Effect of hypoxia-inducible factors in normal and leukemic stem cell regulation and their potential therapeutic impact

References

• Carreau A, El Hafny-Rahbi B, Matejuk A, et al.. Why is the partial oxygen pressure of human tissues a crucial parameter? Small molecules and hypoxia. J Cell Mol Med. 2011;15(6):1239–1253. doi:10.1111/j.1582-4934.2011.01258.x.
   PubMed Web of Science ®Google Scholar
• Giuntoli S, Rovida E, Gozzini A, et al.. Severe hypoxia defines heterogeneity and selects highly immature progenitors within clonal erythroleukemia cells. Stem Cells. 2007;25(5):1119–1125. doi:10.1634/stemcells.2006-0637.
   PubMed Web of Science ®Google Scholar
• Kubota Y, Takubo K, Suda T. Bone marrow long label-retaining cells reside in the sinusoidal hypoxic niche. Biochem Biophys Res Commun. 2008;366(2):335–339.
   PubMed Web of Science ®Google Scholar
• Levesque JP, Winkler IG, Hendy J, et al. Hematopoietic progenitor cell mobilization results in hypoxia with increased hypoxia-inducible transcription factor-1 alpha and vascular endothelial growth factor A in bone marrow. Stem Cells. 2007;25(8):1954–1965.
   PubMed Web of Science ®Google Scholar
• Parmar K, Mauch P, Vergilio JA, et al.. Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc Natl Acad Sci U S A. 2007;104(13):5431–5436.
   PubMed Web of Science ®Google Scholar
• Shima H, Takubo K, Tago N, et al. Acquisition of G(0) state by CD34-positive cord blood cells after bone marrow transplantation. Exp Hematol. 2010;38(12):1231–1240.
   PubMed Web of Science ®Google Scholar
• Lo Celso C, Fleming HE, Wu JW, et al. Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche. Nature. 2009;457(7225):92–96.
   PubMed Web of Science ®Google Scholar
• Suda T, Takubo K, Semenza GL. Metabolic regulation of hematopoietic stem cells in the hypoxic niche. Cell Stem Cell. 2011;9(4):298–310.
   PubMed Web of Science ®Google Scholar
• Xie Y, Yin T, Wiegraebe W, et al. Detection of functional haematopoietic stem cell niche using real-time imaging. Nature. 2009;457(7225):97–101.
   PubMed Web of Science ®Google Scholar
• Semenza GL. HIF-1 inhibitors for cancer therapy: from gene expression to drug discovery. Curr Pharm Des. 2009;15(33):3839–3843.
   PubMed Web of Science ®Google Scholar
• Kirito K, Kaushansky K. Thrombopoietin stimulates vascular endothelial cell growth factor (VEGF) production in hematopoietic stem cells. Cell Cycle. 2005;4(12):1729–1731.
   PubMed Web of Science ®Google Scholar
• Pedersen M, Löfstedt T, Sun J, et al.. Stem cell factor induces HIF-1alpha at normoxia in hematopoietic cells. Biochem Biophys Res Commun. 2008;377(1):98–103. doi:10.1016/j.bbrc.2008.09.102.
   PubMed Web of Science ®Google Scholar
• Gordan JD, Thompson CB, Simon MC. HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell. 2007;12(2):108–113. doi:10.1016/j.ccr.2007.07.006.
   PubMed Web of Science ®Google Scholar
• Keith B, Johnson RS, Simon MC. HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer. 2012;12(1):9–22.
   Web of Science ®Google Scholar
• Koh MY, Powis G. Passing the baton: the HIF switch. Trends Biochem Sci. 2012;37(9):364–372. doi:10.1016/j.tibs.2012.06.004.
   PubMed Web of Science ®Google Scholar
• Ryan HE, Lo J, Johnson RS. HIF-1 alpha is required for solid tumor formation and embryonic vascularization. Embo J. 1998;17(11):3005–3015. DOI:10.1093/emboj/17.11.3005.
   PubMed Web of Science ®Google Scholar
• Adelman DM, Maltepe E, Simon MC. Multilineage embryonic hematopoiesis requires hypoxic ARNT activity. Genes Dev. 1999;13(19):2478–2483. DOI:10.1101/gad.13.19.2478.
   PubMed Web of Science ®Google Scholar
• Scortegagna M, Ding K, Oktay Y, et al.. Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1-/- mice. Nat Genet. 2003;35(4):331–340. DOI:10.1038/ng1266.
   PubMed Web of Science ®Google Scholar
• Scortegagna M, Morris MA, Oktay Y, et al.. The HIF family member EPAS1/HIF-2alpha is required for normal hematopoiesis in mice. Blood. 2003;102(5):1634–1640. doi:10.1182/blood-2003-02-0448.
   PubMed Web of Science ®Google Scholar
• Imanirad P, Solaimani Kartalaei P, Crisan M, et al.. HIF1α is a regulator of hematopoietic progenitor and stem cell development in hypoxic sites of the mouse embryo. Stem Cell Res. 2014;12(1):24–35. DOI:10.1016/j.scr.2013.09.006.
   PubMed Web of Science ®Google Scholar
• Simsek T, Kocabas F, Zheng J, et al.. The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell. 2010;7(3):380–390. DOI:10.1016/j.stem.2010.07.011.
   PubMed Web of Science ®Google Scholar
• Takubo K, Goda N, Yamada W, et al.. Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell. 2010;7(3):391–402.
   PubMed Web of Science ®Google Scholar
• Krock BL, Eisinger-Mathason TS, Giannoukos DN, et al.. The aryl hydrocarbon receptor nuclear translocator is an essential regulator of murine hematopoietic stem cell viability. Blood. 2015;125(21):3263–3272.
   PubMed Web of Science ®Google Scholar
• Kranc KR, Schepers H, Rodrigues NP, et al. Cited2 is an essential regulator of adult hematopoietic stem cells. Cell Stem Cell. 2009;5(6):659–665.
   PubMed Web of Science ®Google Scholar
• Miharada K, Karlsson G, Rehn M, et al. Cripto regulates hematopoietic stem cells as a hypoxic-niche-related factor through cell surface receptor GRP78. Cell Stem Cell. 2011;9(4):330–344.
   PubMed Web of Science ®Google Scholar
• Forristal CE, Nowlan B, Jacobsen RN, et al. HIF-1alpha is required for hematopoietic stem cell mobilization and 4-prolyl hydroxylase inhibitors enhance mobilization by stabilizing HIF-1alpha. Leukemia. 2015;29(6):1366–1378.
   PubMed Web of Science ®Google Scholar
• Speth JM, Hoggatt J, Singh P, et al.. Pharmacologic increase in HIF1alpha enhances hematopoietic stem and progenitor homing and engraftment. Blood. 2014;123(2):203–207.
   PubMed Web of Science ®Google Scholar
• Pietras A, Hansford LM, Johnsson AS, et al. HIF-2alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells. Proc Natl Acad Sci U S A. 2009;106(39):16805–16810.
   PubMed Web of Science ®Google Scholar
• Gruber M, Hu CJ, Johnson RS, et al.. Acute postnatal ablation of Hif-2alpha results in anemia. Proc Natl Acad Sci U S A. 2007;104(7):2301–2306.
   PubMed Web of Science ®Google Scholar
• Li Z, Bao S, Wu Q, et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell. 2009;15(6):501–513.
   PubMed Web of Science ®Google Scholar
• Qing G, Simon MC. Hypoxia inducible factor-2alpha: a critical mediator of aggressive tumor phenotypes. Curr Opin Genet Dev. 2009;19(1):60–66.
   PubMed Web of Science ®Google Scholar
• Guitart AV, Subramani C, Armesilla-Diaz A, et al. Hif-2alpha is not essential for cell-autonomous hematopoietic stem cell maintenance. Blood. 2013;122(10):1741–1745.
   PubMed Web of Science ®Google Scholar
• Danet GH, Pan Y, Luongo JL, et al.. Expansion of human SCID-repopulating cells under hypoxic conditions. J Clin Invest. 2003;112(1):126–135.
   PubMed Web of Science ®Google Scholar
• Piccoli C, D’Aprile A, Ripoli M, et al. The hypoxia-inducible factor is stabilized in circulating hematopoietic stem cells under normoxic conditions. FEBS Lett. 2007;581(16):3111–3119.
   PubMed Web of Science ®Google Scholar
• Hermitte F, Brunet De La Grange P, Belloc F, et al.. Very low O2 concentration (0.1%) favors G0 return of dividing CD34+ cells. Stem Cells. 2006;24(1):65–73.
   PubMed Web of Science ®Google Scholar
• Rouault-Pierre K, Lopez-Onieva L, Foster K, et al.. HIF-2alpha protects human hematopoietic stem/progenitors and acute myeloid leukemic cells from apoptosis induced by endoplasmic reticulum stress. Cell Stem Cell. 2013;13(5):549–563.
   PubMed Web of Science ®Google Scholar
• Kaelin WG Jr., Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008;30(4):393–402.
   PubMed Web of Science ®Google Scholar
• Zhang H, Li H, Xi HS, et al.. HIF1alpha is required for survival maintenance of chronic myeloid leukemia stem cells. Blood. 2012;119(11):2595–2607.
   PubMed Web of Science ®Google Scholar
• Ghosh AK, Shanafelt TD, Cimmino A, et al. Aberrant regulation of pVHL levels by microRNA promotes the HIF/VEGF axis in CLL B cells. Blood. 2009;113(22):5568–5574.
   PubMed Web of Science ®Google Scholar
• Shachar I, Cohen S, Marom A, et al.. Regulation of CLL survival by hypoxia-inducible factor and its target genes. FEBS Lett. 2012;586(18):2906–2910.
   PubMed Web of Science ®Google Scholar
• Giambra V, Jenkins CE, Lam SH, et al. Leukemia stem cells in T-ALL require active Hif1alpha and Wnt signaling. Blood. 2015;125(25):3917–3927.
   PubMed Web of Science ®Google Scholar
• Martin SK, Diamond P, Gronthos S, et al.. The emerging role of hypoxia, HIF-1 and HIF-2 in multiple myeloma. Leukemia. 2011;25(10):1533–1542.
   PubMed Web of Science ®Google Scholar
• Storti P, Bolzoni M, Donofrio G, et al. Hypoxia-inducible factor (HIF)-1alpha suppression in myeloma cells blocks tumoral growth in vivo inhibiting angiogenesis and bone destruction. Leukemia. 2013;27(8):1697–1706.
   PubMed Web of Science ®Google Scholar
• Chiche J, Pommier S, Beneteau M, et al. GAPDH enhances the aggressiveness and the vascularization of non-Hodgkin’s B lymphomas via NF-kappaB-dependent induction of HIF-1alpha. Leukemia. 2015;29(5):1163–1176.
   PubMed Web of Science ®Google Scholar
• Evens AM, Sehn LH, Farinha P, et al. Hypoxia-inducible factor-1 {alpha} expression predicts superior survival in patients with diffuse large B-cell lymphoma treated with R-CHOP. J Clinic Oncol: Official J Am Soc Clin Oncol. 2010;28(6):1017–1024.
   PubMed Web of Science ®Google Scholar
• Coltella N, Percio S, Valsecchi R, et al. HIF factors cooperate with PML-RARalpha to promote acute promyelocytic leukemia progression and relapse. EMBO Mol Med. 2014;6(5):640–650.
   PubMed Web of Science ®Google Scholar
• Velasco-Hernandez T, Hyrenius-Wittsten A, Rehn M, et al.. HIF-1alpha can act as a tumor suppressor gene in murine acute myeloid leukemia. Blood. 2014;124(24):3597–3607.
   PubMed Web of Science ®Google Scholar
• Velasco-Hernandez T, Tornero D, Cammenga J. Loss of HIF-1alpha accelerates murine FLT-3-induced myeloproliferative neoplasia. Leukemia. 2015 Jun 24;29(12):2366–2374.
   PubMed Web of Science ®Google Scholar
• Wang Y, Liu Y, Malek SN, et al.. Targeting HIF1alpha eliminates cancer stem cells in hematological malignancies. Cell Stem Cell. 2011;8(4):399–411.
   PubMed Web of Science ®Google Scholar
• Yonekura S, Itoh M, Okuhashi Y, et al. Effects of the HIF1 inhibitor, echinomycin, on growth and NOTCH signalling in leukaemia cells. Anticancer Res. 2013;33(8):3099–3103.
   PubMed Web of Science ®Google Scholar
• Taussig DC, Vargaftig J, Miraki-Moud F, et al. Leukemia-initiating cells from some acute myeloid leukemia patients with mutated nucleophosmin reside in the CD34(-) fraction. Blood. 2010;115(10):1976–1984.
   PubMed Web of Science ®Google Scholar
• Semenza GL. Involvement of oxygen-sensing pathways in physiologic and pathologic erythropoiesis. Blood. 2009;114(10):2015–2019.
   PubMed Web of Science ®Google Scholar
• Percy MJ, Furlow PW, Lucas GS, et al. A gain-of-function mutation in the HIF2A gene in familial erythrocytosis. The. N Engl J Med. 2008;358(2):162–168.
   PubMed Web of Science ®Google Scholar
• Ang SO, Chen H, Hirota K, et al. Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nat Genet. 2002;32(4):614–621.
   PubMed Web of Science ®Google Scholar
• Hickey MM, Lam JC, Bezman NA, et al.. von Hippel-Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2alpha signaling and splenic erythropoiesis. J Clin Invest. 2007;117(12):3879–3889.
   PubMed Web of Science ®Google Scholar
• James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434(7037):1144–1148.
   PubMed Web of Science ®Google Scholar
• Fatrai S, Wierenga AT, Daenen SM, et al.. Identification of HIF2alpha as an important STAT5 target gene in human hematopoietic stem cells. Blood. 2011;117(12):3320–3330.
   PubMed Web of Science ®Google Scholar
• Giatromanolaki A, Koukourakis MI, Pezzella F, et al. Lactate dehydrogenase 5 expression in non-Hodgkin B-cell lymphomas is associated with hypoxia regulated proteins. Leuk Lymphoma. 2008;49(11):2181–2186.
   PubMed Web of Science ®Google Scholar
• Giatromanolaki A, Koukourakis MI, Pezzella F, et al. Phosphorylated VEGFR2/KDR receptors are widely expressed in B-cell non-Hodgkin’s lymphomas and correlate with hypoxia inducible factor activation. Hematol Oncol. 2008;26(4):219–224.
   PubMed Web of Science ®Google Scholar
• Martin SK, Diamond P, Williams SA, et al. Hypoxia-inducible factor-2 is a novel regulator of aberrant CXCL12 expression in multiple myeloma plasma cells. Haematologica. 2010;95(5):776–784.
   PubMed Web of Science ®Google Scholar
• Forristal CE, Brown AL, Helwani FM, et al.. Hypoxia inducible factor (HIF)-2alpha accelerates disease progression in mouse models of leukemia and lymphoma but is not a poor prognosis factor in human AML. Leukemia. 2015 Apr 29;29(10):2075–2085.
   PubMed Web of Science ®Google Scholar
• Lachance G, Uniacke J, Audas TE, et al. DNMT3a epigenetic program regulates the HIF-2alpha oxygen-sensing pathway and the cellular response to hypoxia. Proc Natl Acad Sci U S A. 2014;111(21):7783–7788.
   PubMed Web of Science ®Google Scholar
• Shlush LI, Zandi S, Mitchell A, et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature. 2014;506(7488):328–333.
   PubMed Web of Science ®Google Scholar
• Tatum JL, Kelloff GJ, Gillies RJ, et al. Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy. Int J Radiat Biol. 2006;82(10):699–757.
   PubMed Web of Science ®Google Scholar
• Wilson A, Trumpp A. Bone-marrow haematopoietic-stem-cell niches. Nat Reviews Immunol. 2006;6(2):93–106.
   PubMed Web of Science ®Google Scholar
• Kiani AA, Abdi J, Halabian R, et al. Over expression of HIF-1alpha in human mesenchymal stem cells increases their supportive functions for hematopoietic stem cells in an experimental co-culture model. Hematology. 2014;19(2):85–98.
   PubMed Web of Science ®Google Scholar
• Huang Y, Lei L, Liu D, et al. Normal glucose uptake in the brain and heart requires an endothelial cell-specific HIF-1alpha-dependent function. Proc Natl Acad Sci U S A. 2012;109(43):17478–17483.
   PubMed Web of Science ®Google Scholar
• Yamashita T, Ohneda K, Nagano M, et al. Hypoxia-inducible transcription factor-2alpha in endothelial cells regulates tumor neovascularization through activation of ephrin A1. J Biol Chem. 2008;283(27):18926–18936.
   PubMed Web of Science ®Google Scholar
• Rankin EB, Wu C, Khatri R, et al. The HIF signaling pathway in osteoblasts directly modulates erythropoiesis through the production of EPO. Cell. 2012;149(1):63–74.
   PubMed Web of Science ®Google Scholar
• Raaijmakers MH, Mukherjee S, Guo S, et al. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature. 2010;464(7290):852–857.
   PubMed Web of Science ®Google Scholar
• Benito J, Shi Y, Szymanska B, et al. Pronounced hypoxia in models of murine and human leukemia: high efficacy of hypoxia-activated prodrug PR-104. PLoS One. 2011;6(8):e23108.
   PubMed Web of Science ®Google Scholar
• Mohle R, Schittenhelm M, Failenschmid C, et al. Functional response of leukaemic blasts to stromal cell-derived factor-1 correlates with preferential expression of the chemokine receptor CXCR4 in acute myelomonocytic and lymphoblastic leukaemia. Br J Haematol. 2000;110(3):563–572.
   PubMed Web of Science ®Google Scholar
• Hu J, Handisides DR, Van Valckenborgh E, et al. Targeting the multiple myeloma hypoxic niche with TH-302, a hypoxia-activated prodrug. Blood. 2010;116(9):1524–1527.
   PubMed Web of Science ®Google Scholar
• Colla S, Storti P, Donofrio G, et al. Low bone marrow oxygen tension and hypoxia-inducible factor-1alpha overexpression characterize patients with multiple myeloma: role on the transcriptional and proangiogenic profiles of CD138(+) cells. Leukemia. 2010;24(11):1967–1970.
   PubMed Web of Science ®Google Scholar
• Giatromanolaki A, Bai M, Margaritis D, et al. Hypoxia and activated VEGF/receptor pathway in multiple myeloma. Anticancer Res. 2010;30(7):2831–2836.
   PubMed Web of Science ®Google Scholar
• Azab AK, Hu J, Quang P, et al. Hypoxia promotes dissemination of multiple myeloma through acquisition of epithelial to mesenchymal transition-like features. Blood. 2012;119(24):5782–5794.
   PubMed Web of Science ®Google Scholar
• Passam FH, Alexandrakis MG, Kafousi M, et al. Histological expression of angiogenic factors: VEGF, PDGFRalpha, and HIF-1alpha in Hodgkin lymphoma. Pathol Res Pract. 2009;205(1):11–20.
   PubMed Web of Science ®Google Scholar
• Evens AM, Schumacker PT, Helenowski IB, et al. Hypoxia inducible factor-alpha activation in lymphoma and relationship to the thioredoxin family. Br J Haematol. 2008;141(5):676–680.
   PubMed Web of Science ®Google Scholar
• Argyriou P, Papageorgiou SG, Panteleon V, et al. Hypoxia-inducible factors in mantle cell lymphoma: implication for an activated mTORC1–>HIF-1alpha pathway. Ann Hematol. 2011;90(3):315–322.
   PubMed Web of Science ®Google Scholar
• Tong H, Hu C, Zhuang Z, et al.. Hypoxia-inducible factor-1alpha expression indicates poor prognosis in myelodysplastic syndromes. Leuk Lymphoma. 2012;53(12):2412–2418.
   PubMed Web of Science ®Google Scholar
• Deeb G, Vaughan MM, McInnis I, et al. Hypoxia-inducible factor-1alpha protein expression is associated with poor survival in normal karyotype adult acute myeloid leukemia. Leuk Res. 2011;35(5):579–584.
   PubMed Web of Science ®Google Scholar
• Koczula KM, Ludwig C, Hayden R, et al.. Metabolic plasticity in CLL: adaptation to the hypoxic niche. Leukemia. 2016;30(1):65–73. DOI:10.1038/leu.2015.187.
   PubMed Web of Science ®Google Scholar
• Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–676.
   PubMed Web of Science ®Google Scholar
• Minoia C, Quero C, Asselti M, et al. Changes in angiogenesis and hypoxia-inducible factor-1alpha protein expression in relapsed/refractory indolent non-Hodgkin lymphomas. Br J Haematol. 2013;163(5):640–645.
   PubMed Web of Science ®Google Scholar
• Korkolopoulou P, Apostolidou E, Pavlopoulos PM, et al. Prognostic evaluation of the microvascular network in myelodysplastic syndromes. Leukemia. 2001;15(9):1369–1376.
   PubMed Web of Science ®Google Scholar
• Koomagi R, Zintl F, Sauerbrey A, et al.. Vascular endothelial growth factor in newly diagnosed and recurrent childhood acute lymphoblastic leukemia as measured by real-time quantitative polymerase chain reaction. Clin Cancer Res. 2001;7(11):3381–3384.
   PubMed Web of Science ®Google Scholar
• Hussong JW, Rodgers GM, Shami PJ. Evidence of increased angiogenesis in patients with acute myeloid leukemia. Blood. 2000;95(1):309–313.
   PubMed Web of Science ®Google Scholar
• Dong-Feng Z, Ting L, Cheng C, et al. Silencing HIF-1alpha reduces the adhesion and secretion functions of acute leukemia hBMSCs. Braz J Med Biol Res. 2012;45(10):906–912.
   PubMed Web of Science ®Google Scholar
• Tadokoro H, Umezu T, Ohyashiki K, et al.. Exosomes derived from hypoxic leukemia cells enhance tube formation in endothelial cells. J Biol Chem. 2013;288(48):34343–34351.
   PubMed Web of Science ®Google Scholar
• Fiegl M, Samudio I, Clise-Dwyer K, et al.. CXCR4 expression and biologic activity in acute myeloid leukemia are dependent on oxygen partial pressure. Blood. 2009;113(7):1504–1512.
   PubMed Web of Science ®Google Scholar
• Iriuchishima H, Takubo K, Miyakawa Y, et al. Neovascular niche for human myeloma cells in immunodeficient mouse bone. PLoS One. 2012;7(2):e30557.
   PubMed Web of Science ®Google Scholar
• Kawano Y, Kikukawa Y, Fujiwara S, et al. Hypoxia reduces CD138 expression and induces an immature and stem cell-like transcriptional program in myeloma cells. Int J Oncol. 2013;43(6):1809–1816.
   PubMed Web of Science ®Google Scholar
• Hernandez-Luna MA, Rocha-Zavaleta L, Vega MI, et al.. Hypoxia inducible factor-1alpha induces chemoresistance phenotype in non-Hodgkin lymphoma cell line via up-regulation of Bcl-xL. Leuk Lymphoma. 2013;54(5):1048–1055.
   PubMed Web of Science ®Google Scholar
• Matsunaga T, Imataki O, Torii E, et al. Elevated HIF-1alpha expression of acute myelogenous leukemia stem cells in the endosteal hypoxic zone may be a cause of minimal residual disease in bone marrow after chemotherapy. Leuk Res. 2012;36(6):e122–4.
   PubMed Web of Science ®Google Scholar
• Frolova O, Samudio I, Benito JM, et al. Regulation of HIF-1alpha signaling and chemoresistance in acute lymphocytic leukemia under hypoxic conditions of the bone marrow microenvironment. Cancer Biol Ther. 2012;13(10):858–870.
   PubMed Web of Science ®Google Scholar
• Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nat Rev Cancer. 2011;11(6):393–410.
   PubMed Web of Science ®Google Scholar
• Denny WA. Hypoxia-activated prodrugs in cancer therapy: progress to the clinic. Future Oncol. 2010;6(3):419–428.
   PubMed Web of Science ®Google Scholar
• Denny WA. The role of hypoxia-activated prodrugs in cancer therapy. Lancet Oncol. 2000;1(1):25–29.
   PubMedGoogle Scholar
• Meng F, Evans JW, Bhupathi D, et al. Molecular and cellular pharmacology of the hypoxia-activated prodrug TH-302. Mol Cancer Ther. 2012;11(3):740–751.
   PubMed Web of Science ®Google Scholar
• Hu J, Van Valckenborgh E, Xu D, et al.. Synergistic induction of apoptosis in multiple myeloma cells by bortezomib and hypoxia-activated prodrug TH-302, in vivo and in vitro. Mol Cancer Ther. 2013;12(9):1763–1773. doi:10.1158/1535-7163.MCT-13-0123.
   PubMed Web of Science ®Google Scholar
• Portwood S, Lal D, Hsu Y-C, et al.. Activity of the hypoxia-activated prodrug, TH-302, in preclinical human acute myeloid leukemia models. Clin Cancer Res. 2013;19(23):6506–6519. doi:10.1158/1078-0432.CCR-13-0674.
   PubMed Web of Science ®Google Scholar
• Konopleva M. Phase I study of TH-302, a hypoxia-activated cytotoxic prodrug, in subjects with advanced leukemias. ASCO Annual Meeting: J Clin Oncol. suppl; abstr 6585 2012.
   Google Scholar
• Singleton RS, Guise CP, Ferry DM, et al.. DNA cross-links in human tumor cells exposed to the prodrug PR-104A: relationships to hypoxia, bioreductive metabolism, and cytotoxicity. Cancer Res. 2009;69(9):3884–3891. doi:10.1158/0008-5472.CAN-08-4023.
   PubMed Web of Science ®Google Scholar
• Konopleva M, Thall PF, Yi CA, et al.. Phase I/II study of the hypoxia-activated prodrug PR104 in refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia. Haematologica. 2015;100(7):927–934. DOI:10.3324/haematol.2014.118455.
   PubMed Web of Science ®Google Scholar
• Patterson LH. Bioreductively activated antitumor N-oxides: the case of AQ4N, a unique approach to hypoxia-activated cancer chemotherapy. Drug Metab Rev. 2002;34(3):581–592. doi:10.1081/DMR-120005659.
   PubMed Web of Science ®Google Scholar
• Chen Y, Jacamo R, Shi YX, et al.. Human extramedullary bone marrow in mice: a novel in vivo model of genetically controlled hematopoietic microenvironment. Blood. 2012;119(21):4971–4980. DOI:10.1182/blood-2011-11-389957.
   PubMed Web of Science ®Google Scholar
• Borsi E, Perrone G, Terragna C, et al.. HIF-1α inhibition blocks the cross talk between multiple myeloma plasma cells and tumor microenvironment. Exp Cell Res. 2014;328(2):444–455. doi:10.1016/j.yexcr.2014.09.018.
   PubMed Web of Science ®Google Scholar
• Koh MY, Spivak-Kroizman T, Venturini S, et al.. Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1alpha. Mol Cancer Ther. 2008;7(1):90–100. doi:10.1158/1535-7163.MCT-07-0463.
   PubMed Web of Science ®Google Scholar