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Transcription Factors in Cancer Stem Cells of the Hematopoietic Lineage

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Stem Cells and Cancer

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Hematopoietic transcription factors play a crucial role in the proliferation and commitment of hematopoietic stem cells (HSCs) and during the differentiation into their mature progeny. Genetic evidence suggests that perturbance of the function of critical transcription factors can result in increased HSC self-renewal, deregulated proliferation, and a block in differentiation, ultimately leading to acute leukemia. The leukemia-initiating cells have been isolated to near homogeneity, and gene expression arrays of these cells have revealed both similarities and disparities between leukemic stem and progenitor cells and their normal counterparts. Most striking was the finding that the leukemia-initiating cells found in AML can resemble HSCs or committed progenitor cells. These studies have also shown that disruption of the function of single transcription factors can induce acute leukemia in mice. Moreover, dysfunction of these factors has been described in human leukemias, and their functional restoration may lead to the eradication of malignant stem cells.

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REFERENCES

  1. Makino S. The role of tumor stem-cells in regrowth of the tumor following drastic applications. Acta Unio Int Contra Cancrum 1959;15(Suppl 1):196–8.

    PubMed  Google Scholar 

  2. McCulloch EA. Stem cells in normal and leukemic hemopoiesis (Henry Stratton Lecture, 1982). Blood 1983;62(1):1–13.

    PubMed  CAS  Google Scholar 

  3. Fialkow PJ, Gartler SM, Yoshida A. Clonal origin of chronic myelocytic leukemia in man. Proc Natl Acad Sci USA 1967;58(4):1468–71.

    Article  PubMed  CAS  Google Scholar 

  4. Arnold A, Cossman J, Bakhshi A, Jaffe ES, Waldmann TA, Korsmeyer SJ. Immunoglobulin-gene rearrangements as unique clonal markers in human lymphoid neoplasms. N Engl J Med 1983;309(26):1593–9.

    Article  PubMed  CAS  Google Scholar 

  5. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997;3(7):730–7.

    Article  PubMed  CAS  Google Scholar 

  6. 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(2):321–30.

    Article  PubMed  CAS  Google Scholar 

  7. Zhang DE, Zhang P, Wang ND, Hetherington CJ, Darlington GJ, Tenen DG. Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice. Proc Natl Acad Sci USA 1997;94(2):569–74.

    Article  PubMed  CAS  Google Scholar 

  8. Scott EW, Simon MC, Anastasi J, Singh H. Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. Science 1994;265(5178):1573–7.

    Article  PubMed  CAS  Google Scholar 

  9. Pevny L, Simon MC, Robertson E, et al Erythroid differentiation in chimaeric mice blocked by a targeted mutation in the gene for transcription factor GATA-1. Nature 1991;349(6306):257–60.

    Article  PubMed  CAS  Google Scholar 

  10. Robb L, Lyons I, Li R, et al Absence of yolk sac hematopoiesis from mice with a targeted disruption of the scl gene. Proc Natl Acad Sci USA 1995;92(15):7075–9.

    Article  PubMed  CAS  Google Scholar 

  11. Shivdasani RA, Mayer EL, Orkin SH. Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal-1/SCL. Nature 1995;373(6513):432–4.

    Article  PubMed  CAS  Google Scholar 

  12. Landry JR, Kinston S, Knezevic K, et al Runx genes are direct targets of Scl/Tal1 in the yolk sac and fetal liver. Blood 2008;111(6):3005–14.

    Article  PubMed  CAS  Google Scholar 

  13. Huang G, Zhang P, Hirai H, et al PU.1 is a major downstream target of AML1 (RUNX1) in adult mouse hematopoiesis. Nat Genet 2008;40(1):51–60.

    Article  PubMed  CAS  Google Scholar 

  14. Yamanaka R, Kim GD, Radomska HS, et al CCAAT/enhancer binding protein epsilon is preferentially up-regulated during granulocytic differentiation and its functional versatility is determined by alternative use of promoters and differential splicing. Proc Natl Acad Sci USA 1997;94(12):6462–7.

    Article  PubMed  CAS  Google Scholar 

  15. Lekstrom-Himes J, Xanthopoulos KG. CCAAT/enhancer binding protein epsilon is critical for effective neutrophil-mediated response to inflammatory challenge. Blood 1999;93(9):3096–105.

    PubMed  CAS  Google Scholar 

  16. Mikkola HK, Klintman J, Yang H, et al Haematopoietic stem cells retain long-term repopulating activity and multipotency in the absence of stem-cell leukaemia SCL/tal-1 gene. Nature 2003;421(6922):547–51.

    Article  PubMed  CAS  Google Scholar 

  17. 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(3):299–304.

    Article  PubMed  CAS  Google Scholar 

  18. Lessard J, Sauvageau G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 2003;423(6937):255–60.

    Article  PubMed  CAS  Google Scholar 

  19. Park IK, Qian D, Kiel M, et al Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 2003;423(6937):302–5.

    Article  PubMed  CAS  Google Scholar 

  20. 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/EBP alpha. Immunity 2004;21(6):853–63.

    Article  PubMed  CAS  Google Scholar 

  21. Akashi K, Traver D, Miyamoto T, Weissman IL. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 2000;404(6774):193–7.

    Article  PubMed  CAS  Google Scholar 

  22. Iwasaki H, Somoza C, Shigematsu H, et al Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation. Blood 2005;106(5):1590–600.

    Article  PubMed  CAS  Google Scholar 

  23. Li Y, Okuno Y, Zhang P, et al Regulation of the PU.1 gene by distal elements. Blood 2001;98(10):2958–65.

    Article  PubMed  CAS  Google Scholar 

  24. Okuno Y, Huang G, Rosenbauer F, et al Potential autoregulation of transcription factor PU.1 by an upstream regulatory element. Mol Cell Biol 2005;25(7):2832–45.

    Article  PubMed  CAS  Google Scholar 

  25. 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(6):624–30.

    Article  PubMed  CAS  Google Scholar 

  26. Steidl U, Rosenbauer F, Verhaak RG, et al Essential role of Jun family transcription factors in PU.1 knockdown-induced leukemic stem cells. Nat Genet 2006;38(11):1269–77.

    Article  PubMed  CAS  Google Scholar 

  27. Rosenbauer F, Owens BM, Yu L, et al Lymphoid cell growth and transformation are suppressed by a key regulatory element of the gene encoding PU.1. Nat Genet 2006;38(1):27–37.

    Article  PubMed  CAS  Google Scholar 

  28. Mueller BU, Pabst T, Osato M, et al Heterozygous PU.1 mutations are associated with acute myeloid leukemia. Blood 2003;101(5):2074.

    Article  PubMed  CAS  Google Scholar 

  29. Zheng R, Friedman AD, Levis M, Li L, Weir EG, Small D. Internal tandem duplication mutation of FLT3 blocks myeloid differentiation through suppression of C/EBPalpha expression. Blood 2004;103(5):1883–90.

    Article  PubMed  CAS  Google Scholar 

  30. Mueller BU, Pabst T, Fos J, et al ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression. Blood 2006;107(8):3330–8.

    Article  PubMed  CAS  Google Scholar 

  31. Steidl U, Steidl C, Ebralidze A, et al A distal single nucleotide polymorphism alters long-range regulation of the PU.1 gene in acute myeloid leukemia. J Clin Invest 2007;117(9):2611–20.

    Article  PubMed  CAS  Google Scholar 

  32. Pabst T, Mueller BU, Zhang P, et al Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia. Nat Genet 2001;27(3):263–70.

    Article  PubMed  CAS  Google Scholar 

  33. Preudhomme C, Sagot C, Boissel 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(8):2717–23.

    Article  PubMed  CAS  Google Scholar 

  34. 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(4):1332–40.

    Article  PubMed  CAS  Google Scholar 

  35. 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(1):72–8.

    Article  PubMed  CAS  Google Scholar 

  36. Barjesteh van Waalwijk van Doorn-Khosrovani S, Erpelinck 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(1):31–40.

    Article  PubMed  Google Scholar 

  37. Frohling 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(4):624–33.

    Article  PubMed  Google Scholar 

  38. Frohling S, Schlenk RF, Krauter J, et al Acute myeloid leukemia with deletion 9q within a noncomplex karyotype is associated with CEBPA loss-of-function mutations. Genes Chromosomes Cancer 2005;42(4):427–32.

    Article  PubMed  Google Scholar 

  39. Smith ML, Cavenagh JD, Lister TA, Fitzgibbon J. Mutation of CEBPA in familial acute myeloid leukemia. N Engl J Med 2004;351(23):2403–7.

    Article  PubMed  CAS  Google Scholar 

  40. Bienz M, Ludwig M, Leibundgut EO, et al Risk assessment in patients with acute myeloid leukemia and a normal karyotype. Clin Cancer Res 2005;11(4):1416–24.

    Article  PubMed  CAS  Google Scholar 

  41. Shih LY, Huang CF, Lin TL, et al Heterogeneous patterns of CEBPalpha mutation status in the progression of myelodysplastic syndrome and chronic myelomonocytic leukemia to acute myelogenous leukemia. Clin Cancer Res 2005;11(5):1821–6.

    Article  PubMed  CAS  Google Scholar 

  42. 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 a distinct immunophenotype of the leukemic cells. Clin Cancer Res 2005;11(4):1372–9.

    Article  PubMed  CAS  Google Scholar 

  43. Sellick GS, Spendlove HE, Catovsky D, Pritchard-Jones K, Houlston RS. Further evidence that germline CEBPA mutations cause dominant inheritance of acute myeloid leukaemia. Leukemia 2005;19(7):1276–8.

    Article  PubMed  CAS  Google Scholar 

  44. Kirstetter P, Schuster MB, Bereshchenko O, Moore S, Dvinge H, Kurz E, Theilgaard-Mönch K, Månsson R, Pedersen TA, Pabst T, Schrock E, Porse BT, Jacobsen SE, Bertone P, Tenen DG, Nerlov C. Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells. Cancer Cell 2008;13(4):299–310.

    Google Scholar 

  45. Wang ND, Finegold MJ, Bradley A, et al Impaired energy homeostasis in C/EBPalpha knockout mice. Science 1995;269(5227):1108–12.

    Article  PubMed  CAS  Google Scholar 

  46. Chapiro E, Russell L, Radford-Weiss I, et al Overexpression of CEBPA resulting from the translocation t(14;19)(q32;q13) of human precursor B acute lymphoblastic leukemia. Blood 2006;108(10):3560–3.

    Article  PubMed  CAS  Google Scholar 

  47. Akasaka T, Balasas T, Russell LJ, et al Five members of the CEBP transcription factor family are targeted by recurrent IGH translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Blood 2007;109(8):3451–61.

    Article  PubMed  CAS  Google Scholar 

  48. Lin TC, Lee CY, Tien HF, Hu CY, Tang JL, Lin LI. Tumor Suppressor activity of CCAAT/enhancer binding protein Alpha is epigenetically down-regulated in acute myeloid leukemia. Blood 2007;110(11):2113A.

    Google Scholar 

  49. 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(36):13312–7.

    Article  PubMed  CAS  Google Scholar 

  50. 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.

    Article  PubMed  CAS  Google Scholar 

  51. Perrotti D, Cesi V, Trotta R, et al BCR-ABL suppresses C/EBPalpha expression through inhibitory action of hnRNP E2. Nat Genet 2002;30(1):48–58.

    Article  PubMed  CAS  Google Scholar 

  52. Halmos B, Huettner CS, Kocher O, Ferenczi K, Karp DD, Tenen DG. Down-regulation and antiproliferative role of C/EBPalpha in lung cancer. Cancer Res 2002;62(2):528–34.

    PubMed  CAS  Google Scholar 

  53. Costa DB, Li S, Kocher O, et al Immunohistochemical analysis of C/EBPalpha in non-small cell lung cancer reveals frequent down-regulation in stage II and IIIA tumors: a correlative study of E3590. Lung Cancer 2007;56(1):97–103.

    Article  PubMed  Google Scholar 

  54. Birkenmeier EH, Gwynn B, Howard S, et al Tissue-specific expression, developmental regulation, and genetic mapping of the gene encoding CCAAT/enhancer binding protein. Genes Dev 1989;3(8):1146–56.

    Article  PubMed  CAS  Google Scholar 

  55. Tan EH, Hooi SC, Laban M, et al CCAAT/enhancer binding protein alpha knock-in mice exhibit early liver glycogen storage and reduced susceptibility to hepatocellular carcinoma. Cancer Res 2005;65(22):10330–7.

    Article  PubMed  CAS  Google Scholar 

  56. Cozzio A, Passegue E, Ayton PM, Karsunky H, Cleary ML, Weissman IL. Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes Dev 2003;17(24):3029–35.

    Article  PubMed  CAS  Google Scholar 

  57. Krivtsov AV, Twomey D, Feng Z, et al Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 2006;442(7104):818–22.

    Article  PubMed  CAS  Google Scholar 

  58. 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(6):587–96.

    Article  PubMed  CAS  Google Scholar 

  59. So CW, Karsunky H, Passegue E, Cozzio A, Weissman IL, Cleary ML. MLL-GAS7 transforms multipotent hematopoietic progenitors and induces mixed lineage leukemias in mice. Cancer Cell 2003;3(2):161–71.

    Article  PubMed  CAS  Google Scholar 

  60. Deshpande AJ, Cusan M, Rawat VP, et al Acute myeloid leukemia is propagated by a leukemic stem cell with lymphoid characteristics in a mouse model of CALM/AF10-positive leukemia. Cancer Cell 2006;10(5):363–74.

    Article  PubMed  CAS  Google Scholar 

  61. 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.

    PubMed  CAS  Google Scholar 

  62. Passegue E, Wagner EF, Weissman IL. JunB deficiency leads to a myeloproliferative disorder arising from hematopoietic stem cells. Cell 2004;119(3):431–43.

    Article  PubMed  CAS  Google Scholar 

  63. Ma Y, Cui W, Yang J, et al SALL4, a novel oncogene, is constitutively expressed in human acute myeloid leukemia (AML) and induces AML in transgenic mice. Blood 2006;108(8):2726–35.

    Article  PubMed  CAS  Google Scholar 

  64. 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(7):657–67.

    Article  PubMed  CAS  Google Scholar 

  65. Zhao C, Blum J, Chen A, et al Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell 2007;12(6):528–41.

    Article  PubMed  CAS  Google Scholar 

  66. Felsher DW, Bishop JM. Reversible tumorigenesis by MYC in hematopoietic lineages. Mol Cell 1999;4(2):199–207.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Medicine, Hematology and Oncology, University of Münster, Münster, Germany

    Steffen Koschmieder & Daniel G Tenen

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  1. Steffen Koschmieder
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Correspondence to Steffen Koschmieder .

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    Koschmieder, S., Tenen, D.G. (2009). Transcription Factors in Cancer Stem Cells of the Hematopoietic Lineage. In: Teicher, B., Bagley, R. (eds) Stem Cells and Cancer. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-60327-933-8_6

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