409
Views
5
CrossRef citations to date
0
Altmetric
Review Article

Hematopoietic stem cells, progenitor cells and leukemic stem cells in adult myeloproliferative neoplasms

Pages 922-933 | Received 01 Jul 2012, Accepted 22 Sep 2012, Published online: 24 Oct 2012

References

  • Dameshek W. Some speculations on the myeloproliferative syndromes. Blood 1951;6:372–375.
  • Chandra HS, Heisterkamp NC, Hungerford A, . Philadelphia Chromosome Symposium: commemoration of the 50th anniversary of the discovery of the Ph chromosome. Cancer Genet 2011;204: 171–179.
  • Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia 2010;24:1128–1138.
  • Vainchenker W, Delhommeau F, Constantinescu SN, . New mutations and pathogenesis of myeloproliferative neoplasms. Blood 2011;118:1723–1735.
  • James C, Ugo V, Le Couédic JP, . A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005;434:1144–1148.
  • Levine RL, Wadleigh M, Cools J, . Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005;7: 387–397.
  • Delhommeau F, Pisani DF, James C, . Oncogenic mechanisms in myeloproliferative disorders. Cell Mol Life Sci 2006;63:2939–2953.
  • Barosi G, Lupo L, Rosti V. Management of myeloproliferative neoplasms: from academic guidelines to clinical practice. Curr Hematol Malig Rep 2012;7:50–56.
  • Swerdlow SH, Campo E, Harris NL, . WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: International Agency for Research on Cancer; 2008.
  • Gupta R, Knight CL, Bain BJ. Receptor tyrosine kinase mutations in myeloid neoplasms. Br J Haematol 2002;117:489–508.
  • Vardiman J, Hyjek E. World Health Organization classification, evaluation, and genetics of the myeloproliferative neoplasm variants. Hematology Am Soc Hematol Educ Program 2011: 250–256.
  • Anastasi J. The myeloproliferative neoplasms including the eosinophilia-related myeloproliferations associated with tyrosine kinase mutations:changes and issues in classification and diagnosis criteria. Semin Diagn Pathol 2011;28:304–313.
  • O’Brien SG, Guilhot F, Larson RA, . Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348:994–1004.
  • Cools J, DeAngelo DJ, Gotlib J, . A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003;348:1201–1214.
  • Tefferi A. JAK inhibitors for myeloproliferative neoplasms:clarifying facts from myths. Blood 2012;119:2721–2730.
  • Arora A, Scholar EM. Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther 2005;315:971–979.
  • Hochhaus A, O’Brien SG, Guilhot F, . Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 2009;23:1054–1061.
  • Hehlmann R. How I treat CML blast crisis. Blood 2012;120: 737–747.
  • Cortes J, Kantarjian H. How I treat newly diagnosed chronic phase CML. Blood 2012;120:1390–1397.
  • Cross NC, White HE, Muller MC, . Standardized definitions of molecular response in chronic myeloid leukemia. Leukemia 2012 Apr 16. [Epub ahead of print]
  • Verstovsek S, Mesa RA, Gotlib J, . A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012; 366:799–807.
  • Harrison C, Kiladjian JJ, Al-Ali HK, . JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 2012;366:787–798.
  • Branford S, Seymour JF, Grigg A, . BCR-ABL messenger RNA levels continue to decline in patients with chronic phase chronic myeloid leukemia treated with imatinib for more than 5 years and approximately half of all first-line treated patients have stable undetectable BCR-ABL using strict sensitivity criteria. Clin Cancer Res 2007;13:7080–7085.
  • Ross DM, Branford S, Seymour JF, . Patients with chronic myeloid leukemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukemia by DNA PCR. Leukemia 2010;24:1719–1724.
  • Goldman JM, Majhail NS, Klein JP, . Relapse and late mortality in 5-year survivors of myeloablative allogeneic hematopoietic cell transplantation for chronic myeloid leukemia in first chronic phase. J Clin Oncol 2010;28:1888–1895.
  • Gupta V, Hari P, Hoffman R. Allogeneic hematopoietic cell transplantation for myelofibrosis in the era of JAK inhibitors. Blood 2012;120:1367–1379.
  • Parmar K, Mauch P, Vergilio JA, . Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc Natl Acad Sci USA 2007;104:5431–5436.
  • Adams GB, Scadden DT. The hematopoietic stem cell in its place. Nat Immunol 2006;7:333–337.
  • Zhang J, Niu C, Ye L, . Identification of the haematopoietic stem cell niche and control of the niche size. Nature 2003;425:836–841.
  • Chan CK, Chen CC, Luppen CA, . Endochondral ossification is required for haematopoietic stem-cell niche formation. Nature 2009;457:490–494.
  • Tajbakhsh S, Rocheteau P, Le Roux I. Asymmetric cell divisions and asymmetric cell fates. Annu Rev Cell Dev Biol 2009;25 671–699.
  • Ting SB, Deneault E, Hope K, . Asymmetric segregation and self-renewal of hematopoietic stem and progenitor cells with endocytic Ap2a2. Blood 2012;119:2510–2522.
  • Blank U, Karlsson G, Karlsson S. Signaling pathways governing stem-cell fate. Blood 2008;111:492–503.
  • Qian H, Buza-Vidas N, Hyland CD, . Critical role of thrombopoietin in maintaining adult quiescent hematopoietic stem cells. Cell Stem Cell 2007;1:671–684.
  • Yoshihara H, Arai F, Hosokawa K, . Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. Cell Stem Cell 2007;1:685–697.
  • Fleming HE, Janzen V, Lo Celso C, . Wnt signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self-renewal in vivo. Cell Stem Cell 2008;2:274–283.
  • Stier S, Cheng T, Dombkowski D, . Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome. Blood 2002;99:2369–2378.
  • Calvi LM, Adams GB, Weibrecht KW, . Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 2003;425:841–846.
  • Nilsson SK, Johnston HM, Whitty GA, . Osteopontin, a key component of the hematopoietic stem cell niche and regulator of primitive hematopoietic progenitor cells. Blood 2005;106:1232–1239.
  • Karlsson G, Blank U, Moody JL, . Smad4 is critical for self-renewal of hematopoietic stem cells. J Exp Med 2007;204:467–474.
  • Arai F, Hirao A, Ohmura M, . Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 2004;118:149–161.
  • Kent D, Copley M, Benz C, . Regulation of hematopoietic stem cells by the steel factor/KIT signaling pathway. Clin Cancer Res 2008;14:1926–1930.
  • Hodgson GS, Bradley TR. Properties of haematopoietic stem cells surviving 5-fluorouracil treatment: evidence for a pre-CFU-S cell?Nature 1979;281:381–382.
  • Ploemacher RE, van Os R, van Beurden CA, . Murine haemopoietic stem cells with long-term engraftment and marrow repopulating ability are more resistant to gamma-radiation than are spleen colony forming cells. Int J Radiat Biol 1992;61:489–499.
  • Opferman JT, Iwasaki H, Ong CC, . Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells. Science 2005;307:1101–1104.
  • Essers MA, Offner S, Blanco-Bose WE, . IFNalpha activates dormant haematopoietic stem cells in vivo. Nature 2009;458:904–908.
  • Baldridge MT, King KY, Boles NC, . Quiescent haematopoietic stem cells are activated by IFN-gamma in response to chronic infection. Nature 2010;465:793–797.
  • North TE, Goessling W, Walkley CR, . Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature 2007;447:1007–1011.
  • Frisch BJ, Porter RL, Gigliotti BJ, . In vivo prostaglandin E2 treatment alters the bone marrow microenvironment and preferentially expands short-term hematopoietic stem cells. Blood 2009;114:4054–4063.
  • Durand EM, Zon LI. Newly emerging roles for prostaglandin E2 regulation of hematopoiesis and hematopoietic stem cell engraftment. Curr Opin Hematol 2010;17:308–312.
  • Miyake T, Kung CK, Goldwasser E. Purification of human erythropoietin. J Biol Chem 1977;252:5558–5564.
  • Gasson JC, Golde DW, Kaufman SE, . Molecular characterization and expression of the gene encoding human erythroid-potentiating activity. Nature 1985;315:768–771.
  • Nicola NA, Metcalf D, Matsumoto M, . Purification of a factor inducing differentiation in murine myelomonocytic leukemia cells. Identification as granulocyte colony-stimulating factor. J Biol Chem 1983;258:9017–9023.
  • Metcalf D, Nicola NA. Proliferative effects of purified granulocyte colony-stimulating factor (G-CSF) on normal mouse hemopoietic cells. J Cell Physiol 1983;116:198–206.
  • Kaushansky K, Lok S, Holly RD, . Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin. Nature 1994;369:568–571.
  • Lok S, Kaushansky K, Holly RD, . Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo. Nature 1994;369:565–568.
  • Ng AP, Kauppi M, Metcalf D, . Characterization of thrombopoietin (TPO)-responsive progenitor cells in adult mouse bone marrow with in vivo megakaryocyte and erythroid potential. Proc Natl Acad Sci USA 2012;109:2364–2369.
  • Metcalf D. The colony-stimulating factors and cancer. Nat Rev Cancer 2010;10:425–434.
  • Robb L. Cytokine receptors and hematopoietic differentiation. Oncogene 2007;26:6715–6723.
  • Constantinescu SN, Ghaffari S, Lodish HF. The erythropoietin receptor: structure, activation and intracellular signal transduction. Trends Endocrinol Metab 1999;10:18–23.
  • Wilks AF, Harpur AG, Kurban RR, . Two novel protein-tyrosine kinases, each with a second phosphotransferase-related catalytic domain, define a new class of protein kinase. Mol Cell Biol 1991;11:2057–2065.
  • Parganas E, Wang D, Stravopodis D, . Jak2 is essential for signaling through a variety of cytokine receptors. Cell 1998;93: 385–395.
  • Neubauer H, Cumano A, Muller M, . Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell 1998;93:397–409.
  • Teglund S, McKay C, Schuetz E, . Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses. Cell 1998;93:841–850.
  • Socolovsky M, Fallon AE, Wang S, . Fetal anemia and apoptosis of red cell progenitors in Stat5a-/-5b-/- mice: a direct role for Stat5 in Bcl-X(L) induction. Cell 1999;98:181–191.
  • Funakoshi-Tago M, Tago K, Abe M, . STAT5 activation is critical for the transformation mediated by myeloproliferative disorder-associated JAK2 V617F mutant. J Biol Chem 2010;285:5296–5307.
  • Yan D, Hutchison RE, Mohi G. Critical requirement for Stat5 in a mouse model of polycythemia vera. Blood 2012;119:3539–3549.
  • Walz C, Ahmed W, Lazarides K, . Essential role for Stat5a/b in myeloproliferative neoplasms induced by BCR-ABL1 and JAK2V617F in mice. Blood 2012;119:3550–3560.
  • Li B, Zhang G, Li C, . Identification of JAK2 as a mediator of FIP1L1-PDGFRA-induced eosinophil growth and function in CEL. PLoS One 2012;7:e34912.
  • Hantschel O, Warsch W, Eckelhart E, . BCR-ABL uncouples canonical JAK2-STAT5 signaling in chronic myeloid leukemia. Nat Chem Biol 2012;8:285–293.
  • Scott LM, Tong W, Levine RL, . JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 2007;356:459–468.
  • Pardanani AD, Levine RL, Lasho T, . MPL515 mutations in myeloproliferative and other myeloid disorders:a study of 1182 patients. Blood 2006;108:3472–3476.
  • Aranaz P, Hurtado C, Erquiaga I, . CBL mutations in myeloproliferative neoplasms are also found in its proline-rich domain and in patients with the V617FJAK2. Haematologica 2012;97: 1234–1241.
  • Pardanani A, Lasho T, Finke C, . LNK mutation studies in blast-phase myeloproliferative neoplasms, and in chronic-phase disease with TET2, IDH, JAK2 or MPL mutations. Leukemia 2010;24:1713–1718.
  • Makishima H, Jankowska AM, McDevitt MA, . CBL, CBLB, TET2, ASXL1, and IDH1/2 mutations and additional chromosomal aberrations constitute molecular events in chronic myelogenous leukemia. Blood 2011;117:e198–e206.
  • Martinez-Aviles L, Besses C, Alvarez-Larran A, . TET2, ASXL1, IDH1, IDH2, and c-CBL genes in JAK2- and MPL-negative myeloproliferative neoplasms. Ann Hematol 2012;91:533–541.
  • Guglielmelli P, Biamonte F, Score J, . EZH2 mutational status predicts poor survival in myelofibrosis. Blood 2011;118:5227–5234.
  • Yoshida K, Sanada M, Shiraishi Y, . Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 2011;478:64–69.
  • Zhang SJ, Rampal R, Manshouri T, . Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome. Blood 2012;119:4480–4485.
  • Stegelmann F, Bullinger L, Schlenk RF, . DNMT3A mutations in myeloproliferative neoplasms. Leukemia 2011;25:1217–1219.
  • Majewski IJ, Blewitt ME, de Graaf CA, . Polycomb repressive complex 2 (PRC2) restricts hematopoietic stem cell activity. PLoS Biol 2008;6:e93.
  • Majewski IJ, Ritchie ME, Phipson B, . Opposing roles of polycomb repressive complexes in hematopoietic stem and progenitor cells. Blood 2010;116:731–739.
  • Moran-Crusio K, Reavie L, Shih A, . Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 2011;20:11–24.
  • Ko M, Bandukwala HS, An J, . Ten-Eleven-Translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice. Proc Natl Acad Sci USA 2011;108:14566–14571.
  • Shide K, Kameda T, Shimoda H, . TET2 is essential for survival and hematopoietic stem cell homeostasis. Leukemia 2012 Apr 3. [Epub ahead of print]
  • Herrera-Merchan A, Arranz L, Ligos JM, . Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease. Nat Commun 2012;3:623.
  • Liu F, Zhao X, Perna F, . JAK2V617F-mediated phosphorylation of PRMT5 downregulates its methyltransferase activity and promotes myeloproliferation. Cancer Cell 2011;19:283–294.
  • Jamieson CH, Gotlib J, Durocher JA, . The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation. Proc Natl Acad Sci USA 2006;103:6224–6229.
  • Butcher CM, Hutton JF, Hahn U, . Cellular origin and lineage specificity of the JAK2 (V617F) allele in polycythemia vera. Blood 2007;109:386–387.
  • Adamson JW, Fialkow PJ, Murphy S, . Polycythemia vera:stem-cell and probable clonal origin of the disease. N Engl J Med 1976;295:913–916.
  • Briere J, el-Kassar N. Clonality markers in polycythaemia and primary thrombocythaemia. Baillieres Clin Haematol 1998;11:787–801.
  • Mitterbauer G, Winkler K, Gisslinger H, . Clonality analysis using X-chromosome inactivation at the human androgen receptor gene (Humara). Evaluation of large cohorts of patients with chronic myeloproliferative diseases, secondary neutrophilia, and reactive thrombocytosis. Am J Clin Pathol 1999;112:93–100.
  • Zamora L, Espinet B, Florensa L, . Clonality analysis by HUMARA assay in Spanish females with essential thrombocythemia and polycythemia vera. Haematologica 2005;90:259–261.
  • Ishii T, Bruno E, Hoffman R, . Involvement of various hematopoietic-cell lineages by the JAK2V617F mutation in polycythemia vera. Blood 2006;108:3128–3134.
  • Berkofsky-Fessler W, Buzzai M, Kim MK, . Transcriptional profiling of polycythemia vera identifies gene expression patterns both dependent and independent from the action of JAK2V617F. Clin Cancer Res 2010;16:4339–4352.
  • Mullally A, Lane SW, Ball B, . Physiological Jak2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells. Cancer Cell 2010;17:584–596.
  • Mullally A, Poveromo L, Schneider RK, . Distinct roles for long-term hematopoietic stem cells and erythroid precursor cells in a murine model of Jak2V617F polycythemia vera. Blood 2012;120: 155–172.
  • Zuber J, Radtke I, Pardee TS, . Mouse models of human AML accurately predict chemotherapy response. Genes Dev 2009;23: 877–889.
  • Dupont S, Massé A, James C, . The JAK2 617V> F mutation triggers erythropoietin hypersensitivity and terminal erythroid amplification in primary cells from patients with polycythemia vera. Blood 2007;110:1013–1021.
  • Ishii T, Zhao Y, Sozer S, . Behavior of CD34+ cells isolated from patients with polycythemia vera in NOD/SCID mice. Exp Hematol 2007;35:1633–1640.
  • James C, Mazurier F, Dupont S, . The hematopoietic stem cell compartment of JAK2V617F-positive myeloproliferative disorders is a reflection of disease heterogeneity. Blood 2008;112:2429–2438.
  • Li J, Spensberger D, Ahn JS, . JAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F-positive essential thrombocythemia. Blood 2010;116:1528–1538.
  • Akada H, Yan D, Zou H, . Conditional expression of heterozygous or homozygous Jak2V617F from its endogenous promoter induces a polycythemia vera-like disease. Blood 2010;115:3589–3597.
  • Li J, Kent DG, Chen E, . Mouse models of myeloproliferative neoplasms: JAK of all grades. Dis Model Mech 2011;4:311–317.
  • Akada H, Akada S, Hutchison RE, . Erythroid lineage-restricted expression of Jak2V617F is sufficient to induce a myeloproliferative disease in mice. Haematologica 2012;97:1389–1393.
  • Dai CH, Krantz SB, Means RTJ, . Polycythemia vera blood burst-forming units-erythroid are hypersensitive to interleukin-3. J Clin Invest 1991;87:391–396.
  • Dai CH, Krantz SB, Dessypris EN, . Polycythemia vera. II. Hypersensitivity of bone marrow erythroid, granulocyte-macrophage, and megakaryocyte progenitor cells to interleukin-3 and granulocyte-macrophage colony-stimulating factor. Blood 1992;80:891–899.
  • Prchal JF, Axelrad AA. Letter: Bone-marrow responses in polycythemia vera. N Engl J Med 1974;290:1382.
  • Tiedt R, Hao-Shen H, Sobas MA, . Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. Blood 2008;111:3931–3940.
  • Jamieson CH, Ailles LE, Dylla SJ, . Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 2004;351:657–667.
  • Hope KJ, Jin L, Dick JE. Human acute myeloid leukemia stem cells. Arch Med Res 2003;34:507–514.
  • Warner JK, Wang JC, Hope KJ, . Concepts of human leukemic development. Oncogene 2004;23:7164–7177.
  • Huntly BJ, Shigematsu H, Deguchi K, . MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell 2004;6:587–596.
  • Graham SM, Jorgensen HG, Allan E, . Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 2002;99:319–325.
  • Graham SM, Vass JK, Holyoake TL, . Transcriptional analysis of quiescent and proliferating CD34+ human hemopoietic cells from normal and chronic myeloid leukemia sources. Stem Cells 2007;25:3111–3120.
  • Bruns I, Czibere A, Fischer JC, . The hematopoietic stem cell in chronic phase CML is characterized by a transcriptional profile resembling normal myeloid progenitor cells and reflecting loss of quiescence. Leukemia 2009;23:892–899.
  • Benito R, Lumbreras E, Abaigar M, . Imatinib therapy of chronic myeloid leukemia restores the expression levels of key genes for DNA damage and cell-cycle progression. Pharmacogenet Genomics 2012;22:381–388.
  • Kuroda J, Puthalakath H, Cragg MS, . Bim and Bad mediate imatinib-induced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic. Proc Natl Acad Sci USA 2006;103:14907–14912.
  • Holyoake T, Jiang X, Eaves C, . Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. Blood 1999;94:2056–2064.
  • Hamilton A, Helgason GV, Schemionek M, . Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival. Blood 2012;119:1501–1510.
  • Holtz MS, Forman SJ, Bhatia R. Nonproliferating CML CD34+ progenitors are resistant to apoptosis induced by a wide range of proapoptotic stimuli. Leukemia 2005;19:1034–1041.
  • Ng KP, Hillmer AM, Chuah CT, . A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. Nat Med 2012;18:521–528.
  • Crews LA, Jamieson CH. Chronic myeloid leukemia stem cell biology. Curr Hematol Malig Rep 2012;7:125–132.
  • Dierks C, Beigi R, Guo GR, . Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell 2008;14:238–249.
  • Heidel FH, Bullinger L, Feng Z, . Genetic and pharmacologic inhibition of beta-catenin targets imatinib-resistant leukemia stem cells in CML. Cell Stem Cell 2012;10:412–424.
  • Kumano K, Arai S, Hosoi M, . Generation of induced pluripotent stem cells from primary chronic myelogenous leukemia patient samples. Blood 2012;119:6234–6242.
  • Ross DM, Hughes TP, Melo JV. Do we have to kill the last CML cell?Leukemia 2011;25:193–200.
  • Ross DM, Bartley PA, Goyne J, . Durable complete molecular remission of chronic myeloid leukemia following dasatinib cessation, despite adverse disease features. Haematologica 2011;96:1720–1722.
  • Mahon FX, Rea D, Guilhot J, . Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 2010;11(11): 1029–1035.
  • Mahon FX, Rea D, Guilhot J, . Discontinuation of imatinib in patients with chronic myeloid leukemia who have maintained complete molecular response: update results of the STIM study. Blood 2011;118(Suppl. 1): Abstract 603.
  • Capel B, Hawley RG, Mintz B. Long- and short-lived murine hematopoietic stem cell clones individually identified with retroviral integration markers. Blood 1990;75:2267–2270.
  • Drize NJ, Olshanskaya YV, Gerasimova LP, . Lifelong hematopoiesis in both reconstituted and sublethally irradiated mice is provided by multiple sequentially recruited stem cells. Exp Hematol 2001;29:786–794.
  • Cao YA, Wagers AJ, Beilhack A, . Shifting foci of hematopoiesis during reconstitution from single stem cells. Proc Natl Acad Sci USA 2004;101:221–226.
  • Laukkanen MO, Kuramoto K, Calmels B, . Low-dose total body irradiation causes clonal fluctuation of primate hematopoietic stem and progenitor cells. Blood 2005;105:1010–1015.
  • Radich JP, Gooley T, Bryant E, . The significance of bcr-abl molecular detection in chronic myeloid leukemia patients “late,” 18 months or more after transplantation. Blood 2001;98: 1701–1707.
  • Palandri F, Castagnetti F, Iacobucci I, . The response to imatinib and interferon-alpha is more rapid than the response to imatinib alone: a retrospective analysis of 495 Philadelphia-positive chronic myeloid leukemia patients in early chronic phase. Haematologica 2010;95:1415–1419.
  • Simonsson B, Gedde-Dahl T, Markevarn B, . Combination of pegylated IFN-alpha2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia. Blood 2011;118:3228–3235.
  • Preudhomme C, Guilhot J, Nicolini FE, . Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med 2010;363:2511–2521.
  • Hehlmann R, Lauseker M, Jung-Munkwitz S, . Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-alpha in newly diagnosed chronic myeloid leukemia. J Clin Oncol 2011;29:1634–1642.
  • Selleri C, Sato T, Del Vecchio L, . Involvement of Fas-mediated apoptosis in the inhibitory effects of interferon-alpha in chronic myelogenous leukemia. Blood 1997;89:957–964.
  • Burchert A, Muller MC, Kostrewa P, . Sustained molecular response with interferon alfa maintenance after induction therapy with imatinib plus interferon alfa in patients with chronic myeloid leukemia. J Clin Oncol 2010;28:1429–1435.
  • Kiladjian JJ, Cassinat B, Chevret S, . Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood 2008;112:3065–3072.
  • Quintas-Cardama A, Kantarjian H, Manshouri T, . Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol 2009;27:5418–5424.
  • Silver RT, Vandris K, Goldman JJ. Recombinant interferon-alpha may retard progression of early primary myelofibrosis:a preliminary report. Blood 2011;117:6669–6672.
  • Pasquier F, Tonetti C, Besancenot R, . Interferon-alpha preferentially targets JAK2V617F-positive rather than wild-type early progenitor cells in myeloproliferative disorders. Blood 2009;114(Suppl. 1): Abstract 436.
  • Lu M, Zhang W, Li Y . Interferon-alpha targets JAK2V617F-positive hematopoietic progenitor cells and acts through the p38 MAPK pathway. Exp Hematol 2010;38(6):472–480.
  • Lu M, Wang J, Li Y, . Treatment with the Bcl-xL inhibitor ABT-737 in combination with interferon alpha specifically targets JAK2V617F-positive polycythemia vera hematopoietic progenitor cells. Blood 2010;116:4284–4287.
  • Lu M, Wang X, Li Y, . Combination treatment in vitro with Nutlin, a small-molecule antagonist of MDM2, and pegylated interferon alpha 2a specifically targets JAK2V617F positive polycythemia vera cells. Blood 2012 Aug 7. [Epub ahead of print]
  • Marty C, Lacout C, Cuingnet M, . JAK2V617F promotes stem cell amplification driving MPN clonal dominance in mice and treatment by IFNa prevents this effect. Blood 2011;118(Suppl. 1): Abstract 616.
  • Zhang B, Strauss AC, Chu S, . Effective targeting of quiescent chronic myelogenous leukemia stem cells by histone deacetylase inhibitors in combination with imatinib mesylate. Cancer Cell 2010;17:427–442.
  • Li L, Wang L, Li L, . Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell 2012;21:266–281.
  • Verstovsek S, Kantarjian H, Mesa RA, . Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med 2010;363:1117–1127.
  • Pardanani A, Gotlib JR, Jamieson C, . Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol 2011;29:789–796.
  • Khwaja A. The role of Janus kinases in haemopoiesis and haematological malignancy. Br J Haematol 2006;134:366–384.
  • Tybulewicz VL, Crawford CE, Jackson PK, . Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell 1991;65:1153–1163.
  • Schwartzberg PL, Stall AM, Hardin JD, . Mice homozygous for the ablm1 mutation show poor viability and depletion of selected B and T cell populations. Cell 1991;65:1165–1175.
  • Kantarjian H, Sawyers C, Hochhaus A, . Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002;346:645–652.
  • Jabbour E, Kantarjian HM, O’Brien S, . Front-line therapy with second-generation tyrosine kinase inhibitors in patients with early chronic phase chronic myeloid leukemia: what is the optimal response?J Clin Oncol 2011;29:4260–4265.
  • Kantarjian HM, Shah NP, Cortes JE, . Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia:2-year follow-up from a randomized phase 3 trial (DASISION). Blood 2012;119:1123–1129.
  • Marubayashi S, Koppikar P, Taldone T, . HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans. J Clin Invest 2010;120:3578–3593.
  • Bareng J, Jilani I, Gorre M, . A potential role for HSP90 inhibitors in the treatment of JAK2 mutant-positive diseases as demonstrated using quantitative flow cytometry. Leuk Lymphoma 2007;48:2189–2195.
  • Wang Y, Fiskus W, Chong DG, . Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells. Blood 2009;114:5024–5033.
  • Proia DA, Foley KP, Korbut T, . Multifaceted intervention by the Hsp90 inhibitor ganetespib (STA-9090) in cancer cells with activated JAK/STAT signaling. PLoS One 2011;6:e18552.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.