Advertisement

Lineage-Specific Transcription Factor Aberrations in AML

  • Beatrice U. Mueller
  • Thomas Pabst
Chapter
Part of the Cancer Treatment and Research book series (CTAR, volume 145)

Abstract

Transcription factors play a key role in the commitment of hematopoietic stem cells to differentiate into specific lineages [78]. This is particularly important in that a block in terminal differentiation is the key contributing factor in acute leukemias. This general theme of the role of transcription factors in differentiation may also extend to other tissues, both in terms of normal development and cancer. Consistent with the role of transcription factors in hematopoietic lineage commitment is the frequent finding of aberrations in transcription factors in AML patients. Here, we intend to review recent findings on aberrations in lineage-restricted transcription factors as observed in patients with acute myeloid leukemia (AML).

Keywords

Acute Myeloid Leukemia Acute Promyelocytic Leukemia Acute Myeloid Leukemia Patient RUNX1 Gene Runt Domain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

Research grants: This work was supported by grants from the Swiss National Science Foundation SF 3100A0-100445 to B.U.M. and SF 310000-109388 to TP.We apologize to all authors whose contribution to the field could not be cited due to limitations in space.

References

  1. 1.
    Akashi K, Traver D, Miyamoto T, Weissman IL. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature. 2000;404:193–197.PubMedCrossRefGoogle Scholar
  2. 2.
    Avivi I, Rowe JM. Prognostic factors in acute myeloid leukemia. Curr Opin Hematol. 2005;12:62–67.PubMedCrossRefGoogle Scholar
  3. 3.
    Barjesteh van Waalwijk van Doorn-Khosrovani S, Erpelinck C, van Putten WL, et al. High EVI1 expression predicts poor survival in acute myeloid leukemia: a study of 319 de novo AML patients. Blood. 2003;101:837–845.CrossRefGoogle Scholar
  4. 4.
    Behre G, Singh SM, Liu H, et al. Ras signaling enhances the ability of CEBPA to induce granulocytic differentiation by phosphorylation of serine 248. J Biol Chem. 2002;277:26293–26299.PubMedCrossRefGoogle Scholar
  5. 5.
    Bienz M, Ludwig M, Mueller BU, et al. Risk assessment in patients with acute myeloid leukemia and a normal karyotype. Clin Cancer Res. 2005;11:1416–1425.PubMedCrossRefGoogle Scholar
  6. 6.
    Bullinger L, Dohner K, Bair E, et al. Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. N Engl J Med. 2004;350:1605–1616.PubMedCrossRefGoogle Scholar
  7. 7.
    Calligaris R, Bottardi S, Cogoi S, Apezteguia I, Santoro C. Alternative translation initiation site usage results in two functionally distinct forms of the GATA-1 transcription factor. Proc Natl Acad Sci USA. 1995;92:11598–11602.PubMedCrossRefGoogle Scholar
  8. 8.
    Chim CS, Wong ASY, Kwong YL. Infrequent hypermethylation of CEBPA promoter in acute myeloid leukaemia. Br J Haemat. 2002;119:988–990.CrossRefGoogle Scholar
  9. 9.
    Cook WD, McCaw BJ, Herring CD, et al. PU.1 is a suppressor of myeloid leukemia, inactivated in mice by gene deletion and mutation of its DNA-binding domain. Blood. 2004;104:3437–3444.PubMedCrossRefGoogle Scholar
  10. 10.
    Dahl R, Walsh JC, Lancki D, et al. Regulation of macrophage and neutrophil cell fates by the PU.1:C/EBPalpha ratio and granulocyte colony-stimulating factor. Nat Immunol. 2003;4:1029–1036.PubMedCrossRefGoogle Scholar
  11. 11.
    Dakic A, Metcalf D, Di Rago L, et al. Pu.1 regulates the commitment of adult hematopoietic progenitors and restricts granulopoiesis. J Exp Med. 2005;201:1487–1502.PubMedCrossRefGoogle Scholar
  12. 12.
    DeKoter RP, Singh H. Regulation of B lymphocyte and macrophage development by graded expression of PU.1 Science. 2000;288:1439–1441.PubMedCrossRefGoogle Scholar
  13. 13.
    Dohner K, Tobis K, Bischof T, et al. Mutation analysis of the transcription factor PU.1 in younger adults (16 to 60 years) with acute myeloid leukemia: a study of the AML Study Group Ulm (AMLSG ULM). Blood. 2002;100:4680–4681.CrossRefGoogle Scholar
  14. 14.
    Emambokus N, Vegiopoulos A, Haman B, et al. Progression through key stages of hematopoiesis is dependent on distinct threshold levels of c-myb. EMBO J. 2003;22;4478–4488.PubMedCrossRefGoogle Scholar
  15. 15.
    Falini B, Mecucci C, Tiacci E, et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005;352:254–266.PubMedCrossRefGoogle Scholar
  16. 16.
    Fröhling S, Schlenk RF, Krauter J. Acute myeloid leukemia with deletion 9q within a noncomplex karyotype is associated with CEBPA loss-of-function mutations. Genes Chrom Cancer. 2005;42:427–432.PubMedCrossRefGoogle Scholar
  17. 17.
    Fröhling S, Schlenk RF, Stolze I, et al. CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations. J Clin Oncol. 2004;22:624–633.PubMedCrossRefGoogle Scholar
  18. 18.
    Gilliland DG, Tallman MS. Focus on acute leukemias. Cancer Cell. 2002;1:417–420.PubMedCrossRefGoogle Scholar
  19. 19.
    Gombart AF, Hofmann WK, Kawano S, et al. Mutations in the gene encoding the transcription factor CCAAT/enhancer binding protein alpha in myelodysplastic syndromes and acute myeloid leukemias. Blood. 2002;99:1332–1340.PubMedCrossRefGoogle Scholar
  20. 20.
    Gurbuxani S, Vyas P, Crispino JD. Recent insights into the mechanisms of myeloid leukemogenesis in Down syndrome. Blood. 2004;103:399–406.PubMedCrossRefGoogle Scholar
  21. 21.
    Hall MA, Curtis DJ, Metcalf D. The critical regulator of embryonic hematopoiesis, SCL, is vital in the adult for megakaryopoiesis, erythropoiesis, and lineage choice in CFU-S12. Proc Natl Acad Sci USA. 2003;100:992–997.PubMedCrossRefGoogle Scholar
  22. 22.
    Harada H, Harada Y, Niimi H, Kyo T, Kimura A, Inaba T. High incidence of somatic mutations in the AML1/RUNX1 gene in myelodysplastic syndrome and low blast percentage myeloid leukemia with myelodysplasia. Blood. 2004;103:2316–2324.PubMedCrossRefGoogle Scholar
  23. 23.
    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;106:1369–1375.PubMedCrossRefGoogle Scholar
  24. 24.
    Helbling D, Mueller BU, Timchenko NA, et al. The leukemic fusion gene AML1-MDS1-EVI1 suppresses CEBPA in acute myeloid leukemia by activation of calreticulin. Proc Natl Acad Sci USA. 2004;101:13312–13317.PubMedCrossRefGoogle Scholar
  25. 25.
    Hitzler JK, Zipursky A. origins of leukaemia in children with Down’s syndrome. Nat Rev Cancer. 2005;5:11–20.PubMedCrossRefGoogle Scholar
  26. 26.
    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;5:738–743.PubMedCrossRefGoogle Scholar
  27. 27.
    Huntly BJ, Shigematsu H, Deguchi K, et al. MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell. 2004;6:587–596.PubMedCrossRefGoogle Scholar
  28. 28.
    Ichikawa M, Asai T, Saito T, et al. AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in adult hematopoiesis. Nat Med. 2004;10:299–304.PubMedCrossRefGoogle Scholar
  29. 29.
    Iwama A, Oguro H, Negishi M, et al. Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1. Immunity. 2004;21:843–851.PubMedCrossRefGoogle Scholar
  30. 30.
    Jamieson CH, Ailles LE, Dylla SJ, et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast crisis CML. N Engl J Med. 2004;351:657–667.PubMedCrossRefGoogle Scholar
  31. 31.
    Kelly LM, Gilliland DG. Genetics of myeloid leukemias. Annu Rev Genomics Hum Genet. 2002;3:179–198.PubMedCrossRefGoogle Scholar
  32. 32.
    Kim HG, De Guzman CG, Swindle CS, et al. The ETS family transcription factor PU.1 is necessary for the maintenance of fetal liver hematopoietic stem cells. Blood. 2004;104:3894–3900.PubMedCrossRefGoogle Scholar
  33. 33.
    Langabeer SE, Gale RE, Rollinson SJ, Morgan GJ, Linch DC. Mutations of the AML1 gene in acute myeloid leukemia of FAB types M0 and M7. Genes Chromosomes Cancer. 2002;34:24–32.PubMedCrossRefGoogle Scholar
  34. 34.
    Lange B. The management of neoplastic disorders of haematopoiesis in children with Down’s syndrome. Br J Haematol. 2000;110:512–524.PubMedCrossRefGoogle Scholar
  35. 35.
    Leroy H, Roumier C, Huyghe P, et al. CEBPA point mutations in haematological malignancies. Leukemia. 2005;19:329–334.PubMedCrossRefGoogle Scholar
  36. 36.
    Lessard J, Sauvageau G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature. 2003;423:255–260.PubMedCrossRefGoogle Scholar
  37. 37.
    Lin LI, Chen CY, Lin DT, et al. Characterization of CEBPA mutations in acute myeloid leukemia: most patients with CEBPA mutations have biallelic mutations and show distinct immunophenotype of the leukemic cells. Clin Cancer Res. 2005;11:1372–1379.PubMedCrossRefGoogle Scholar
  38. 38.
    Look AT. Oncogenic transcription factors in the human acute leukemias. Science. 1997;278:1059–1064.PubMedCrossRefGoogle Scholar
  39. 39.
    Marcucci G, Mrozek K, Bloomfield CD. Molecular heterogeneity and prognostic biomarkers in adults with acute myeloid leukemia and normal cytogenetics. Curr Opinion Hematol. 2005;12:68–75.CrossRefGoogle Scholar
  40. 40.
    Matsuno N, Osato M, Yamashita N, et al. Dual mutations in the AML1 and FLT3 genes are associated with leukemogenesis in acute myeloblastic leukemia of the M0 subtype. Leukemia. 2003;17:2492–2499.PubMedCrossRefGoogle Scholar
  41. 41.
    Michaud J, Wu F, Osato M, Cottles GM, et al. In vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesis. Blood. 2002;99:1364–1372.PubMedCrossRefGoogle Scholar
  42. 42.
    Migliaccio AR, Rana RA, Sanchez M, et al. GATA-1 as a regulator of mast cell differentiation revealed by the phenotype of the GATA-1 low mouse mutant. J Exp Med. 2003;197:281–296.PubMedCrossRefGoogle Scholar
  43. 43.
    Mizuki M, Schwable J, Steur C, et al. Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations. Blood. 2003;101:3164–3173.PubMedCrossRefGoogle Scholar
  44. 44.
    Mueller BU, Pabst T, Osato M, et al. Heterozygous PU.1 mutations are associated with acute myeloid leukemia. Blood. 2002;100:998–1007.PubMedCrossRefGoogle Scholar
  45. 45.
    Mueller BU, Pabst T, Petkovic V, et al. ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression through CEBP induction. Blood. 2006;107:3330–3338.PubMedCrossRefGoogle Scholar
  46. 46.
    Nerlov C. C/EBPα mutations in acute myeloid leukaemias. Nat Rev. 2004;4:394–400.CrossRefGoogle Scholar
  47. 47.
    Nichols KE, Crispino JD, Poncz M, et al. Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1. Nat Genet. 2000;24:266–270.PubMedCrossRefGoogle Scholar
  48. 48.
    Nutt SL, Metcalf D, D’Amico A, et al. Dynamic regulation of PU.1 expression in multipotent hematopoietic progenitors. J Exp Med. 2005;201:221–231.PubMedCrossRefGoogle Scholar
  49. 49.
    Okuda T, van Deursen J, Hiebert SW, Grosveld G, Downing JR. AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell. 1996;84:321–330.PubMedCrossRefGoogle Scholar
  50. 50.
    Orkin SH. Diversification of haematopoietic stem cells to specific lineages. Nat Rev Genet. 2000;1:57–64.PubMedCrossRefGoogle Scholar
  51. 51.
    Osato M, Asou N, Abdalla E, et al. Biallelic and heterozygous point mutations in the runt domain of the AML1/PEBP2alphaB gene associated with myeloblastic leukemias. Blood. 1999;93:1817–1824.PubMedGoogle Scholar
  52. 52.
    Pabst T, Mueller BU, Harakawa N, et al. AML1-ETO downregulates the granulocytic differentiation factor CEBPA in t(8:21) myeloid leukemia. Nat Med. 2001;7:444–451.PubMedCrossRefGoogle Scholar
  53. 53.
    Pabst T, Mueller BU, Zhang P, et al. Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (CEBPA), in acute myeloid leukemia. Nat Genet. 2001;27:263–270.PubMedCrossRefGoogle Scholar
  54. 54.
    Pabst T, Stillner E, Neuberg D, et al. Mutations of the myeloid transcription factor CEBPA are not associated with the blast crisis of chronic myeloid leukemia. Br J Haematol. 2006. In press.Google Scholar
  55. 55.
    Parkin SE, Baer M, Copeland TD, et al. Regulation of CCAAT/enhancer binding protein (C/EBP) activator proteins by heterodimerization with C/EBP□ (Ig/EBP). J Biol Chem. 2002;277:23563–23572.PubMedCrossRefGoogle Scholar
  56. 56.
    Passegue E, Jamieson CH, Ailles LE, Weissman IL. Normal and leukemic hematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cell characteristics? Proc Natl Acad Sci USA. 2003;100(suppl 1):11842–11849.PubMedCrossRefGoogle Scholar
  57. 57.
    Passegue E, Wagner EF, Weissman IL. JunB deficiency leads to a myeloproliferative disorder arising from hematopoietic stem cells. Cell. 2004;119:431–443.PubMedCrossRefGoogle Scholar
  58. 58.
    Perrotti D, Calabretta B. Translational regulation by the p210 BCR/ABL oncoprotein. Oncogene. 2004;23:3222–3229.PubMedCrossRefGoogle Scholar
  59. 59.
    Perrotti D, Cesi V, Trotta R, et al. BCR-ABL suppresses CEBPA expression through inhibitory action of hnRNP E2. Nat Genet. 2002;30:48–58.PubMedCrossRefGoogle Scholar
  60. 60.
    Perrotti D, Marcucci G, Caliguri MA. Loss of CEBPA and favorable prognosis of acute myeloid leukemias: a biological paradox. J Clin Oncol. 2004;22:582–584.PubMedCrossRefGoogle Scholar
  61. 61.
    Preudhomme C, Sagot C, Boisset N, et al. Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia : a study from the Acute Leukemia French Association (ALFA). Blood. 2002;100:2717–2723.PubMedCrossRefGoogle Scholar
  62. 62.
    Preudhomme C, Warot-Loze D, Roumier C, et al. High incidence of biallelic point mutations in the Runt domain of the AML1/PEBP2 alpha B gene in Mo acute myeloid leukemia and in myeloid malignancies with acquired trisomy 21. Blood. 2000;96:2862–2869.PubMedGoogle Scholar
  63. 63.
    Rosenbauer F, Wagner K, Kutok JL, et al. Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor PU.1. Nat Genet. 2004;36:624–630.PubMedCrossRefGoogle Scholar
  64. 64.
    Ross SE, Radomska HS, Wu B, et al. Phosphorylation of C/EBPα inhibits granulopoiesis. Mol Cell Biol. 2004;24:675–686.PubMedCrossRefGoogle Scholar
  65. 65.
    Schwieger M, Löhler J, Fischer M. A dominant-negative mutant of CEBPA, associated with acute myeloid leukemias, inhibits differentiation of myeloid and erythroid progenitors of man but not mouse. Blood. 2004;103:2744–2752.PubMedCrossRefGoogle Scholar
  66. 66.
    Scott EW, Fisher RC, Olson MC, et al. PU.1 function in a cell-autonomous manner to control the differentiation of multipotential lymphoid-myeloid progenitors. Immunity. 1997;6:437–447.PubMedCrossRefGoogle Scholar
  67. 67.
    Sellick GS, Spendlove HE, Catovsky D, et al. Further evidence that germline CEBPA mutations cause dominant inheritance of acute myeloid leukemia. Leukemia. 2005;19:1276–1278.PubMedCrossRefGoogle Scholar
  68. 68.
    Shimizu R, Kuroha T, Ohneda O, et al. Leukemogenesis caused by incapacitated GATA-1 function. Mol Cell Biol. 2004;24:10814–10825.PubMedCrossRefGoogle Scholar
  69. 69.
    Shivdasani RA, Fujiwara Y, McDevitt MA, Orkin SH. A lineage-selective knockout establishes the critical role of transcription factor GATA-1 in megakaryocyte growth and platelet development. EMBO J. 1997;16:3965–3973.PubMedCrossRefGoogle Scholar
  70. 70.
    Shivdasani RA, Mayer EL, Orkin SH. Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal-1/SCL. Nature. 1995;373:432–434.PubMedCrossRefGoogle Scholar
  71. 71.
    Silva FP, Morolli B, Storlazzi CT, et al. Identification of RUNX1/AML1 as a classical tumor suppressor gene. Oncogene. 2003;22:538–547.PubMedCrossRefGoogle Scholar
  72. 72.
    Smith ML, Arch R, Smith LL, et al. Development of a human acute myeloid leukaemia screening panel and consequent identification of novel gene mutation in FLT3 and CCND3. Br J Haemat. 2005;128:318–323.CrossRefGoogle Scholar
  73. 73.
    Smith ML, Cavenagh JD, Lister TA, Fitzgibbon J. Mutation of CEBPA in familial acute myeloid leukemia. N Engl J Med. 2004;351:2403–2407.PubMedCrossRefGoogle Scholar
  74. 74.
    Snaddon J, Smith ML, Neat M, et al. Mutations of CEBPA in acute myeloid leukemia FAB types M1 and M2. Genes Chromosomes Cancer. 2003;37:72–78.PubMedCrossRefGoogle Scholar
  75. 75.
    Song WJ, Sullivan MG, Legare RD, et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet. 1999;23:166–75.PubMedCrossRefGoogle Scholar
  76. 76.
    Takahashi S, Onodera K, Motohashi H, et al. Arrest in primitive erythroid cell development caused by promoter-specific disruption of the GATA-1 gene. J Biol Chem. 1997;272:12611–12615.PubMedCrossRefGoogle Scholar
  77. 77.
    Tenen DG, Hromas R, Licht JD, Zhang DE. Transcription factors, normal myeloid development, and leukemia. Blood. 1997;90:489–519.PubMedGoogle Scholar
  78. 78.
    Tenen, DG. Transcription factors in myeloid differentiation and leukemia. Nat Rev Cancer. 2003;3:89–101.PubMedCrossRefGoogle Scholar
  79. 79.
    Timchenko NA, Iakova P, Welm AL, et al. Calreticulin interacts with C/EBPα and C/EBPβ mRNAs and represses translation of C/EBP proteins. Mol Cell Biol. 2002;22:7242–7257.PubMedCrossRefGoogle Scholar
  80. 80.
    Truong BTH, Lee YJ, Lodie TA, et al. CCAAT/enhancer binding proteins repress the leukemic phenotype of acute myeloid leukemia. Blood. 2003;101:1141–1148.PubMedCrossRefGoogle Scholar
  81. 81.
    Valk PJM, Delwel R, Lowenberg B. Gene expression profiling in acute myeloid leukemia. Curr Opinion Hemat. 2005;12:76–81.CrossRefGoogle Scholar
  82. 82.
    Valk PJM, Verhaak RGW, Beijen MA, et al. Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med. 2004;350:1617–1628.PubMedCrossRefGoogle Scholar
  83. 83.
    Van Waalwijk van Doorn-Khosrovani SB, Erpelnick C, Meijer J, et al. Biallelic mutations in the CEBPA gene and low CEBPA expression levels as prognostic markers in intermediate-risk AML. Hematol J. 2003;4:31–40.CrossRefGoogle Scholar
  84. 84.
    Vangala RK, Heiss-Neumann MS, Rangatia JS, et al. The myeloid transcription factor PU.1 is inactivated by AML1-ETO in t(8;21) myeloid leukemia. Blood. 2003;101:270–277.PubMedCrossRefGoogle Scholar
  85. 85.
    Wang GL, Iakova P, Wilde M, et al. Liver tumors escape negative control of proliferation via PI3K/Akt-mediated block of CEBPA growth inhibitory activity. Genes Dev. 2004;18:912–925.PubMedCrossRefGoogle Scholar
  86. 86.
    Wechsler J, Greene M, McDevitt MA, et al. Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet. 2002;32:148–152.PubMedCrossRefGoogle Scholar
  87. 87.
    Yu C, Cantor AB, Yang H, et al. Targeted deletion of a high-affinity GATA-binding site in the GATA-1 promoter leads to selective loss of the eosinophil lineage in vivo. J Exp Med. 2002;195:1387–1395.PubMedCrossRefGoogle Scholar
  88. 88.
    Zhang P, Iwasaki-Arai J, Iwasaki H, et al. Enhancement of hematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor C/EBPα. Immunity. 2004;21:853–863.PubMedCrossRefGoogle Scholar
  89. 89.
    Zheng R, Friedman AD, Levis M, et al. Internal tandem duplication mutation of FLT3 blocks myeloid differentiation through suppression of C/EBPα expression. Blood. 2004;103:1883–1890.PubMedCrossRefGoogle Scholar
  90. 90.
    Zipursky A. Transient leukemia – a benign form of leukaemia in newborn infants with trisomy 21. Br J Haematol. 2003;120:930–968.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Internal MedicineUniversity HospitalBernSwitzerland
  2. 2.Department of OncologyUniversity HospitalBernSwitzerland

Personalised recommendations