Advances in Clinical and Experimental Medicine
2018, vol. 27, nr 2, February, p. 271–275
Publication type: review article
The role of hypoxia-inducible factors in leukemias
1 Department of Hematology, Wroclaw Medical University, Poland
Hypoxia, understood as low partial oxygen pressure, has become one of the most explored fields in recent years. Cellular response to hypoxia is mediated by hypoxia-inducible factors (HIFs) – potent transcription regulators, and their downstream pathways. In general, HIFs modify energy metabolism, inflammation and immune response, enhance cancer invasion, metastasis, resistance to treatment, and relapse. The influence of HIFs on the progression of leukemia is still under investigation in various studies, but in mice and some human models HIFs have been recognized as leukemia immortalizers by promoting leukemic stem cell quiescence and inhibiting their cell cycle. This makes leukemic stem cells resistant to most known treatment approaches. The role of HIFs in solid tumors and leukemia makes them almost ideal targets for an anticancer treatment. Although the first attempts with new molecules are encouraging, there is a need to investigate the ambiguous role of HIFs to develop a modern antileukemic treatment.
leukemia, hypoxia, hypoxia-inducible factor-1
- Jiang BH, Semenza GL, Bauer C, Marti HH. Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am J Physiol. 1996;271:C1172–C1180.
- McNamee EN, Korns Johnson D, Homann D, Clambey ET. Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function. Immunol Res. 2013;55:58–70.
- Parks SK, Cormerais Y, Marchiq I, Pouyssegur J. Hypoxia optimises tumour growth by controlling nutrient import and acidic metabolite export. Mol Aspects Med. 2016;47–48:3–14.
- Courtnay R, Ngo DC, Malik N, Ververis K, Tortorella SM, Karagiannis TC. Cancer metabolism and the Warburg effect: The role of HIF-1 and PI3K. Mol Biol Rep. 2015;42:841–51.
- Semenza GL. Oxygen sensing, homeostasis, and disease. N Engl J Med. 2011;365:537–547.
- Otrock ZK, Hatoum HA, Awada AH, Ishak RS, Shamseddine AI. Hypoxia-inducible factor in cancer angiogenesis: Structure, regulation and clinical perspectives. Crit Rev Oncol Hematol. 2009;70:93–102.
- Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene. 2010;29:625–634.
- Semenza GL. Regulation of cancer cell metabolism by hypoxia-inducible factor 1. Semin Cancer Biol. 2009;19:12–16.
- Semenza GL. Hypoxia-inducible factors: Mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci. 2012;33:207–214.
- Dang EV, Barbi J, Yang HY, et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell. 2011;146:772–784.
- Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC. Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol. 2003;23:9361–9374.
- Imtiyaz HZ, Williams EP, Hickey MM, et al. Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation. J Clin Invest. 2010;120:2699–2714.
- Talks KL, Turley H, Gatter KC, et al. The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol. 2000;157:411–421.
- Haase VH. Hypoxic regulation of erythropoiesis and iron metabolism. Am J Physiol Renal Physiol. 2010;299:F1–13.
- Franke K, Gassmann M, Wielockx B. Erythrocytosis: The HIF pathway in control. Blood. 2013;122:1122–1128.
- Ito K, Suda T. Metabolic requirements for the maintenance of self-renewing stem cells. Nat Rev Mol Cell Biol. 2014;15:243–256.
- Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995;92:5510–5514.
- Semenza GL, Agani F, Booth G, et al. Structural and functional analysis of hypoxia-inducible factor 1. Kidney Int. 1997;51:553–555.
- Tian H, McKnight SL, Russell DW. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev. 1997;11:72–82.
- Yang SL, Wu C, Xiong ZF, Fang X. Progress on hypoxia-inducible factor-3: Its structure, gene regulation and biological function (Review). Mol Med Rep. 2015;12:2411–2416.
- Huang LE, Gu J, Schau M, Bunn HF. Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci U S A. 1998;95:7987–7992.
- Majmundar AJ, Wong WJ, Simon MC. Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell. 2010;40:294–309.
- Greer SN, Metcalf JL, Wang Y, Ohh M. The updated biology of hypoxia-inducible factor. EMBO J. 2012;31:2448–2460.
- Zhong H, Chiles K, Feldser D, et al. Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: Implications for tumor angiogenesis and therapeutics. Cancer Res. 2000;60:1541–1545.
- Klatte T, Seligson DB, Riggs SB, et al. Hypoxia-inducible factor 1 alpha in clear cell renal cell carcinoma. Clin Cancer Res. 2007;13:7388–7393.
- Dai CX, Gao Q, Qiu SJ, et al. Hypoxia-inducible factor-1 alpha, in association with inflammation, angiogenesis and MYC, is a critical prognostic factor in patients with HCC after surgery. BMC Cancer. 2009;9:418.
- Rajaganeshan R, Prasad R, Guillou PJ, Poston G, Scott N, Jayne DG. The role of hypoxia in recurrence following resection of Dukes’ B colorectal cancer. Int J Colorectal Dis. 2008;23:1049–1055.
- D’Ignazio L, Bandarra D, Rocha S. NF-κB and HIF crosstalk in immune responses. FEBS J. 2016;283:413–424.
- Han S, Xu W, Wang Z, et al. Crosstalk between the HIF-1 and Toll-like receptor/nuclear factor-κB pathways in the oral squamous cell carcinoma microenvironment. Oncotarget. 2016;7:37773–37789.
- Chen C, Pore N, Behrooz A, Ismail-Beigi F, Maity A. Regulation of glut1 mRNA by hypoxia-inducible factor-1. Interaction between H-ras and hypoxia. J Biol Chem. 2001;276:9519–9525.
- Semenza GL, Roth PH, Fang HM, Wang GL. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem. 1994;269:23757–23763.
- Ryan HE, Lo J, Johnson RS. HIF-1 alpha is required for solid tumor formation and embryonic vascularization. EMBO J. 1998;17:3005–3015.
- Takubo K, Goda N, Yamada W, et al. Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell. 2010;7:391–402.
- Zhang H, Li H, Xi HS, Li S. HIF1α is required for survival maintenance of chronic myeloid leukemia stem cells. Blood. 2012;119:2595–2607.
- Forristal CE, Brown AL, Helwani FM, et al. Hypoxia inducible factor (HIF)-2α accelerates disease progression in mouse models of leukemia and lymphoma but is not a poor prognosis factor in human AML. Leukemia. 2015;29:2075–2085.
- Guitart AV, Subramani C, Armesilla-Diaz A, et al. Hif-2α is not essential for cell-autonomous hematopoietic stem cell maintenance. Blood. 2013;122:1741–1745.
- Fatrai S, Wierenga AT, Daenen SM, Vellenga E, Schuringa JJ. Identification of HIF2alpha as an important STAT5 target gene in human hematopoietic stem cells. Blood. 2011;117:3320–3330.
- Zou J, Li P, Lu F, et al. Notch1 is required for hypoxia-induced proliferation, invasion and chemoresistance of T-cell acute lymphoblastic leukemia cells. J Hematol Oncol. 2013;6:3.
- Kawada H, Kaneko M, Sawanobori M, et al. High concentrations of L-ascorbic acid specifically inhibit the growth of human leukemic cells via downregulation of HIF-1α transcription. PloS One. 2013;8:e62717.
- Wang Y, Liu Y, Malek SN, Zheng P, Liu Y. Targeting HIF1α eliminates cancer stem cells in hematological malignancies. Cell Stem Cell. 2011;8:399–411.
- Rankin EB, Biju MP, Liu Q, et al. Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J Clin Invest. 2007;117:1068–1177.
- Keith B, Johnson RS, Simon MC. HIF1α and HIF2α: Sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer. 2011;12: 9–22.
- Schepers K, Campbell TB, Passegue E. Normal and leukemic stem cell niches: Insights and therapeutic opportunities. Cell Stem Cell. 2015;16:254–267.
- Tabe Y, Konopleva M. Advances in understanding the leukaemia microenvironment. Br J Haematol. 2014;164:767–778.
- Deynoux M, Sunter N, Herault O, Mazurier F. Hypoxia and hypoxia-inducible factors in leukemias. Front Oncol. 2016;6:41.
- Chow DC, Wenning LA, Miller WM, Papoutsakis ET. Modeling pO(2) distributions in the bone marrow hematopoietic compartment.Krogh’s model. Biophys J. 2001;81:675–684.
- Semenza GL. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Invest. 2013;123:3664–3671.
- Semenza GL. Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1. Biochem J. 2007;405:1–9.
- Mimeault M, Batra SK. Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells. J Cell Mol Med. 2013;17:30–54.
- Deeb G, Vaughan MM, McInnis I, et al. Hypoxia-inducible factor-1α protein expression is associated with poor survival in normal karyotype adult acute myeloid leukemia. Leukemia Res. 2011;35:579–584.
- Song K, Li M, Xu XJ, et al. HIF-1α and GLUT1 gene expression is associated with chemoresistance of acute myeloid leukemia. Asian Pac J Cancer Prev. 2014;15:1823–1829.
- Tong H, Hu C, Zhuang Z, Wang L, Jin J. Hypoxia-inducible factor-1α expression indicates poor prognosis in myelodysplastic syndromes. Leuk Lymphoma. 2012;53:2412–2418.
- 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;7:380–390.
- Gao XN, Yan F, Lin J, et al. AML1/ETO cooperates with HIF1α to promote leukemogenesis through DNMT3a transactivation. Leukemia. 2015;29:1730–1740.
- Ng KP, Manjeri A, Lee KL, et al. Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition. Blood. 2014;123:3316–3326.
- Spinello I, Quaranta MT, Paolillo R, et al. Differential hypoxic regulation of the microRNA-146a/CXCR4 pathway in normal and leukemic monocytic cells: Impact on response to chemotherapy. Haematologica. 2015;100:1160–1171.
- Belmonte M, Hoofd C, Weng AP, Giambra V. Targeting leukemia stem cells: Which pathways drive self-renewal activity in T-cell acute lymphoblastic leukemia? Curr Oncol. 2016;23:34–41.
- Wang Y, Liu Y, Tang F, et al. Echinomycin protects mice against relapsed acute myeloid leukemia without adverse effect on hematopoietic stem cells. Blood. 2014;124:1127–1135.
- Coltella N, Valsecchi R, Ponente M, Ponzoni M, Bernardi R. Synergistic leukemia eradication by combined treatment with retinoic acid and HIF inhibition by EZN-2208 (PEG-SN38) in preclinical models of PML-RARα and PLZF-RARα-driven leukemia. Clin Cancer Res. 2015;21:3685–3694.
- Portwood S, Lal D, Hsu YC, et al. Activity of the hypoxia-activated prodrug, TH-302, in preclinical human acute myeloid leukemia models. Clin Cancer Res. 2013;19:6506–6519.