN, France DS, et al. Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex. Cancer Cell 2004;5:91-102
   PubMed Web of Science ®Google Scholar
• Barker N, Clevers H. Mining the Wnt pathway for cancer therapeutics. Nat Rev Drug Discov 2006;5:997-1014
   PubMed Web of Science ®Google Scholar
• Wei W, Chua MS, Grepper S, So S. Small molecule antagonists of Tcf4/beta-catenin complex inhibit the growth of HCC cells in vitro and in vivo. Int J Cancer 2010;126:2426-36
   PubMed Web of Science ®Google Scholar
• Im AP, Sehgal AR, Carroll MP, et al. DNMT3A and IDH mutations in acute myeloid leukemia and other myeloid malignancies: associations with prognosis and potential treatment strategies. Leukemia 2014. [Epub ahead of print]
   PubMed Web of Science ®Google Scholar
• Patel KP, Ravandi F, Ma D, et al. Acute myeloid leukemia with IDH1 or IDH2 mutation: frequency and clinicopathologic features. Am J Clin Pathol 2011;135:35-45
   PubMed Web of Science ®Google Scholar
• Janin M, Mylonas E, Saada V, et al. Serum 2-hydroxyglutarate production in IDH1- and IDH2-mutated de novo acute myeloid leukemia: a study by the Acute Leukemia French Association group. J Clin Oncol 2014;32:297-305
   PubMed Web of Science ®Google Scholar
• Ravandi F, Patel K, Luthra R, et al. Prognostic significance of alterations in IDH enzyme isoforms in patients with AML treated with high-dose cytarabine and idarubicin. Cancer 2012;118:2665-73
   PubMed Web of Science ®Google Scholar
• Fathi AT, Sadrzadeh H, Borger DR, et al. Prospective serial evaluation of 2-hydroxyglutarate, during treatment of newly diagnosed acute myeloid leukemia, to assess disease activity and therapeutic response. Blood 2012;120:4649-52
   PubMed Web of Science ®Google Scholar
• Losman JA, Looper RE, Koivunen P, et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 2013;339:1621-5
   PubMed Web of Science ®Google Scholar
• Wang JH, Chen WL, Li JM, et al. Prognostic significance of 2-hydroxyglutarate levels in acute myeloid leukemia in China. Proc Natl Acad Sci USA 2013;110:17017-22
   PubMed Web of Science ®Google Scholar
• Pollyea DA, Kohrt HE, Zhang B, et al. 2-Hydroxyglutarate in IDH mutant acute myeloid leukemia: predicting patient responses, minimal residual disease and correlations with methylcytosine and hydroxymethylcytosine levels. Leuk Lymphoma 2013;54:408-10
   PubMed Web of Science ®Google Scholar
• Chaturvedi A, Araujo Cruz MM, Jyotsana N, et al. Mutant IDH1 promotes leukemogenesis in vivo and can be specifically targeted in human AML. Blood 2013;122:2877-87
   PubMed Web of Science ®Google Scholar
• Wang F, Travins J, DeLaBarre B, et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 2013;340:622-6
   PubMed Web of Science ®Google Scholar
• Stein E TM, et al. Clinical safety and activity in a phase I trial of AG-221, a first in class, potent inhibitor of the IDH2-mutant protein, in patients with IDH2 mutant positive advanced hematologic malignancies. In: AACR Annual Meeting 2014; 2014
   Google Scholar
• Cowan AJ, Laszlo GS, Estey EH, Walter RB. Antibody-based therapy of acute myeloid leukemia with gemtuzumab ozogamicin. Front Biosci (Landmark Ed) 2013;18:1311-34
   PubMed Web of Science ®Google Scholar
• Burnett AK, Hills RK, Milligan D, et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol 2011;29:369-77
   PubMed Web of Science ®Google Scholar
• Recher C, Pigneux A, Witz F, et al. Addition of gemtuzumab ozogamycin to chemotherapy improves event-free survival but not overall survival of AML patients with intermediate cytogenetics not eligible for allogeneic transplantation. Results of the GOELAMS AML 2006 IR study. In: ASHH Annual meeting 2011; 2011
   Google Scholar
• Castaigne S, Pautas C, Terre C, et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet 2012;379:1508-16
   PubMed Web of Science ®Google Scholar
• Rowe JM, Lowenberg B. Gemtuzumab ozogamicin in acute myeloid leukemia: a remarkable saga about an active drug. Blood 2013;121:4838-41
   PubMed Web of Science ®Google Scholar
• Breccia M, Cimino G, Diverio D, et al. Sustained molecular remission after low dose gemtuzumab-ozogamicin in elderly patients with advanced acute promyelocytic leukemia. Haematologica 2007;92:1273-4
   PubMed Web of Science ®Google Scholar
• Lo-Coco F, Cimino G, Breccia M, et al. Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood 2004;104:1995-9
   PubMed Web of Science ®Google Scholar
• Ravandi F, Estey E, Jones D, et al. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol 2009;27:504-10
   PubMed Web of Science ®Google Scholar
• Chames P, Baty D. Bispecific antibodies for cancer therapy: the light at the end of the tunnel? MAbs 2009;1:539-47
   PubMed Web of Science ®Google Scholar
• Frankel SR, Baeuerle PA. Targeting T cells to tumor cells using bispecific antibodies. Curr Opin Chem Biol 2013;17:385-92
   PubMed Web of Science ®Google Scholar
• Satta A, Mezzanzanica D, Turatti F, et al. Redirection of T-cell effector functions for cancer therapy: bispecific antibodies and chimeric antigen receptors. Future Oncol 2013;9:527-39
   PubMed Web of Science ®Google Scholar
• Aigner M, Feulner J, Schaffer S, et al. T lymphocytes can be effectively recruited for ex vivo and in vivo lysis of AML blasts by a novel CD33/CD3-bispecific BiTE antibody construct. Leukemia 2013;27:1107-15
   PubMed Web of Science ®Google Scholar
• AL Hussaini M RJ, Rettig M, et al. Targeting CD123 in leukemic stem cells using dual affinity re-targeting molecules (DARTs®). In: 55th ASH Annual Meeting 2013; 2013
   Google Scholar
• Bargou R, Leo E, Zugmaier G, et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science 2008;321:974-7
   PubMed Web of Science ®Google Scholar
• Topp MS, Kufer P, Gokbuget N, et al. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol 2011;29:2493-8
   PubMed Web of Science ®Google Scholar
• Klinger M, Brandl C, Zugmaier G, et al. Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab. Blood 2012;119:6226-33
   PubMed Web of Science ®Google Scholar
• Wong R, Pepper C, Brennan P, et al. Blinatumomab induces autologous T-cell killing of chronic lymphocytic leukemia cells. Haematologica 2013;98:1930-8
   PubMed Web of Science ®Google Scholar
• Clinical study with blinatumomab in patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). Available from: http://clinicaltrials.gov/ct2/show/NCT01466179
   Google Scholar
• Reikvam H, Kittang AO, Melve G, et al. Targeted anti-leukemic therapy as disease-stabilizing treatment for acute myeloid leukemia relapse after allogeneic stem cell transplantation: will it be possible to combine these strategies with retransplantation or donor lymphocyte infusions? Curr Cancer Drug Targets 2013;13:30-47
   PubMed Web of Science ®Google Scholar
• Alfaro C, Suarez N, Gonzalez A, et al. Influence of bevacizumab, sunitinib and sorafenib as single agents or in combination on the inhibitory effects of VEGF on human dendritic cell differentiation from monocytes. Br J Cancer 2009;100:1111-19
   PubMed Web of Science ®Google Scholar
• Alisertib for acute myeloid leukemia. Available from: www.clinicaltrials.gov/ct2/show/NCT01779843
   Google Scholar
• Study evaluating orally administered AMG900 in adult subjects with acute myeloid leukemia. Available from: http://clinicaltrials.gov/ct2/show/NCT01380756
   Google Scholar
• Lestaurtinib, cytarabine, and idarubicin in treating younger patients with relapsed or refractory acute myeloid leukemia. Available from: http://data.linkedct.org/resource/trial/NCT00469859
   Google Scholar
• Disease stabilization in aml by treatment with atra, valproic acid and low-dose cytarabine. Available from: http://clinicaltrials.gov/show/NCT00995332
   Google Scholar
• A trial to evaluate two schedules of MS275 in combination with 5AC in elderly patients with acute myeloid leukemia (AML). Available from: http://clinicaltrials.gov/show/NCT01305499
   Google Scholar
• Phase II temozolomide + vorinostat in patients (>60) w/newly diagnosed or relapse/refractory AML. Available from: http://clinicaltrials.gov/ct2/show/NCT01550224
   Google Scholar
• Cytarabine and daunorubicin hydrochloride or idarubicin and cytarabine with or without vorinostat in treating younger patients with previously untreated acute myeloid leukemia. Available from: http://clinicaltrials.gov/ct2/show/NCT01802333
   Google Scholar
• Decitabine with or without bortezomib in treating older patients with acute myeloid leukemia. Available from: http://clinicaltrials.gov/ct2/show/NCT01420926
   Google Scholar
• Ixazomib in treating patients with relapsed or refractory acute myeloid leukemia. Available from: http://clinicaltrials.gov/show/NCT02030405
   Google Scholar
• Decitabine and plerixafor in elderly acute myeloid leukemia (AML). Available from: http://clinicaltrials.gov/show/NCT01352650
   Google Scholar
• Chemosensitization with plerixafor plus G-CSF in acute myeloid leukemia. Available from: http://clinicaltrials.gov/ct2/show/NCT00906945
   Google Scholar
• Phase IIa study evaluating safety and efficacy of BL-8040 in relapsed/refractory AML patients. Available from: http://clinicaltrials.gov/show/NCT01838395
   Google Scholar
• First in human study to determine the safety, tolerability and preliminary efficacy of an anti-CXCR4 antibody in subjects with acute myelogenous leukemia and selected B-cell cancers. Available from: http://clinicaltrials.gov/show/NCT01120457
   Google Scholar
• A trial to establish the feasibility of combining either the tyrosine kinase inhibitor AC220,CXCR4 inhibitor plerixafor or HSP90 inhibitor ganetespib with chemotherapy in older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome. Available from: http://clinicaltrials.gov/show/NCT01236144
   Google Scholar
• Phase II study of crenolanib in subjects with relapsed/refractory AML with FLT3 activating mutations. Available from: http://clinicaltrials.gov/ct2/show/NCT01522469
   Google Scholar
• Phase I/II study of combination of sorafenib, vorinostat, and bortezomib for the treatment of acute myeloid leukemia with complex- or poor-risk (monosomy 5/7) cytogenetics or FLT3-ITD positive genotype. Available from: http://clinicaltrials.gov/show/NCT01534260
   Google Scholar
• Sorafenib maintenance therapy for patients with AML after allogeneic stem cell transplant. Available from: http://clinicaltrials.gov/ct2/show/NCT01398501
   Google Scholar
• Bortezomib and sorafenib tosylate in treating patients with newly diagnosed acute myeloid leukemia. Available from: http://clinicaltrials.gov/show/NCT01371981
   Google Scholar
• Trial to assess the efficacy of midostaurin (PKC412) in patients with c-KIT or FLT3-ITD mutated t(8;21) AML (MIDOKIT). Available from: www.clinicaltrials.gov/ct2/show/NCT01830361
   Google Scholar
• Safety and efficacy study of nilotinib combined with mitoxantrone, etoposide, and high-dose cytarabine induction chemotherapy followed by consolidation for patients with C-kit positive acute myeloid leukemia. Available from: http://clinicaltrials.gov/show/NCT01222143
   Google Scholar
• PF-04449913 for patients with acute leukemia at high risk of relapse after donor stem cell transplant. Available from: http://clinicaltrials.gov/ct2/show/NCT01841333
   Google Scholar
• Safety and efficacy study of PRI-724 in subjects with advanced myeloid malignancies. Available from: http://clinicaltrials.gov/ct2/show/NCT01606579
   Google Scholar
• Phase I clinical study of CWP232291 in acute myeloid leukemia patients. Available from: http://clinicaltrials.gov/ct2/show/NCT01398462
   Google Scholar
• Study of orally administered AG-120 in subjects with advanced hematologic malignancies with an IDH1 mutation. Available from: http://clinicaltrials.gov/ct2/show/NCT02074839
   Google Scholar
• Phase I study of AG-221 in subjects with advanced hematologic malignancies with an IDH2 mutation. Available from: http://clinicaltrials.gov/ct2/show/NCT01915498
   Google Scholar
• Ramirez P, Rettig MP, Uy GL, et al. BIO5192, a small molecule inhibitor of VLA-4, mobilizes hematopoietic stem and progenitor cells. Blood 2009;114:1340-3
   PubMed Web of Science ®Google Scholar
• Jacamo R, Chen Y, Wang Z, et al. Reciprocal leukemia-stroma VCAM-1/VLA-4-dependent activation of NF-kappaB mediates chemoresistance. Blood 2014;123:2691-702
   PubMed Web of Science ®Google Scholar
• Ossenkoppele GJ, Stussi G, Maertens J, et al. Addition of bevacizumab to chemotherapy in acute myeloid leukemia at older age: a randomized phase 2 trial of the Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON) and the Swiss Group for Clinical Cancer Research (SAKK). Blood 2012;120:4706-11
   PubMed Web of Science ®Google Scholar
• Reikvam H, Nepstad I, Bruserud O, Hatfield KJ. Pharmacological targeting of the PI3K/mTOR pathway alters the release of angioregulatory mediators both from primary human acute myeloid leukemia cells and their neighboring stromal cells. Oncotarget 2013;4:830-43
   PubMed Web of Science ®Google Scholar
• Zhang J, Ye J, Ma D, et al. Cross-talk between leukemic and endothelial cells promotes angiogenesis by VEGF activation of the Notch/Dll4 pathway. Carcinogenesis 2013;34:667-77
   PubMed Web of Science ®Google Scholar
• Konopleva MY, Jordan CT. Leukemia stem cells and microenvironment: biology and therapeutic targeting. J Clin Oncol 2011;29:591-9
   PubMed Web of Science ®Google Scholar
• Staller P, Sulitkova J, Lisztwan J, et al. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature 2003;425:307-11
   PubMed Web of Science ®Google Scholar
• Ceradini DJ, Kulkarni AR, Callaghan MJ, et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 2004;10:858-64
   PubMed Web of Science ®Google Scholar
• Wang Y, Liu Y, Malek SN, Zheng P. Targeting HIF1alpha eliminates cancer stem cells in hematological malignancies. Cell Stem Cell 2011;8:399-411
   PubMed Web of Science ®Google Scholar
• Mussai F, De Santo C, Abu-Dayyeh I, et al. Acute myeloid leukemia creates an arginase-dependent immunosuppressive microenvironment. Blood 2013;122:749-58
   PubMed Web of Science ®Google Scholar
• Bronte V, Serafini P, Mazzoni A, et al. L-arginine metabolism in myeloid cells controls T-lymphocyte functions. Trends Immunol 2003;24:302-6
   PubMed Web of Science ®Google Scholar
• Jin L, Hope KJ, Zhai Q, et al. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med 2006;12:1167-74
   PubMed Web of Science ®Google Scholar