Hypoxia inducible factor-1α and leukemic cell differentiation

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CHEN Guo-Qiang()
PENG Zhen-Gang()
LIU Wei()
SONG Li-Ping()
HUANG Ying()
ZHAO Qian()
Journal Title:
Volume 58, Issue 01, 2006
Key Word:
leukemia;hypoxia inducible factor-1;CCAAT/enhancer-binding protein-α;arsenic trioxide;differentiation

Abstract: Arsenic trioxide (As2O3, ATO) is a recently developed drug for the effective treatment of acute promyelocytic leukemia (APL). Experimental studies showed that in vitro differentiation-inducing ability on APL cells of this drug is not significant compared with its in vivo activity. We unexpectedly found recently that hypoxia-mimetic agents and moderate real hypoxia triggered acute myeloid leukemic cells to undergo differentiation. Furthermore, intermittent hypoxia significantly prolonged the survival of the transplanted leukemic mice with inhibition of infiltration and induction of differentiation of leukemic cells. In the following works,molecular mechanisms of hypoxia-induced differentiation were investigated and some interesting results have been obtained. This review will shortly summarize the related progresses and discuss the questions remained to be further investigated.

  • [1]Xie H,Ye M,Feng R,Graf T.Stepwise reprogramming of B cells into macrophages.Cell 2004; 117(5):663-676.
  • [2]Scandura JM,Boccuni P,Cammenga J,Nimer SD.Transcription factor fusions in acute leukemia:variations on a theme.Oncogene 2002; 21(21):3422-3444.
  • [3]Melnick A,Licht JD.Deconstructing a disease:RARalpha,its fusion partners,and their roles in the pathogenesis of acute promyelocytic leukemia.Blood 1999; 93(10):3167-3215.
  • [4]Huang ME,Ye YC,Chen SR,Chai JR,Lu JX,Zhoa L,Gu LJ,Wang ZY.Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia.Blood 1988; 72(2):567-572.
  • [5]Lo Coco F,Nervi C,Avvisati G,Mandelli F.Acute promyelocytic leukemia:a curable disease.Leukemia 1998; 12(12):1866-1880.
  • [6]Chen GQ,Shen ZX,Wu F,Han JY,Miao JM,Zhong HJ,Li XS,Zhao JQ,Zhu J,Fang ZW,Chen S J,Chen Z,Wang ZY.Pharmacokinetics and efficacy of low-dose all-trans retinoic acid in the treatment of acute promyelocytic leukemia.Leukemia 1996; 10(5):825-828.
  • [7]Sun HD (孙鸿德),Hu XC,Zhang TD.Treatment of acute promyelocytic leukemia by Al-1 therapy.Chin J Integrat Chin Trad Med Western Med (中国中西医结合杂志) 1992; 12(8):170-172 (Chinese).
  • [8]ShenZX,ChenGQ,NiJH,LiXS,XiongSM,QiuQY,ZhuJ,Tang W,Sun GL,Yang KQ,Chen Y,Zhou L,Fang ZW,Wang YT,Ma J,Zhang P,Zhang TD,Chen S J,Chen Z,Wang ZY.Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL):Ⅱ.Clinical efficacy and pharmacokinetics in relapsed patients.Blood 1997; 89(9):3354-3360.
  • [9]Chen GQ,Zhu J,Shi XG,Ni JH,Zhong HJ,Si GY,Jin XL,Tang W,Li XS,Xong SM,Shen ZX,Sun GL,Ma J,Zhang P,Zhang TD,Gazin C,Naoe T,Chen S J,Wang ZY,Chen Z.In vitro studies on cellular and molecular mechanisms of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia:As2O3 induces NB4 cell apoptosis with downregulation of Bcl-2 expression and modulation of PML-RAR alpha/PML proteins.Blood 1996; 88(3):1052-1061.
  • [10]Zhang TD,Chen GQ,Wang ZG,Wang ZY,Chen SJ,Chen Z.Arsenic trioxide,a therapeutic agent for APL.Oncogene 2001; 20(49):7146-7153.
  • [11]Chen GQ,Wang Q,Yah H,Chen Z.Arsenic trioxide and leukemia:from bedside to bench.In:Zhang LX,Demain AL.eds.Natural Products:Drug Discovery and Therapeutic Medicine.New Jersy:Humana Press Inc.,2005,245-266.
  • [12]Chen GQ,Shi XG,Tang W,Xiong SM,Zhu J,Cai X,Han ZG,Ni JH,Shi GY,Jia PM,Liu MM,He KL,Niu C,Ma J,Zhang P,Zhang TD,Paul P,Naoe T,Kitamura K,Miller W,Waxman S,Wang ZY,de The H,Chen S J,Chen Z.Use of arsenic trioxide(As2O3) in the treatment of acute promyelocytic leukemia (APL):I.As2O3 exerts dose-dependent dual effects on APL cells.Blood 1997; 89(9):3345-3353.
  • [13]Soignet SL,Maslak P,Wang ZG,Jhanwar S,Calleja E,Dardashti LJ,Corso D,DeBlasio A,Gabrilove J,Scheinberg DA,Pandolfi PP,Warrell RP Jr.Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide.N Engl J Med 1998;339(19):1341-1348.
  • [14]Lallemand-Breitenbach V,Guillemin MC,Janin A,Daniel MT,Degos L,Kogan SC,Bishop JM,de The H.Retinoic acid and arsenic synergize to eradicate leukemic cells in a mouse model of acute promyelocytic leukemia.J Exp Med 1999; 189(7):1043-1052.
  • [15]Kinjo K,Kizaki M,Muto A,Fukuchi Y,Umezawa A,Yamato K,Nishihara T,Hata J,Ito M,Ueyama Y,Ikeda Y.Arsenic trioxide (As2O3)-induced apoptosis and differentiation in retinoic acidresistant acute promyelocytic leukemia model in hGM-CSF-producing transgenic SCID mice.Leukemia 2000; 14(3):431-438.
  • [16]Cai X,Shen YL,Zhu Q,Jia PM,Yu Y,Zhou L,Huang Y,Zhang JW,Xiong SM,Chen S J,Wang ZY,Chen Z,Chen GQ.Arsenic trioxide-induced apoptosis and differentiation are associated respectively with mitochondrial transmembrane potential collapse and retinoic acid signaling pathways in acute promyelocytic leukemia.Leukemia 2000; 14(2):262-270.
  • [17]Chen GQ,Zhou L,Styblo M,Walton F,Jing Y,Weinberg R,Chen Z,Waxman S.Methylated metabolites of arsenic trioxide are more potent than arsenic trioxide as apoptotic but not differentiation inducers in leukemia and lymphoma cells.Cancer Res 2003;63(8):1853-1859.
  • [18]Jiang G,Bi K,Tang T,Zhang Y,Ren H,Jiang F,Ren Q,Zhen G,Liu C,Peng J,Guo G,Liu X,Tian Z.Effect of arsenic trioxide on cytokine expression by acute promyelocytic leukemia cells.Chin Med J (Engl) 2003; 116:1639-1643.
  • [19]Chelbi-alix MK,Bobe P,Benoit G,Canova A,Pine R.Arsenic enhances the activation of Stat1 by interferon gamma leading to synergistic expression of IRF-1.Oncogene 2003; 22(57):9121-9130.
  • [20]Zhu Q,Zhang JW,Zhu HQ,Shen YL,Flexor M,Jia PM,Yu Y,Cai X,Waxman S,Lanotte M,Chen S J,Chen Z,Tong JH.Synergic effects of arsenic trioxide and cAMP during acute promyelocytic leukemia cell maturation subtends a novel signaling cross-talk.Blood 2002; 99(3):1014-1022.
  • [21]Jensen PO,Mortensen BT,Hodgkiss RJ,Iversen PO,Christensen IJ,Helledie N,Larsen JK.Increased cellular hypoxia and reduced proliferation of both normal and leukaemic cells during progression of acute myeloid leukaemia in rats.Cell Prolif 2000; 33(6):381-395.
  • [22]Hussong JW,Rodgers GM,Shami PJ.Evidence of increased angiogenesis in patients with acute myeloid leukemia.Blood 2000;95(1):309-313.
  • [23]Padro T,Ruiz S,Bieker R,Burger H,Steins M,Kienast J,Buchner T,Berdel WE,Mesters RM.Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia.Blood 2000; 95(8):2637-2644.
  • [24]Di Raimondo F,Palumbo GA,Molica S,Giustolisi R.Angiogenesis in chronic myeloproliferative diseases.Acta Haemato12001;106(4):177-183.
  • [25]Kini AR,Peterson LA,Tallman MS,Lingen MW.Angiogenesis in acute promyelocytic leukemia:induction by vascular endothelial growth factor and inhibition by all-trans retinoic acid.Blood2001; 97(12):3919-3924.
  • [26]Roboz GJ,Dias S,Lam G,Lane WJ,Soignet SL,Warrell RP Jr,Rafii S.Arsenic trioxide induces dose-and time-dependent apoptosis of endothelium and may exert an antileukemic effect via inhibition of angiogenesis.Blood 2000; 96(4):1525-1530.
  • [27]Ivanovic Z,Dello Sbarba P,Trimoreau F,Faucher JL,Praloran V.Primitive human HPCs are better maintained and expanded in vitro at 1 percent oxygen than at 20 percent.Transfusion 2000;40(12):1482-1488.
  • [28]Desplat V,Faucher JL,Mahon FX,Dello Sbarba P,Praloran V,Ivanovic Z.Hypoxia modifies proliferation and differentiation of CD34+ CML cells.Stem Cells 2002; 20(4):347-354.
  • [29]Huang Y,Du KM,Xue ZH,Yan H,Li D,Liu W,Chen Z,Zhao Q,Tong JH,Zhu YS,Chen GQ.Cobalt chloride and low oxygen tension trigger differentiation of acute myeloid leukemic cells:possible mediation of hypoxia-inducible factor-1 alpha.Leukemia 2003; 17(11):2065-2073.
  • [30]Jiang Y,Xue ZH,Shen WZ,Du KM,Yan H,Yu Y,Peng ZG,Song MG,Tong JH,Chen Z,Huang Y,Lubbert M,Chen GQ.Desferrioxamine induces leukemic cell differentiation potentially by hypoxia-inducible factor-1 alpha that augments transcriptional activity of CCAAT/enhancer-binding protein-alpha.Leukemia 2005; 19(7):1239-1247.
  • [31]Guo M,Song LP,Jiang Y,Liu W,Yu Y,Chen GQ.Hypoxiamimetic agents desferrioxamine and cobalt chloride induce leukemic cell apoptosis through different hypoxia-inducible factor-1 alpha independent mechanisms.Apoptosis 2006; 11(1):67-77.
  • [32]Liu W,Guo M,Xu YB,Dao L,Zhou ZN,Wu YL,Chen Z,Kogan SC,Chen GQ.Induction of tumor arrest and differentiation with prolonged survival by intermittent hypoxia in a mouse model of acute myeloid leukemia.Blood 2006; 107(2):698-907.
  • [33]Semenza GL.Targeting HIF-1 for cancer therapy.Nat Rev Cancer2003; 3(10):721-732.
  • [34]Xue ZH,Jiang Y,Yu Y,Wang LS,Chen GQ,Zhao Q.Metavanadate suppresses desferrioxamine-induced leukemic cell differentiation with reduced hypoxia-inducible factor-lalpha protein.Biochem Biophys Res Commun 2005; 332(4):1140-1145.
  • [35]Rapisarda A,Uranchimeg B,Scudiero DA,Selby M,Sausville EA,Shoemaker RH,Melillo G.Identification of small molecule inhibitors of hypoxia-inducible factor 1 transcriptional activation pathway.Cancer Res 2002; 62(15):4316-4324.
  • [36]Song MG,Gao SM,Du KM,Xu M,Yu Y,Zhou YH,Wang Q,Chen Z,Zhu YS,Chen GQ.Nanomolar concentration of NSC606985,a camptothecin analog,induces leukemic-cell apoptosis through protein kinase C delta-dependent mechanisms.Blood 2005; 105(9):3714-3721.
  • [37]Zhao KW,Li X,Zhao Q,Huang Y,Peng ZG,Shen WZ,Ji Zhao,Zhou Q,Chen Z,Sims PJ,Wiedmer T,Chen GQ.Protein kinase Cδ mediates retinoic acid and phorbol myristate acetate-induced phospholipid scramblase 1 gene expression:its role in leukemic cell differentiation.Blood 2004; 104(12):3731-3738.
  • [38]Zhao KW,Li D,Zhao Q,Huang Y,Silverman RH,Sims PJ,Chen GQ.Interferon-alpha induced expression of phospholipid scramblase 1 through STAT1 required the sequential activation of protein kinase Cdelta & JNK.J Biol Chem 2005; 280(52):42707-42714.
  • [39]Radomska HS,Huettner CS,Zhang P,Cheng T,Scadden DT,Tenen DG.CCAAT/enhancer binding protein alpha is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors.Mol Cell Biol 1998; 18(7):4301-4314.
  • [40]Pabst T,Mueller BU,Harakawa N,Schoch C,Haferlach T,Behre G,Hiddemann W,Zhang DE,Tenen DG.AML1-ETO downregulates the granulocytic differentiation factor C/EBPalpha in t(8;21) myeloid leukemia.Nat Med 2001; 7(4):444-451.
  • [41]Westendorf JJ,Yamamoto CM,Lenny N,Downing JR,Selsted ME,Hiebert SW.The t(8;21) fusion product,AML-1-ETO,associates with C/EBP-α,inhibits C/EBP-α-dependent transcription,and blocks granulocytic differentiation.Mol Cell Biol 1998; 18(1):322-333.
  • [42]Yan H,Peng ZG,Wu YL,Jiang Y,Yu Y,Huang Y,Chen Z,Zhu YS,Zhao Q,Chen GQ.Hypoxia-simulating agents and selective stimulation of arsenic trioxide-induced growth arrest and cell differentiation in acute promyelocytic leukemlic cells.Haematologica 2005; 90(12):1607-1616.
  • [43]Suda T,Takakura N,Oike Y.Hematopoiesis and angiogenesis.Int J Hematol2000; 71(2):99-107.
  • [44]Ribatti D,Vacca A,Nico B,Crivellato E,de Falco G,Presta M.Cross talk between haematopoiesis and angiogenesis.Adv Exp Med Biol2003; 522:25-36.
  • [45]Adelman DM,Maltepe E,Simon MC.HIF-1 is essential for multilineage hematopoiesis in the embryo.Adv Exp Med Biol 2000; 475:275-284.
  • [46]Maltepe E,Krampitz GW,Okazaki KM,Red-Horse K,Mak W,Simon MC,Fisher SJ.Hypoxia-inducible factor-dependent histone deacetylase activity determines stem cell fate in the placenta.Development 2005; 132(15):3393-3403.
  • [47]Koshiji M,Kageyama Y,Pete EA,Horikawa I,Barrett JC,Huang LE.HIF-1α induces cell cycle arrest by functionally counteracting Myc.Embo J 2004; 23(9):1949-1956.
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