International Journal of Hematology

, Volume 91, Issue 5, pp 735–741

Grist for the MLL: how do MLL oncogenic fusion proteins generate leukemia stem cells?

Progress in Hematology Molecular pathogenesis of leukemia and leukemia stem cells

Abstract

MLL fusion oncogenes are pathogenically associated with 5–10% of human acute leukemias. Through multiple interactions with chromatin regulatory factors, they convert a normal hematopoietic hierarchy into a leukemia cell hierarchy sustained at its apex by a population of inappropriately self-renewing myeloid cells termed leukemia stem cells (LSCs). Initiation of the aberrant leukemia cell hierarchy is associated with an abnormal epigenetic state at Hoxa and Meis1 loci, with concomitant high level Hoxa and Meis1 expression. This introduces at the level of the myeloblast, or thereabouts, a finite probability of self-renewal division where none previously existed. In contrast, differentiation-mediated exit of LSCs from the self-renewing compartment of the leukemia clone depends on the prevailing levels of the transcription factor Myb, which functions as part of an LSC maintenance program influenced, but not directly controlled, by Hoxa and Meis1. Critical biologic and molecular differences between self-renewing progenitor-like LSCs and hematopoietic stem cells could potentially be targeted by novel therapeutic strategies.

Keywords

MLL HOX Leukemia stem cell Self-renewal 

References

  1. 1.
    Clarke MF, Dick JE, Dirks PB, et al. Cancer stem cells—perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 2006;66:9339–44.CrossRefPubMedGoogle Scholar
  2. 2.
    Mackillop WJ, Ciampi A, Till JE, Buick RN. A stem cell model of human tumor growth: implications for tumor cell clonogenic assays. J Natl Cancer Inst. 1983;70:9–16.PubMedGoogle Scholar
  3. 3.
    Buick RN, Pollak MN. Perspectives on clonogenic tumor cells, stem cells, and oncogenes. Cancer Res. 1984;44:4909–18.PubMedGoogle Scholar
  4. 4.
    Minden MD, Till JE, McCulloch EA. Proliferative state of blast cell progenitors in acute myeloblastic leukemia (AML). Blood. 1978;52:592–600.PubMedGoogle Scholar
  5. 5.
    Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367:645–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3:730–7.CrossRefPubMedGoogle Scholar
  7. 7.
    Somervaille TC, Cleary ML. Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. Cancer Cell. 2006;10:257–68.CrossRefPubMedGoogle Scholar
  8. 8.
    Somervaille TC, Matheny CJ, Spencer GJ, et al. Hierarchical maintenance of MLL myeloid leukemia stem cells employs a transcriptional program shared with embryonic rather than adult stem cells. Cell Stem Cell. 2009;4:129–40.CrossRefPubMedGoogle Scholar
  9. 9.
    Krivtsov AV, Twomey D, Feng Z, et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature. 2006;442:818–22.CrossRefPubMedGoogle Scholar
  10. 10.
    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;17:3029–35.CrossRefPubMedGoogle Scholar
  11. 11.
    Taussig DC, Miraki-Moud F, Anjos-Afonso F, et al. Anti-CD38 antibody-mediated clearance of human repopulating cells masks the heterogeneity of leukemia-initiating cells. Blood. 2008;112:568–75.CrossRefPubMedGoogle Scholar
  12. 12.
    Look AT. Oncogenic transcription factors in the human acute leukemias. Science. 1997;278:1059–64.CrossRefPubMedGoogle Scholar
  13. 13.
    Basecke J, Whelan JT, Griesinger F, Bertrand FE. The MLL partial tandem duplication in acute myeloid leukaemia. Br J Haematol. 2006;135:438–49.CrossRefPubMedGoogle Scholar
  14. 14.
    Meyer C, Kowarz E, Hofmann J, et al. New insights to the MLL recombinome of acute leukemias. Leukemia. 2009;23(8):1490–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Lavau C, Szilvassy SJ, Slany R, Cleary ML. Immortalization and leukemic transformation of a myelomonocytic precursor by retrovirally transduced HRX-ENL. EMBO J. 1997;16:4226–37.CrossRefPubMedGoogle Scholar
  16. 16.
    Corral J, Lavenir I, Impey H, et al. An Mll-AF9 fusion gene made by homologous recombination causes acute leukemia in chimeric mice: a method to create fusion oncogenes. Cell. 1996;85:853–61.CrossRefPubMedGoogle Scholar
  17. 17.
    Jude CD, Climer L, Xu D, Artinger E, Fisher JK, Ernst P. Unique and independent roles for MLL in adult hematopoietic stem cells and progenitors. Cell Stem Cell. 2007;1:324–37.CrossRefPubMedGoogle Scholar
  18. 18.
    McMahon KA, Hiew SY, Hadjur S, et al. Mll has a critical role in fetal and adult hematopoietic stem cell self-renewal. Cell Stem Cell. 2007;1:338–45.CrossRefPubMedGoogle Scholar
  19. 19.
    Yu BD, Hess JL, Horning SE, Brown GA, Korsmeyer SJ. Altered Hox expression and segmental identity in Mll-mutant mice. Nature. 1995;378:505–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Yokoyama A, Wang Z, Wysocka J, et al. Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression. Mol Cell Biol. 2004;24:5639–49.CrossRefPubMedGoogle Scholar
  21. 21.
    Milne TA, Martin ME, Brock HW, Slany RK, Hess JL. Leukemogenic MLL fusion proteins bind across a broad region of the Hox a9 locus, promoting transcription and multiple histone modifications. Cancer Res. 2005;65:11367–74.CrossRefPubMedGoogle Scholar
  22. 22.
    Guenther MG, Lawton LN, Rozovskaia T, et al. Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia. Genes Dev. 2008;22:3403–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Hsieh JJ, Cheng EH, Korsmeyer SJ. Taspase1: a threonine aspartase required for cleavage of MLL and proper HOX gene expression. Cell. 2003;115:293–303.CrossRefPubMedGoogle Scholar
  24. 24.
    Yokoyama A, Somervaille TC, Smith KS, Rozenblatt-Rosen O, Meyerson M, Cleary ML. The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis. Cell. 2005;123:207–18.CrossRefPubMedGoogle Scholar
  25. 25.
    Ayton PM, Chen EH, Cleary ML. Binding to nonmethylated CpG DNA is essential for target recognition, transactivation, and myeloid transformation by an MLL oncoprotein. Mol Cell Biol. 2004;24:10470–8.CrossRefPubMedGoogle Scholar
  26. 26.
    Chen W, Kumar AR, Hudson WA, et al. Malignant transformation initiated by Mll-AF9: gene dosage and critical target cells. Cancer Cell. 2008;13:432–40.CrossRefPubMedGoogle Scholar
  27. 27.
    Muntean AG, Giannola D, Udager AM, Hess JL. The PHD fingers of MLL block MLL fusion protein-mediated transformation. Blood. 2008;112:4690–3.CrossRefPubMedGoogle Scholar
  28. 28.
    DiMartino JF, Ayton PM, Chen EH, Naftzger CC, Young BD, Cleary ML. The AF10 leucine zipper is required for leukemic transformation of myeloid progenitors by MLL-AF10. Blood. 2002;99:3780–5.CrossRefPubMedGoogle Scholar
  29. 29.
    Yokoyama A, Cleary ML. Menin critically links MLL proteins with LEDGF on cancer-associated target genes. Cancer Cell. 2008;14:36–46.CrossRefPubMedGoogle Scholar
  30. 30.
    Erfurth FE, Popovic R, Grembecka J, et al. MLL protects CpG clusters from methylation within the Hoxa9 gene, maintaining transcript expression. Proc Natl Acad Sci USA. 2008;105:7517–22.CrossRefPubMedGoogle Scholar
  31. 31.
    Krivtsov AV, Feng Z, Lemieux ME, et al. H3K79 methylation profiles define murine and human MLL-AF4 leukemias. Cancer Cell. 2008;14:355–68.CrossRefPubMedGoogle Scholar
  32. 32.
    Okada Y, Feng Q, Lin Y, et al. hDOT1L links histone methylation to leukemogenesis. Cell. 2005;121:167–78.CrossRefPubMedGoogle Scholar
  33. 33.
    Mueller D, Bach C, Zeisig D, et al. A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification. Blood. 2007;110:4445–54.CrossRefPubMedGoogle Scholar
  34. 34.
    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;16:92–106.CrossRefPubMedGoogle Scholar
  35. 35.
    Nie Z, Yan Z, Chen EH, et al. Novel SWI/SNF chromatin-remodeling complexes contain a mixed-lineage leukemia chromosomal translocation partner. Mol Cell Biol. 2003;23:2942–52.CrossRefPubMedGoogle Scholar
  36. 36.
    Cheung N, Chan LC, Thompson A, Cleary ML, So CW. Protein arginine-methyltransferase-dependent oncogenesis. Nat Cell Biol. 2007;9:1208–15.CrossRefPubMedGoogle Scholar
  37. 37.
    So CW, Cleary ML. Common mechanism for oncogenic activation of MLL by forkhead family proteins. Blood. 2003;101:633–9.CrossRefPubMedGoogle Scholar
  38. 38.
    So CW, Lin M, Ayton PM, Chen EH, Cleary ML. Dimerization contributes to oncogenic activation of MLL chimeras in acute leukemias. Cancer Cell. 2003;4:99–110.CrossRefPubMedGoogle Scholar
  39. 39.
    Liu H, Cheng EH, Hsieh JJ. Bimodal degradation of MLL by SCFSkp2 and APCCdc20 assures cell cycle execution: a critical regulatory circuit lost in leukemogenic MLL fusions. Genes Dev. 2007;21:2385–98.CrossRefPubMedGoogle Scholar
  40. 40.
    Wang Z, Smith KS, Murphy M, Piloto O, Somervaille TC, Cleary ML. Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy. Nature. 2008;455:1205–9.CrossRefPubMedGoogle Scholar
  41. 41.
    Rozovskaia T, Feinstein E, Mor O, et al. Upregulation of Meis1 and HoxA9 in acute lymphocytic leukemias with the t(4:11) abnormality. Oncogene. 2001;20:874–8.CrossRefPubMedGoogle Scholar
  42. 42.
    Armstrong SA, Staunton JE, Silverman LB, et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet. 2002;30:41–7.CrossRefPubMedGoogle Scholar
  43. 43.
    Yeoh EJ, Ross ME, Shurtleff SA, et al. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell. 2002;1:133–43.CrossRefPubMedGoogle Scholar
  44. 44.
    Ferrando AA, Armstrong SA, Neuberg DS, et al. Gene expression signatures in MLL-rearranged T-lineage and B-precursor acute leukemias: dominance of HOX dysregulation. Blood. 2003;102:262–8.CrossRefPubMedGoogle Scholar
  45. 45.
    Kawagoe H, Humphries RK, Blair A, Sutherland HJ, Hogge DE. Expression of HOX genes, HOX cofactors, and MLL in phenotypically and functionally defined subpopulations of leukemic and normal human hematopoietic cells. Leukemia. 1999;13:687–98.CrossRefPubMedGoogle Scholar
  46. 46.
    Ross ME, Mahfouz R, Onciu M, et al. Gene expression profiling of pediatric acute myelogenous leukemia. Blood. 2004;104:3679–87.CrossRefPubMedGoogle Scholar
  47. 47.
    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;350:1605–16.CrossRefPubMedGoogle Scholar
  48. 48.
    Valk PJ, Verhaak RG, Beijen MA, et al. Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med. 2004;350:1617–28.CrossRefPubMedGoogle Scholar
  49. 49.
    Roche J, Zeng C, Baron A, et al. Hox expression in AML identifies a distinct subset of patients with intermediate cytogenetics. Leukemia. 2004;18:1059–63.CrossRefPubMedGoogle Scholar
  50. 50.
    Alcalay M, Tiacci E, Bergomas R, et al. Acute myeloid leukemia bearing cytoplasmic nucleophosmin (NPMc + AML) shows a distinct gene expression profile characterized by up-regulation of genes involved in stem-cell maintenance. Blood. 2005;106:899–902.CrossRefPubMedGoogle Scholar
  51. 51.
    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;106:3747–54.CrossRefPubMedGoogle Scholar
  52. 52.
    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;17:3714–25.CrossRefPubMedGoogle Scholar
  53. 53.
    Wong P, Iwasaki M, Somervaille TC, So CW, Cleary ML. Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential. Genes Dev. 2007;21:2762–74.CrossRefPubMedGoogle Scholar
  54. 54.
    Ayton PM, Cleary ML. Transformation of myeloid progenitors by MLL oncoproteins is dependent on Hoxa7 and Hoxa9. Genes Dev. 2003;17:2298–307.CrossRefPubMedGoogle Scholar
  55. 55.
    So CW, Karsunky H, Wong P, Weissman IL, Cleary ML. Leukemic transformation of hematopoietic progenitors by MLL-GAS7 in the absence of Hoxa7 or Hoxa9. Blood. 2004;103:3192–9.CrossRefPubMedGoogle Scholar
  56. 56.
    Kumar AR, Hudson WA, Chen W, Nishiuchi R, Yao Q, Kersey JH. Hoxa9 influences the phenotype but not the incidence of Mll-AF9 fusion gene leukemia. Blood. 2004;103:1823–8.CrossRefPubMedGoogle Scholar
  57. 57.
    Faber J, Krivtsov AV, Stubbs MC, et al. HOXA9 is required for survival in human MLL-rearranged acute leukemias. Blood. 2009;113:2375–85.CrossRefPubMedGoogle Scholar
  58. 58.
    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;24:617–28.CrossRefPubMedGoogle Scholar
  59. 59.
    Nakanishi H, Nakamura T, Canaani E, Croce CM. ALL1 fusion proteins induce deregulation of EphA7 and ERK phosphorylation in human acute leukemias. Proc Natl Acad Sci USA. 2007;104:14442–7.CrossRefPubMedGoogle Scholar
  60. 60.
    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;113:3314–22.CrossRefPubMedGoogle Scholar
  61. 61.
    Hess JL, Bittner CB, Zeisig DT, et al. c-Myb is an essential downstream target for homeobox-mediated transformation of hematopoietic cells. Blood. 2006;108:297–304.CrossRefPubMedGoogle Scholar
  62. 62.
    Horton SJ, Grier DG, McGonigle GJ, et al. Continuous MLL-ENL expression is necessary to establish a “Hox Code” and maintain immortalization of hematopoietic progenitor cells. Cancer Res. 2005;65:9245–52.CrossRefPubMedGoogle Scholar
  63. 63.
    Taketani T, Taki T, Sugita K, et al. FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangements and pediatric ALL with hyperdiploidy. Blood. 2004;103:1085–8.CrossRefPubMedGoogle Scholar
  64. 64.
    Liang DC, Shih LY, Fu J, et al. K-Ras mutations and N-Ras mutations in childhood acute leukemias with or without mixed-lineage leukemia gene rearrangements. Cancer. 2006;106:950–6.CrossRefPubMedGoogle Scholar
  65. 65.
    Barabe F, Kennedy JA, Hope KJ, Dick JE. Modeling the initiation and progression of human acute leukemia in mice. Science. 2007;316:600–4.CrossRefPubMedGoogle Scholar
  66. 66.
    Wei J, Wunderlich M, Fox C, et al. Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia. Cancer Cell. 2008;13:483–95.CrossRefPubMedGoogle Scholar
  67. 67.
    Yilmaz OH, Valdez R, Theisen BK, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature. 2006;441:475–82.CrossRefPubMedGoogle Scholar
  68. 68.
    Scholl C, Frohling S, Dunn IF, et al. Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell. 2009;137:821–34.CrossRefPubMedGoogle Scholar
  69. 69.
    Liedtke M, Cleary ML. Therapeutic targeting of MLL. Blood. 2009;113:6061–8.CrossRefPubMedGoogle Scholar
  70. 70.
    Pearce DJ, Taussig D, Zibara K, et al. AML engraftment in the NOD/SCID assay reflects the outcome of AML: implications for our understanding of the heterogeneity of AML. Blood. 2006;107:1166–73.CrossRefPubMedGoogle Scholar
  71. 71.
    Wojiski S, Guibal FC, Kindler T, et al. PML-RARalpha initiates leukemia by conferring properties of self-renewal to committed promyelocytic progenitors. Leukemia. 2009.Google Scholar
  72. 72.
    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;38:1269–77.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2010

Authors and Affiliations

  1. 1.Cancer Research UK Leukaemia Biology GroupPaterson Institute for Cancer ResearchManchesterUK
  2. 2.Department of PathologyStanford University School of MedicineStanfordUSA

Personalised recommendations