The Etiology of Acute Leukemia

  • Jessica N. Nichol
  • Sarit Assouline
  • Wilson H. Miller


Acute leukemia is characterized by a rapid increase and accumulation of immature hematopoietic cells. The resultant crowding of the bone marrow hinders production of healthy blood cells. As well, the malignant cells spill over into the bloodstream and can spread to other organs of the body. Acute leukemia is usually characterized by unchecked growth of the malignant cells and early death, if left untreated. Specifics concerning the clinical features and treatment of acute leukemia can be found elsewhere in this textbook. This chapter will focus on the molecular pathogenesis of acute leukemia.


Class I (activating) mutations Class II mutations Two-hit phenomenon Twin studies Leukemia stem cell Hematopoietic stem cells HSC differentiation Hierarchical model Stochastic model Stem cell niche Epigenetics DNA methylation CpG island Hypermethylation Histones Histone code Histone acetyltransferase) Histone ­­deacetylase Activating histone marks Repressive histone marks MicroRNAs Protein translation S6 kinase eIF4E 4E binding proteins Ribavirin Chromosomal abnormalities in acute leukemia Chromosome translocation Chromosome inversion Acute ­promyelocytic leukemia Reinoic acid receptor alpha Fusions in APL Core-binding ­factor leukemias RUNX1 CBFbeta RUNX1–CBFA2T1 (previously known as AML1–ETO) CBFB–MYH11 MLL fusions HOX genes MLL fusions partners Nuclear MLL fusions partners Cytoplasmic MLL fusion partners BCR–ABL ETV6–RUNX1 E2A fusions Gene mutations in acute leukemia FMS-like tyrosine kinas (FLT3) Nucleophosmin NPM cytoplasmic mutant Paired box protein 5 


  1. 1.
    Kelly LM, Gilliland DG. Genetics of myeloid leukemias. Annu Rev Genomics Hum Genet. 2002;3:179–98.PubMedCrossRefGoogle Scholar
  2. 2.
    Grisolano JL, Wesselschmidt RL, Pelicci PG, Ley TJ. Altered myeloid development and acute leukemia in transgenic mice expressing PML-RAR alpha under control of cathepsin G regulatory sequences. Blood. 1997;89(2):376–87.PubMedGoogle Scholar
  3. 3.
    Higuchi M, O’Brien D, Kumaravelu P, Lenny N, Yeoh EJ, Downing JR. Expression of a conditional AML1-ETO oncogene bypasses embryonic lethality and establishes a murine model of human t(8;21) acute myeloid leukemia. Cancer Cell. 2002;1(1):63–74.PubMedCrossRefGoogle Scholar
  4. 4.
    Castilla LH, Garrett L, Adya N, et al. The fusion gene Cbfb-MYH11 blocks myeloid differentiation and predisposes mice to acute myelomonocytic leukaemia. Nat Genet. 1999;23(2):144–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Wang J, Iwasaki H, Krivtsov A, et al. Conditional MLL-CBP targets GMP and models therapy-related myeloproliferative disease. EMBO J. 2005;24(2):368–81.PubMedCrossRefGoogle Scholar
  6. 6.
    Ford AM, Bennett CA, Price CM, Bruin MC, Van Wering ER, Greaves M. Fetal origins of the TEL-AML1 fusion gene in identical twins with leukemia. Proc Natl Acad Sci USA. 1998;95(8):4584–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Buckley JD, Buckley CM, Breslow NE, Draper GJ, Roberson PK, Mack TM. Concordance for childhood cancer in twins. Med Pediatr Oncol. 1996;26(4):223–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Wiemels JL, Cazzaniga G, Daniotti M, et al. Prenatal origin of acute lymphoblastic leukaemia in children. Lancet. 1999;354(9189):1499–503.PubMedCrossRefGoogle Scholar
  9. 9.
    Orlic D, Bodine DM. What defines a pluripotent hematopoietic stem cell (PHSC): will the real PHSC please stand up! Blood. 1994;84(12):3991–4.PubMedGoogle Scholar
  10. 10.
    Orkin SH. Diversification of haematopoietic stem cells to specific lineages. Nat Rev Genet. 2000;1(1):57–64.PubMedCrossRefGoogle Scholar
  11. 11.
    Fisher AG. Cellular identity and lineage choice. Nat Rev Immunol. 2002;2(12):977–82.PubMedCrossRefGoogle Scholar
  12. 12.
    Bonifer C, Lefevre P, Tagoh H. The regulation of chromatin and DNA-methylation patterns in blood cell development. Curr Top Microbiol Immunol. 2006;310:1–12.PubMedCrossRefGoogle Scholar
  13. 13.
    Fialkow PJ. Clonal origin of human tumors. Biochim Biophys Acta. 1976;458(3):283–321.PubMedGoogle Scholar
  14. 14.
    Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105–11.PubMedCrossRefGoogle Scholar
  15. 15.
    McCulloch EA. Stem cells in normal and leukemic hemopoiesis (Henry Stratton Lecture, 1982). Blood. 1983;62(1):1–13.PubMedGoogle Scholar
  16. 16.
    Griffin JD, Lowenberg B. Clonogenic cells in acute myeloblastic leukemia. Blood. 1986;68(6):1185–95.PubMedGoogle Scholar
  17. 17.
    Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367(6464):645–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Yuan Y, Zhou L, Miyamoto T, et al. AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations. Proc Natl Acad Sci USA. 2001;98(18):10398–403.PubMedCrossRefGoogle Scholar
  19. 19.
    Miyamoto T, Weissman IL, Akashi K. AML1/ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8;21 chromosomal translocation. Proc Natl Acad Sci USA. 2000;97(13):7521–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Hope KJ, Jin L, Dick JE. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol. 2004;5(7):738–43.PubMedCrossRefGoogle Scholar
  21. 21.
    Saito Y, Uchida N, Tanaka S, et al. Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML. Nat Biotechnol. 2010;28(3):275–80.PubMedGoogle Scholar
  22. 22.
    Lowenberg B, van Putten W, Theobald M, et al. Effect of priming with granulocyte colony-stimulating factor on the outcome of ­chemotherapy for acute myeloid leukemia. N Engl J Med. 2003;349(8):743–52.PubMedCrossRefGoogle Scholar
  23. 23.
    Nasr R, Guillemin MC, Ferhi O, et al. Eradication of acute ­promyelocytic leukemia-initiating cells through PML-RARA ­degradation. Nat Med. 2008;14(12):1333–42.PubMedCrossRefGoogle Scholar
  24. 24.
    Hendrich BD, Willard HF. Epigenetic regulation of gene expression: the effect of altered chromatin structure from yeast to mammals. Hum Mol Genet 1995;4 Spec No:1765–1777.Google Scholar
  25. 25.
    Galm O, Herman JG, Baylin SB. The fundamental role of epigenetics in hematopoietic malignancies. Blood Rev. 2006;20(1):1–13.PubMedCrossRefGoogle Scholar
  26. 26.
    Lanzuolo C, Orlando V. The function of the epigenome in cell reprogramming. Cell Mol Life Sci. 2007;64(9):1043–62.PubMedCrossRefGoogle Scholar
  27. 27.
    Feinberg AP, Vogelstein B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature. 1983;301(5895):89–92.PubMedCrossRefGoogle Scholar
  28. 28.
    Gama-Sosa MA, Slagel VA, Trewyn RW, et al. The 5-methylcytosine content of DNA from human tumors. Nucleic Acids Res. 1983;11(19):6883–94.PubMedCrossRefGoogle Scholar
  29. 29.
    Ehrlich M. DNA methylation in cancer: too much, but also too little. Oncogene. 2002;21(35):5400–13.PubMedCrossRefGoogle Scholar
  30. 30.
    Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003;349(21):2042–54.PubMedCrossRefGoogle Scholar
  31. 31.
    Fazi F, Zardo G, Gelmetti V, et al. Heterochromatic gene repression of the retinoic acid pathway in acute myeloid leukemia. Blood. 2007;109(10):4432–40.PubMedCrossRefGoogle Scholar
  32. 32.
    Bhaumik SR, Smith E, Shilatifard A. Covalent modifications of histones during development and disease pathogenesis. Nat Struct Mol Biol. 2007;14(11):1008–16.PubMedCrossRefGoogle Scholar
  33. 33.
    Jenuwein T, Allis CD. Translating the histone code. Science. 2001;293(5532):1074–80.PubMedCrossRefGoogle Scholar
  34. 34.
    Ellis L, Atadja PW, Johnstone RW. Epigenetics in cancer: targeting chromatin modifications. Mol Cancer Ther. 2009;8(6):1409–20.PubMedCrossRefGoogle Scholar
  35. 35.
    Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci USA. 2004;101(2):540–5.PubMedCrossRefGoogle Scholar
  36. 36.
    Murray K. The occurrence of Epsilon-N-methyl lysine in histones. Biochemistry. 1964;3:10–5.PubMedCrossRefGoogle Scholar
  37. 37.
    DeLange RJ, Fambrough DM, Smith EL, Bonner J. Calf and pea histone IV. II. The complete amino acid sequence of calf thymus histone IV; presence of epsilon-N-acetyllysine. J Biol Chem. 1969;244(2):319–34.PubMedGoogle Scholar
  38. 38.
    Patterson BD, Davies DD. Specificity of the enzymatic methylation of pea histone. Biochem Biophys Res Commun. 1969;34(6):791–4.PubMedCrossRefGoogle Scholar
  39. 39.
    Gershey EL, Haslett GW, Vidali G, Allfrey VG. Chemical studies of histone methylation. Evidence for the occurrence of 3-methylhistidine in avian erythrocyte histone fractions. J Biol Chem. 1969;244(18):4871–7.PubMedGoogle Scholar
  40. 40.
    Oki Y, Aoki E, Issa JP. Decitabine–bedside to bench. Crit Rev Oncol Hematol. 2007;61(2):140–52.PubMedCrossRefGoogle Scholar
  41. 41.
    Quintas-Cardama A, Santos FP, Garcia-Manero G. Therapy with azanucleosides for myelodysplastic syndromes. Nat Rev Clin Oncol. 2010;7(8):433–44.PubMedCrossRefGoogle Scholar
  42. 42.
    Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75(5):843–54.PubMedCrossRefGoogle Scholar
  43. 43.
    Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 2009;19(1):92–105.PubMedCrossRefGoogle Scholar
  44. 44.
    Liu CG, Calin GA, Meloon B, et al. An oligonucleotide microchip for genome-wide microRNA profiling in human and mouse tissues. Proc Natl Acad Sci USA. 2004;101(26):9740–4.PubMedCrossRefGoogle Scholar
  45. 45.
    Selbach M, Schwanhausser B, Thierfelder N, Fang Z, Khanin R, Rajewsky N. Widespread changes in protein synthesis induced by microRNAs. Nature. 2008;455(7209):58–63.PubMedCrossRefGoogle Scholar
  46. 46.
    Li Z, Lu J, Sun M, et al. Distinct microRNA expression profiles in acute myeloid leukemia with common translocations. Proc Natl Acad Sci USA. 2008;105(40):15535–40.PubMedCrossRefGoogle Scholar
  47. 47.
    Mi S, Li Z, Chen P, et al. Aberrant overexpression and function of the miR-17-92 cluster in MLL-rearranged acute leukemia. Proc Natl Acad Sci USA. 2010;107(8):3710–5.PubMedCrossRefGoogle Scholar
  48. 48.
    O’Connell RM, Rao DS, Chaudhuri AA, et al. Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder. J Exp Med. 2008;205(3):585–94.PubMedCrossRefGoogle Scholar
  49. 49.
    Popovic R, Riesbeck LE, Velu CS, et al. Regulation of mir-196b by MLL and its overexpression by MLL fusions contributes to immortalization. Blood. 2009;113(14):3314–22.PubMedCrossRefGoogle Scholar
  50. 50.
    Johnson SM, Grosshans H, Shingara J, et al. RAS is regulated by the let-7 microRNA family. Cell. 2005;120(5):635–47.PubMedCrossRefGoogle Scholar
  51. 51.
    Mayr C, Hemann MT, Bartel DP. Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science. 2007;315(5818):1576–9.PubMedCrossRefGoogle Scholar
  52. 52.
    Jongen-Lavrencic M, Sun SM, Dijkstra MK, Valk PJ, Lowenberg B. MicroRNA expression profiling in relation to the genetic heterogeneity of acute myeloid leukemia. Blood. 2008;111(10):5078–85.PubMedCrossRefGoogle Scholar
  53. 53.
    Garzon R, Pichiorri F, Palumbo T, et al. MicroRNA gene expression during retinoic acid-induced differentiation of human acute promyelocytic leukemia. Oncogene. 2007;26(28):4148–57.PubMedCrossRefGoogle Scholar
  54. 54.
    Slack FJ, Basson M, Liu Z, Ambros V, Horvitz HR, Ruvkun G. The lin-41 RBCC gene acts in the C. elegans heterochronic pathway between the let-7 regulatory RNA and the LIN-29 transcription factor. Mol Cell. 2000;5(4):659–69.PubMedCrossRefGoogle Scholar
  55. 55.
    Cheung VG, Conlin LK, Weber TM, et al. Natural variation in human gene expression assessed in lymphoblastoid cells. Nat Genet. 2003;33(3):422–5.PubMedCrossRefGoogle Scholar
  56. 56.
    Pianese G. Beitrag zur Histologie und Aetiologie der Carcinoma. Histologische und experimentelle Untersuchungen. Beitr Pathol Anat Allgem Pathol. 1896;142:1–193.Google Scholar
  57. 57.
    Pandolfi PP. Aberrant mRNA translation in cancer pathogenesis: an old concept revisited comes finally of age. Oncogene. 2004;23(18):3134–7.PubMedCrossRefGoogle Scholar
  58. 58.
    Graff JR, Konicek BW, Carter JH, Marcusson EG. Targeting the eukaryotic translation initiation factor 4E for cancer therapy. Cancer Res. 2008;68(3):631–4.PubMedCrossRefGoogle Scholar
  59. 59.
    Assouline S, Culjkovic B, Cocolakis E, et al. Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): a proof-of-principle clinical trial with ribavirin. Blood. 2009;114(2):257–60.PubMedCrossRefGoogle Scholar
  60. 60.
    de The H, Lavau C, Marchio A, Chomienne C, Degos L, Dejean A. The PML-RAR alpha fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell. 1991;66(4):675–84.PubMedCrossRefGoogle Scholar
  61. 61.
    Kakizuka A, Miller Jr WH, Umesono K, et al. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. Cell. 1991;66(4):663–74.PubMedCrossRefGoogle Scholar
  62. 62.
    Fenaux P, Le Deley MC, Castaigne S, et al. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. European APL 91 Group. Blood. 1993;82(11):3241–9.PubMedGoogle Scholar
  63. 63.
    Pollock JL, Westervelt P, Kurichety AK, Pelicci PG, Grisolano JL, Ley TJ. A bcr-3 isoform of RARalpha-PML potentiates the development of PML-RARalpha-driven acute promyelocytic leukemia. Proc Natl Acad Sci USA. 1999;96(26):15103–8.PubMedCrossRefGoogle Scholar
  64. 64.
    He LZ, Bhaumik M, Tribioli C, et al. Two critical hits for promyelocytic leukemia. Mol Cell. 2000;6(5):1131–41.PubMedCrossRefGoogle Scholar
  65. 65.
    Sitterlin D, Tiollais P, Transy C. The RAR alpha-PLZF chimera associated with acute promyelocytic leukemia has retained a sequence-specific DNA-binding domain. Oncogene. 1997;14(9):1067–74.PubMedCrossRefGoogle Scholar
  66. 66.
    Mozziconacci MJ, Liberatore C, Brunel V, et al. In vitro response to all-trans retinoic acid of acute promyelocytic leukemias with nonreciprocal PML/RARA or RARA/PML fusion genes. Genes Chromosomes Cancer. 1998;22(3):241–50.PubMedCrossRefGoogle Scholar
  67. 67.
    Guidez F, Parks S, Wong H, et al. RARalpha-PLZF overcomes PLZF-mediated repression of CRABPI, contributing to retinoid resistance in t(11;17) acute promyelocytic leukemia. Proc Natl Acad Sci USA. 2007;104(47):18694–9.PubMedCrossRefGoogle Scholar
  68. 68.
    Ogawa E, Inuzuka M, Maruyama M, et al. Molecular cloning and characterization of PEBP2 beta, the heterodimeric partner of a novel Drosophila runt-related DNA binding protein PEBP2 alpha. Virology. 1993;194(1):314–31.PubMedCrossRefGoogle Scholar
  69. 69.
    Zhang DE, Fujioka K, Hetherington CJ, et al. Identification of a region which directs the monocytic activity of the colony-stimulating factor 1 (macrophage colony-stimulating factor) receptor promoter and binds PEBP2/CBF (AML1). Mol Cell Biol. 1994;14(12):8085–95.PubMedGoogle Scholar
  70. 70.
    Takahashi A, Satake M, Yamaguchi-Iwai Y, et al. Positive and negative regulation of granulocyte-macrophage colony-stimulating factor promoter activity by AML1-related transcription factor, PEBP2. Blood. 1995;86(2):607–16.PubMedGoogle Scholar
  71. 71.
    Nuchprayoon I, Meyers S, Scott LM, Suzow J, Hiebert S, Friedman AD. PEBP2/CBF, the murine homolog of the human myeloid AML1 and PEBP2 beta/CBF beta proto-oncoproteins, regulates the murine myeloperoxidase and neutrophil elastase genes in immature myeloid cells. Mol Cell Biol. 1994;14(8):5558–68.PubMedGoogle Scholar
  72. 72.
    Cameron S, Taylor DS, TePas EC, Speck NA, Mathey-Prevot B. Identification of a critical regulatory site in the human interleukin-3 promoter by in vivo footprinting. Blood. 1994;83(10):2851–9.PubMedGoogle Scholar
  73. 73.
    Erickson P, Gao J, Chang KS, et al. Identification of breakpoints in t(8;21) acute myelogenous leukemia and isolation of a fusion transcript, AML1/ETO, with similarity to Drosophila segmentation gene, runt. Blood. 1992;80(7):1825–31.PubMedGoogle Scholar
  74. 74.
    Wang J, Hoshino T, Redner RL, Kajigaya S, Liu JM. ETO, fusion partner in t(8;21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC1 complex. Proc Natl Acad Sci USA. 1998;95(18):10860–5.PubMedCrossRefGoogle Scholar
  75. 75.
    Lutterbach B, Westendorf JJ, Linggi B, et al. ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors. Mol Cell Biol. 1998;18(12):7176–84.PubMedGoogle Scholar
  76. 76.
    Gelmetti V, Zhang J, Fanelli M, Minucci S, Pelicci PG, Lazar MA. Aberrant recruitment of the nuclear receptor corepressor-histone deacetylase complex by the acute myeloid leukemia fusion partner ETO. Mol Cell Biol. 1998;18(12):7185–91.PubMedGoogle Scholar
  77. 77.
    Linggi B, Muller-Tidow C, van de Locht L, et al. The t(8;21) fusion protein, AML1 ETO, specifically represses the transcription of the p14(ARF) tumor suppressor in acute myeloid leukemia. Nat Med. 2002;8(7):743–50.PubMedCrossRefGoogle Scholar
  78. 78.
    Pabst T, Mueller BU, Harakawa N, et al. AML1-ETO downregulates the granulocytic differentiation factor C/EBPalpha in t(8;21) myeloid leukemia. Nat Med. 2001;7(4):444–51.PubMedCrossRefGoogle Scholar
  79. 79.
    Wang J, Saunthararajah Y, Redner RL, Liu JM. Inhibitors of ­histone deacetylase relieve ETO-mediated repression and induce differentiation of AML1-ETO leukemia cells. Cancer Res. 1999;59(12):2766–9.PubMedGoogle Scholar
  80. 80.
    Liu S, Shen T, Huynh L, et al. Interplay of RUNX1/MTG8 and DNA methyltransferase 1 in acute myeloid leukemia. Cancer Res. 2005;65(4):1277–84.PubMedCrossRefGoogle Scholar
  81. 81.
    Alcalay M, Meani N, Gelmetti V, et al. Acute myeloid leukemia fusion proteins deregulate genes involved in stem cell maintenance and DNA repair. J Clin Invest. 2003;112(11):1751–61.PubMedGoogle Scholar
  82. 82.
    Klampfer L, Zhang J, Zelenetz AO, Uchida H, Nimer SD. The AML1/ETO fusion protein activates transcription of BCL-2. Proc Natl Acad Sci USA. 1996;93(24):14059–64.PubMedCrossRefGoogle Scholar
  83. 83.
    Elagib KE, Goldfarb AN. Oncogenic pathways of AML1-ETO in acute myeloid leukemia: multifaceted manipulation of marrow maturation. Cancer Lett. 2007;251(2):179–86.PubMedCrossRefGoogle Scholar
  84. 84.
    Lessard J, Faubert A, Sauvageau G. Genetic programs regulating HSC specification, maintenance and expansion. Oncogene. 2004;23(43):7199–209.PubMedCrossRefGoogle Scholar
  85. 85.
    Vangala RK, Heiss-Neumann MS, Rangatia JS, et al. The myeloid master regulator transcription factor PU.1 is inactivated by AML1-ETO in t(8;21) myeloid leukemia. Blood. 2003;101(1):270–7.PubMedCrossRefGoogle Scholar
  86. 86.
    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-alpha, inhibits C/EBP-alpha-dependent transcription, and blocks granulocytic differentiation. Mol Cell Biol. 1998;18(1):322–33.PubMedGoogle Scholar
  87. 87.
    Choi Y, Elagib KE, Delehanty LL, Goldfarb AN. Erythroid inhibition by the leukemic fusion AML1-ETO is associated with impaired acetylation of the major erythroid transcription factor GATA-1. Cancer Res. 2006;66(6):2990–6.PubMedCrossRefGoogle Scholar
  88. 88.
    Zhang J, Kalkum M, Yamamura S, Chait BT, Roeder RG. E protein silencing by the leukemogenic AML1-ETO fusion protein. Science. 2004;305(5688):1286–9.PubMedCrossRefGoogle Scholar
  89. 89.
    Lukasik SM, Zhang L, Corpora T, et al. Altered affinity of CBF beta-SMMHC for Runx1 explains its role in leukemogenesis. Nat Struct Biol. 2002;9(9):674–9.PubMedCrossRefGoogle Scholar
  90. 90.
    Speck NA, Gilliland DG. Core-binding factors in haematopoiesis and leukaemia. Nat Rev Cancer. 2002;2(7):502–13.PubMedCrossRefGoogle Scholar
  91. 91.
    Helbling D, Mueller BU, Timchenko NA, et al. CBFB-SMMHC is correlated with increased calreticulin expression and suppresses the granulocytic differentiation factor CEBPA in AML with inv(16). Blood. 2005;106(4):1369–75.PubMedCrossRefGoogle Scholar
  92. 92.
    Hyde RK, Kamikubo Y, Anderson S, et al. Cbfb/Runx1 repression-independent blockage of differentiation and accumulation of Csf2rb-expressing cells by Cbfb-MYH11. Blood. 2010;115(7):1433–43.PubMedCrossRefGoogle Scholar
  93. 93.
    Guenther MG, Jenner RG, Chevalier B, et al. Global and Hox-specific roles for the MLL1 methyltransferase. Proc Natl Acad Sci USA. 2005;102(24):8603–8.PubMedCrossRefGoogle Scholar
  94. 94.
    Milne TA, Dou Y, Martin ME, Brock HW, Roeder RG, Hess JL. MLL associates specifically with a subset of transcriptionally active target genes. Proc Natl Acad Sci USA. 2005;102(41):14765–70.PubMedCrossRefGoogle Scholar
  95. 95.
    Milne TA, Briggs SD, Brock HW, et al. MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol Cell. 2002;10(5):1107–17.PubMedCrossRefGoogle Scholar
  96. 96.
    Dou Y, Hess JL. Mechanisms of transcriptional regulation by MLL and its disruption in acute leukemia. Int J Hematol. 2008;87(1):10–8.PubMedCrossRefGoogle Scholar
  97. 97.
    Krivtsov AV, Armstrong SA. MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer. 2007;7(11):823–33.PubMedCrossRefGoogle Scholar
  98. 98.
    Lavau C, Szilvassy SJ, Slany R, Cleary ML. Immortalization and leukemic transformation of a myelomonocytic precursor by retrovirally transduced HRX-ENL. EMBO J. 1997;16(14):4226–37.PubMedCrossRefGoogle Scholar
  99. 99.
    Slany RK, Lavau C, Cleary ML. The oncogenic capacity of HRX-ENL requires the transcriptional transactivation activity of ENL and the DNA binding motifs of HRX. Mol Cell Biol. 1998;18(1):122–9.PubMedGoogle Scholar
  100. 100.
    Zeisig BB, Milne T, Garcia-Cuellar MP, et al. Hoxa9 and Meis1 are key targets for MLL-ENL-mediated cellular immortalization. Mol Cell Biol. 2004;24(2):617–28.PubMedCrossRefGoogle Scholar
  101. 101.
    Kroon E, Krosl J, Thorsteinsdottir U, Baban S, Buchberg AM, Sauvageau G. Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b. EMBO J. 1998;17(13):3714–25.PubMedCrossRefGoogle Scholar
  102. 102.
    Sobulo OM, Borrow J, Tomek R, et al. MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid ­leukemia with a t(11;16)(q23;p13.3). Proc Natl Acad Sci USA. 1997;94(16):8732–7.PubMedCrossRefGoogle Scholar
  103. 103.
    Lavau C, Du C, Thirman M, Zeleznik-Le N. Chromatin-related properties of CBP fused to MLL generate a myelodysplastic-like syndrome that evolves into myeloid leukemia. EMBO J. 2000;19(17):4655–64.PubMedCrossRefGoogle Scholar
  104. 104.
    Bitoun E, Oliver PL, Davies KE. The mixed-lineage leukemia fusion partner AF4 stimulates RNA polymerase II transcriptional elongation and mediates coordinated chromatin remodeling. Hum Mol Genet. 2007;16(1):92–106.PubMedCrossRefGoogle Scholar
  105. 105.
    Schubeler D, MacAlpine DM, Scalzo D, et al. The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher eukaryote. Genes Dev. 2004;18(11):1263–71.PubMedCrossRefGoogle Scholar
  106. 106.
    Shilatifard A. Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression. Annu Rev Biochem. 2006;75:243–69.PubMedCrossRefGoogle Scholar
  107. 107.
    Dorrance AM, Liu S, Yuan W, et al. Mll partial tandem duplication induces aberrant Hox expression in vivo via specific epigenetic alterations. J Clin Invest. 2006;116(10):2707–16.PubMedCrossRefGoogle Scholar
  108. 108.
    Dobson CL, Warren AJ, Pannell R, Forster A, Rabbitts TH. Tumorigenesis in mice with a fusion of the leukaemia oncogene Mll and the bacterial lacZ gene. EMBO J. 2000;19(5):843–51.PubMedCrossRefGoogle Scholar
  109. 109.
    So CW, Lin M, Ayton PM, Chen EH, Cleary ML. Dimerization contributes to oncogenic activation of MLL chimeras in acute leukemias. Cancer Cell. 2003;4(2):99–110.PubMedCrossRefGoogle Scholar
  110. 110.
    Grabocka E, Wedegaertner PB. Disruption of oligomerization induces nucleocytoplasmic shuttling of leukemia-associated rho Guanine-nucleotide exchange factor. Mol Pharmacol. 2007;72(4):993–1002.PubMedCrossRefGoogle Scholar
  111. 111.
    Zhuang Y, Soriano P, Weintraub H. The helix-loop-helix gene E2A is required for B cell formation. Cell. 1994;79(5):875–84.PubMedCrossRefGoogle Scholar
  112. 112.
    Bain G, Maandag EC, Izon DJ, et al. E2A proteins are required for proper B cell development and initiation of immunoglobulin gene rearrangements. Cell. 1994;79(5):885–92.PubMedCrossRefGoogle Scholar
  113. 113.
    Murre C, McCaw PS, Vaessin H, et al. Interactions between heterologous helix-loop-helix proteins generate complexes that bind specifically to a common DNA sequence. Cell. 1989;58(3):537–44.PubMedCrossRefGoogle Scholar
  114. 114.
    Sigvardsson M, Clark DR, Fitzsimmons D, et al. Early B-cell ­factor, E2A, and Pax-5 cooperate to activate the early B cell-specific mb-1 promoter. Mol Cell Biol. 2002;22(24):8539–51.PubMedCrossRefGoogle Scholar
  115. 115.
    Sayegh CE, Quong MW, Agata Y, Murre C. E-proteins directly regulate expression of activation-induced deaminase in mature B cells. Nat Immunol. 2003;4(6):586–93.PubMedCrossRefGoogle Scholar
  116. 116.
    Kee BL, Murre C. Induction of early B cell factor (EBF) and multiple B lineage genes by the basic helix-loop-helix transcription factor E12. J Exp Med. 1998;188(4):699–713.PubMedCrossRefGoogle Scholar
  117. 117.
    Decker T, Pasca di Magliano M, McManus S, et al. Stepwise activation of enhancer and promoter regions of the B cell commitment gene Pax5 in early lymphopoiesis. Immunity. 2009;30(4):508–20.PubMedCrossRefGoogle Scholar
  118. 118.
    Carow CE, Levenstein M, Kaufmann SH, et al. Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias. Blood. 1996;87(3):1089–96.PubMedGoogle Scholar
  119. 119.
    Renneville A, Roumier C, Biggio V, et al. Cooperating gene mutations in acute myeloid leukemia: a review of the literature. Leukemia. 2008;22(5):915–31.PubMedCrossRefGoogle Scholar
  120. 120.
    Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358(18):1909–18.PubMedCrossRefGoogle Scholar
  121. 121.
    Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood. 2002;100(5):1532–42.PubMedCrossRefGoogle Scholar
  122. 122.
    Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer. 2003;3(9):650–65.PubMedCrossRefGoogle Scholar
  123. 123.
    Mackarehtschian K, Hardin JD, Moore KA, Boast S, Goff SP, Lemischka IR. Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors. Immunity. 1995;3(1):147–61.PubMedCrossRefGoogle Scholar
  124. 124.
    McKenna HJ, Stocking KL, Miller RE, et al. Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells. Blood. 2000;95(11):3489–97.PubMedGoogle Scholar
  125. 125.
    Griffith J, Black J, Faerman C, et al. The structural basis for ­autoinhibition of FLT3 by the juxtamembrane domain. Mol Cell. 2004;13(2):169–78.PubMedCrossRefGoogle Scholar
  126. 126.
    Small D. FLT3 mutations: biology and treatment. Hematology Am Soc Hematol Educ Program. 2006:178–184.Google Scholar
  127. 127.
    Kelly LM, Liu Q, Kutok JL, Williams IR, Boulton CL, Gilliland DG. FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model. Blood. 2002;99(1):310–8.PubMedCrossRefGoogle Scholar
  128. 128.
    Levis M, Murphy KM, Pham R, et al. Internal tandem duplications of the FLT3 gene are present in leukemia stem cells. Blood. 2005;106(2):673–80.PubMedCrossRefGoogle Scholar
  129. 129.
    Shih LY, Huang CF, Wu JH, et al. Internal tandem duplication of FLT3 in relapsed acute myeloid leukemia: a comparative analysis of bone marrow samples from 108 adult patients at diagnosis and relapse. Blood. 2002;100(7):2387–92.PubMedCrossRefGoogle Scholar
  130. 130.
    Shih LY, Huang CF, Wu JH, et al. Heterogeneous patterns of FLT3 Asp(835) mutations in relapsed de novo acute myeloid leukemia: a comparative analysis of 120 paired diagnostic and relapse bone marrow samples. Clin Cancer Res. 2004;10(4):1326–32.PubMedCrossRefGoogle Scholar
  131. 131.
    Falini B, Mecucci C, Tiacci E, et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005;352(3):254–66.PubMedCrossRefGoogle Scholar
  132. 132.
    Verhaak RG, Goudswaard CS, van Putten W, et al. Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood. 2005;106(12):3747–54.PubMedCrossRefGoogle Scholar
  133. 133.
    Thiede C, Koch S, Creutzig E, et al. Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood. 2006;107(10):4011–20.PubMedCrossRefGoogle Scholar
  134. 134.
    Colombo E, Marine JC, Danovi D, Falini B, Pelicci PG. Nucleophosmin regulates the stability and transcriptional activity of p53. Nat Cell Biol. 2002;4(7):529–33.PubMedCrossRefGoogle Scholar
  135. 135.
    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(11):1593–8.CrossRefGoogle Scholar
  136. 136.
    Grisendi S, Mecucci C, Falini B, Pandolfi PP. Nucleophosmin and cancer. Nat Rev Cancer. 2006;6(7):493–505.PubMedCrossRefGoogle Scholar
  137. 137.
    Cheng K, Grisendi S, Clohessy JG, et al. The leukemia-associated cytoplasmic nucleophosmin mutant is an oncogene with paradoxical functions: Arf inactivation and induction of cellular senescence. Oncogene. 2007;26(53):7391–400.PubMedCrossRefGoogle Scholar
  138. 138.
    Cheng K, Sportoletti P, Ito K, et al. The cytoplasmic NPM mutant induces myeloproliferation in a transgenic mouse model. Blood. 2010;115(16):3341–5.PubMedCrossRefGoogle Scholar
  139. 139.
    Leong SM, Tan BX, Bte Ahmad B, et al. Mutant nucleophosmin deregulates cell death and myeloid differentiation through excessive caspase-6 and -8 inhibition. Blood. 2010;116(17):3286–96.PubMedCrossRefGoogle Scholar
  140. 140.
    Nutt SL, Heavey B, Rolink AG, Busslinger M. Commitment to the B-lymphoid lineage depends on the transcription factor Pax5. Nature. 1999;401(6753):556–62.PubMedCrossRefGoogle Scholar
  141. 141.
    Urbanek P, Wang ZQ, Fetka I, Wagner EF, Busslinger M. Complete block of early B cell differentiation and altered patterning of the posterior midbrain in mice lacking Pax5/BSAP. Cell. 1994;79(5):901–12.PubMedCrossRefGoogle Scholar
  142. 142.
    Czerny T, Schaffner G, Busslinger M. DNA sequence recognition by Pax proteins: bipartite structure of the paired domain and its binding site. Genes Dev. 1993;7(10):2048–61.PubMedCrossRefGoogle Scholar
  143. 143.
    Kozmik Z, Wang S, Dorfler P, Adams B, Busslinger M. The promoter of the CD19 gene is a target for the B-cell-specific transcription factor BSAP. Mol Cell Biol. 1992;12(6):2662–72.PubMedGoogle Scholar
  144. 144.
    Zwollo P, Desiderio S. Specific recognition of the blk promoter by the B-lymphoid transcription factor B-cell-specific activator protein. J Biol Chem. 1994;269(21):15310–7.PubMedGoogle Scholar
  145. 145.
    Ying H, Healy JI, Goodnow CC, Parnes JR. Regulation of mouse CD72 gene expression during B lymphocyte development. J Immunol. 1998;161(9):4760–7.PubMedGoogle Scholar
  146. 146.
    Souabni A, Cobaleda C, Schebesta M, Busslinger M. Pax5 ­promotes B lymphopoiesis and blocks T cell development by repressing Notch1. Immunity. 2002;17(6):781–93.PubMedCrossRefGoogle Scholar
  147. 147.
    Holmes ML, Carotta S, Corcoran LM, Nutt SL. Repression of Flt3 by Pax5 is crucial for B-cell lineage commitment. Genes Dev. 2006;20(8):933–8.PubMedCrossRefGoogle Scholar
  148. 148.
    Mullighan CG, Goorha S, Radtke I, et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature. 2007;446(7137):758–64.PubMedCrossRefGoogle Scholar
  149. 149.
    Nutt SL, Vambrie S, Steinlein P, et al. Independent regulation of the two Pax5 alleles during B-cell development. Nat Genet. 1999;21(4):390–5.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Jessica N. Nichol
    • 1
  • Sarit Assouline
    • 1
    • 2
  • Wilson H. Miller
    • 1
    • 2
  1. 1.Division of Experimental Medicine, Segal Cancer Center, Lady Davis InstituteMcGill University Jewish General HospitalMontrealCanada
  2. 2.Department of Oncology, Segal Cancer Center, Lady Davis InstituteMcGill University Jewish General HospitalMontrealCanada

Personalised recommendations