[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

MLL translocations, histone modifications and leukaemia stem-cell development

Nature Reviews Cancer volume 7, pages 823–833 (2007)Cite this article

Key Points

  • Mixed lineage leukaemia (MLL) translocations define a unique group of leukaemias, which phenotypically can be defined as acute myeloid leukaemias (AML), acute lymphoblastic leukaemias (ALL) or biphenotypic (mixed lineage) leukaemias (MLL).

  • MLL is a methyltransferase that is involved in the positive regulation of Hox gene expression and methylation of histone H3 lysine residue 4 (H3K4).

  • As a result of inter-chromosomal translocations, the N terminus of MLL can be 'fused' to the C terminus of over 50 different partners, which results in the loss of the H3K4 methyl transferase domain.

  • A major group of MLL fusion partners appear to interact with the DOT1L methyltransferase that positively regulates transcription by methylation of histone H3 lysine residue 79 (H3K79).

  • MLL fusion proteins efficiently transform haematopoietic precursors to leukaemia stem cells.

Abstract

Translocations that involve the mixed lineage leukaemia (MLL) gene identify a unique group of acute leukaemias, and often predict a poor prognosis. The MLL gene encodes a DNA-binding protein that methylates histone H3 lysine 4 (H3K4), and positively regulates gene expression including multiple Hox genes. Leukaemogenic MLL translocations encode MLL fusion proteins that have lost H3K4 methyltransferase activity. A key feature of MLL fusion proteins is their ability to efficiently transform haematopoietic cells into leukaemia stem cells. The link between a chromatin modulator and leukaemia stem cells provides support for epigenetic landscapes as an important part of leukaemia and normal stem-cell development.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Distribution of major MLL fusion partner genes in de novo childhood and adult leukaemias.
Figure 2: Schematic representation of the MLL protein and MLL fusions.
Figure 3: Histone methylation and transcription.
Figure 4: Gene-expression programmes of normal myeloid cells compared with MLL–AF9 leukaemia stem cells.
Figure 5: The leukaemia cell of origin and the LSC phenotype.

Similar content being viewed by others

References

  1. Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Rice, J. C. & Allis, C. D. Histone methylation versus histone acetylation: new insights into epigenetic regulation. Curr. Opin. Cell Biol. 13, 263–273 (2001).

    CAS  PubMed  Google Scholar 

  3. Shilatifard, A. Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression. Annu. Rev. Biochem. 75, 243–269 (2006).

    CAS  PubMed  Google Scholar 

  4. Sparmann, A. & van Lohuizen, M. Polycomb silencers control cell fate, development and cancer. Nature Rev. Cancer 6, 846–856 (2006).

    CAS  Google Scholar 

  5. Ayton, P. M. & Cleary, M. L. Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins. Oncogene 20, 5695–5707 (2001).

    CAS  PubMed  Google Scholar 

  6. Biondi, A., Cimino, G., Pieters, R. & Pui, C. H. Biological and therapeutic aspects of infant leukemia. Blood 96, 24–33 (2000).

    CAS  PubMed  Google Scholar 

  7. Huret, J. L., Dessen, P. & Bernheim, A. An atlas of chromosomes in hematological malignancies. Example: 11q23 and MLL partners. Leukemia 15, 987–989 (2001).

    CAS  PubMed  Google Scholar 

  8. Meyer, C. et al. The MLL recombinome of acute leukemias. Leukemia 20, 777–784 (2006).

    CAS  PubMed  Google Scholar 

  9. Chen, C. S. et al. Molecular rearrangements on chromosome 11q23 predominate in infant acute lymphoblastic leukemia and are associated with specific biologic variables and poor outcome. Blood 81, 2386–2393 (1993).

    CAS  PubMed  Google Scholar 

  10. Felix, C. A. et al. ALL-1 gene rearrangements in DNA topoisomerase II inhibitor-related leukemia in children. Blood 85, 3250–3256 (1995).

    CAS  PubMed  Google Scholar 

  11. Mrozek, K. et al. Adult patients with de novo acute myeloid leukemia and t(9;11)(p22; q23) have a superior outcome to patients with other translocations involving band 11q23: a cancer and leukemia group B study. Blood 90, 4532–4538 (1997).

    CAS  PubMed  Google Scholar 

  12. Rubnitz, J. E. et al. Favorable impact of the t(9;11) in childhood acute myeloid leukemia. J. Clin. Oncol. 20, 2302–2309 (2002).

    CAS  PubMed  Google Scholar 

  13. Gu, Y. et al. The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene. Cell 71, 701–708 (1992).

    CAS  PubMed  Google Scholar 

  14. Tkachuk, D. C., Kohler, S. & Cleary, M. L. Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias. Cell 71, 691–700 (1992).

    CAS  PubMed  Google Scholar 

  15. Butler, L. H., Slany, R., Cui, X., Cleary, M. L. & Mason, D. Y. The HRX proto-oncogene product is widely expressed in human tissues and localizes to nuclear structures. Blood 89, 3361–3370 (1997).

    CAS  PubMed  Google Scholar 

  16. Kawagoe, H., Humphries, R. K., Blair, A., Sutherland, H. J. & Hogge, D. E. Expression of HOX genes, HOX cofactors, and MLL in phenotypically and functionally defined subpopulations of leukemic and normal human hematopoietic cells. Leukemia 13, 687–698 (1999).

    CAS  PubMed  Google Scholar 

  17. Phillips, R. L. et al. The genetic program of hematopoietic stem cells. Science 288, 1635–1640 (2000).

    CAS  PubMed  Google Scholar 

  18. Daser, A. & Rabbitts, T. H. Extending the repertoire of the mixed-lineage leukemia gene MLL in leukemogenesis. Genes Dev. 18, 965–674 (2004).

    CAS  PubMed  Google Scholar 

  19. Popovic, R. & Zeleznik-Le, N. J. MLL: how complex does it get? J. Cell Biochem. 95, 234–242 (2005).

    CAS  PubMed  Google Scholar 

  20. Ernst, P., Wang, J., Huang, M., Goodman, R. H. & Korsmeyer, S. J. MLL and CREB bind cooperatively to the nuclear coactivator CREB-binding protein. Mol. Cell Biol. 21, 2249–2258 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Briggs, S. D. et al. Histone H3 lysine 4 methylation is mediated by Set1 and required for cell growth and rDNA silencing in Saccharomyces cerevisiae. Genes Dev. 15, 3286–3295 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Milne, T. A. et al. MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol. Cell 10, 1107–1117 (2002). This paper and reference 28 were the first to demonstrate H3K4 methyltransferase activity of the SET domain in mammalian MLL.

    CAS  PubMed  Google Scholar 

  23. Dou, Y. et al. Regulation of MLL1 H3K4 methyltransferase activity by its core components. Nature Struct. Mol. Biol. 13, 713–719 (2006).

    CAS  Google Scholar 

  24. Steward, M. M. et al. Molecular regulation of H3K4 trimethylation by ASH2L, a shared subunit of MLL complexes. Nature Struct. Mol. Biol. 13, 852–854 (2006).

    CAS  Google Scholar 

  25. Couture, J. F., Collazo, E. & Trievel, R. C. Molecular recognition of histone H3 by the WD40 protein WDR5. Nature Struct. Mol. Biol. 13, 698–703 (2006).

    CAS  Google Scholar 

  26. Crawford, B. D. & Hess, J. L. MLL core components give the green light to histone methylation. ACS Chem. Biol. 1, 495–498 (2006).

    CAS  PubMed  Google Scholar 

  27. Sims, R. J. III & Reinberg, D. Histone H3 Lys 4 methylation: caught in a bind? Genes Dev. 20, 2779–2786 (2006).

    CAS  PubMed  Google Scholar 

  28. Nakamura, T. et al. ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation. Mol. Cell 10, 1119–1128 (2002).

    CAS  PubMed  Google Scholar 

  29. Yokoyama, A. et al. Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression. Mol. Cell Biol. 24, 5639–5649 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Dou, Y. et al. Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF. Cell 121, 873–885 (2005).

    CAS  PubMed  Google Scholar 

  31. Zeleznik-Le, N. J., Harden, A. M. & Rowley, J. D. 11q23 translocations split the “AT-hook” cruciform DNA-binding region and the transcriptional repression domain from the activation domain of the mixed-lineage leukemia (MLL) gene. Proc. Natl Acad. Sci. USA 91, 10610–10614 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Birke, M. et al. The MT domain of the proto-oncoprotein MLL binds to CpG-containing DNA and discriminates against methylation. Nucleic Acids Res. 30, 958–965 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Yokoyama, A. et al. The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis. Cell 123, 207–218 (2005).

    CAS  PubMed  Google Scholar 

  34. Xia, Z. B., Anderson, M., Diaz, M. O. & Zeleznik-Le, N. J. MLL repression domain interacts with histone deacetylases, the polycomb group proteins HPC2 and BMI-1, and the corepressor C-terminal-binding protein. Proc. Natl Acad. Sci. USA 100, 8342–8347 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Abramovich, C. & Humphries, R. K. Hox regulation of normal and leukemic hematopoietic stem cells. Curr. Opin. Hematol. 12, 210–216 (2005).

    CAS  PubMed  Google Scholar 

  36. Yu, B. D., Hess, J. L., Horning, S. E., Brown, G. A. & Korsmeyer, S. J. Altered Hox expression and segmental identity in Mll-mutant mice. Nature 378, 505–508 (1995).

    CAS  PubMed  Google Scholar 

  37. Yagi, H. et al. Growth disturbance in fetal liver hematopoiesis of Mll-mutant mice. Blood 92, 108–117 (1998).

    CAS  PubMed  Google Scholar 

  38. Terranova, R., Agherbi, H., Boned, A., Meresse, S. & Djabali, M. Histone and DNA methylation defects at Hox genes in mice expressing a SET domain-truncated form of Mll. Proc. Natl Acad. Sci. USA 103, 6629–6634 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Hanson, R. D. et al. Mammalian Trithorax and polycomb-group homologues are antagonistic regulators of homeotic development. Proc. Natl Acad. Sci. USA 96, 14372–14377 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Guenther, M. G. et al. Global and Hox-specific roles for the MLL1 methyltransferase. Proc. Natl Acad. Sci. USA 102, 8603–8608 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Hess, J. L., Yu, B. D., Li, B., Hanson, R. & Korsmeyer, S. J. Defects in yolk sac hematopoiesis in Mll-null embryos. Blood 90, 1799–1806 (1997).

    CAS  PubMed  Google Scholar 

  42. Ernst, P. et al. Definitive hematopoiesis requires the mixed-lineage leukemia gene. Dev. Cell 6, 437–443 (2004).

    CAS  PubMed  Google Scholar 

  43. Pardal, R., Molofsky, A. V., He, S. & Morrison, S. J. Stem cell self-renewal and cancer cell proliferation are regulated by common networks that balance the activation of proto-oncogenes and tumor suppressors. Cold Spring Harb. Symp. Quant. Biol. 70, 177–185 (2005).

    CAS  PubMed  Google Scholar 

  44. Lessard, J. & Sauvageau, G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423, 255–260 (2003).

    CAS  PubMed  Google Scholar 

  45. Park, I. K. et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423, 302–305 (2003).

    CAS  PubMed  Google Scholar 

  46. Milne, T. A. et al. MLL associates specifically with a subset of transcriptionally active target genes. Proc. Natl Acad. Sci. USA 102, 14765–14770 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Richardson, C. & Jasin, M. Frequent chromosomal translocations induced by DNA double-strand breaks. Nature 405, 697–700 (2000).

    CAS  PubMed  Google Scholar 

  48. Strissel, P. L., Strick, R., Rowley, J. D. & Zeleznik-Le, N. J. An in vivo topoisomerase II cleavage site and a DNase I hypersensitive site colocalize near exon 9 in the MLL breakpoint cluster region. Blood 92, 3793–3803 (1998).

    CAS  PubMed  Google Scholar 

  49. So, C. W., Lin, M., Ayton, P. M., Chen, E. H. & Cleary, M. L. Dimerization contributes to oncogenic activation of MLL chimeras in acute leukemias. Cancer Cell 4, 99–110 (2003).

    CAS  PubMed  Google Scholar 

  50. So, C. W. & Cleary, M. L. Common mechanism for oncogenic activation of MLL by forkhead family proteins. Blood 101, 633–639 (2003).

    CAS  PubMed  Google Scholar 

  51. Hall, P. A. & Russell, S. E. The pathobiology of the septin gene family. J. Pathol. 204, 489–505 (2004).

    CAS  PubMed  Google Scholar 

  52. Ida, K. et al. Adenoviral E1A-associated protein p300 is involved in acute myeloid leukemia with t(11;22)(q23;q13). Blood 90, 4699–4704 (1997).

    CAS  PubMed  Google Scholar 

  53. Taki, T., Sako, M., Tsuchida, M. & Hayashi, Y. The t(11;16)(q23;p13) translocation in myelodysplastic syndrome fuses the MLL gene to the CBP gene. Blood 89, 3945–3950 (1997).

    CAS  PubMed  Google Scholar 

  54. Rowley, J. D. et al. All patients with the T(11;16)(q23;p13.3) that involves MLL and CBP have treatment-related hematologic disorders. Blood 90, 535–541 (1997).

    CAS  PubMed  Google Scholar 

  55. Caligiuri, M. A. et al. Partial tandem duplication of ALL1 as a recurrent molecular defect in acute myeloid leukemia with trisomy 11. Cancer Res. 56, 1418–1425 (1996).

    CAS  PubMed  Google Scholar 

  56. Schichman, S. A. et al. ALL-1 partial duplication in acute leukemia. Proc. Natl Acad. Sci. USA 91, 6236–6239 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Lochner, K. et al. A specific deletion in the breakpoint cluster region of the ALL-1 gene is associated with acute lymphoblastic T-cell leukemias. Cancer Res. 56, 2171–2177 (1996).

    CAS  PubMed  Google Scholar 

  58. Slany, R. K., Lavau, C. & Cleary, M. L. The oncogenic capacity of HRX-ENL requires the transcriptional transactivation activity of ENL and the DNA binding motifs of HRX. Mol. Cell Biol. 18, 122–129 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Milne, T. A., Martin, M. E., Brock, H. W., Slany, R. K. & Hess, J. L. Leukemogenic MLL fusion proteins bind across a broad region of the Hox a9 locus, promoting transcription and multiple histone modifications. Cancer Res. 65, 11367–11374 (2005).

    CAS  PubMed  Google Scholar 

  60. Corral, J. et al. An Mll-AF9 fusion gene made by homologous recombination causes acute leukemia in chimeric mice: a method to create fusion oncogenes. Cell 85, 853–861 (1996). Demonstrates that Mll–AF9 induces leukaemia in mice and describes a method for the generation of 'knock-in' mouse models of translocation-associated human leukaemias.

    CAS  PubMed  Google Scholar 

  61. Collins, E. C., Pannell, R., Simpson, E. M., Forster, A. & Rabbitts, T. H. Inter-chromosomal recombination of Mll and Af9 genes mediated by cre-loxP in mouse development. EMBO Rep. 1, 127–132 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Forster, A. et al. Engineering de novo reciprocal chromosomal translocations associated with Mll to replicate primary events of human cancer. Cancer Cell 3, 449–458 (2003).

    CAS  PubMed  Google Scholar 

  63. Wang, J. et al. Conditional MLL-CBP targets GMP and models therapy-related myeloproliferative disease. EMBO J. 24, 368–381 (2005).

    PubMed  PubMed Central  Google Scholar 

  64. Chen, W. et al. A murine Mll-AF4 knock-in model results in lymphoid and myeloid deregulation and hematologic malignancy. Blood 108, 669–677 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Metzler, M. et al. A conditional model of MLL-AF4 B-cell tumourigenesis using invertor technology. Oncogene 25, 3093–3103 (2006).

    CAS  PubMed  Google Scholar 

  66. Lavau, C., Szilvassy, S. J., Slany, R. & Cleary, M. L. Immortalization and leukemic transformation of a myelomonocytic precursor by retrovirally transduced HRX-ENL. EMBO J. 16, 4226–4237 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. So, C. W. et al. MLL-GAS7 transforms multipotent hematopoietic progenitors and induces mixed lineage leukemias in mice. Cancer Cell 3, 161–171 (2003).

    CAS  PubMed  Google Scholar 

  68. Zeisig, B. B., Garcia-Cuellar, M. P., Winkler, T. H. & Slany, R. K. The oncoprotein MLL-ENL disturbs hematopoietic lineage determination and transforms a biphenotypic lymphoid/myeloid cell. Oncogene 22, 1629–1637 (2003).

    CAS  PubMed  Google Scholar 

  69. Barabe, F., Kennedy, J. A., Hope, K. J. & Dick, J. E. Modeling the initiation and progression of human acute leukemia in mice. Science 316, 600–604 (2007).

    CAS  PubMed  Google Scholar 

  70. Yu, M. et al. MLL tandem duplication and multiple splicing in adult acute myeloid leukemia with normal karyotype. Leukemia 10, 774–780 (1996).

    CAS  PubMed  Google Scholar 

  71. Caligiuri, M. A. et al. The partial tandem duplication of ALL1 in acute myeloid leukemia with normal cytogenetics or trisomy 11 is restricted to one chromosome. Proc. Natl Acad. Sci. USA 94, 3899–3902 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Dorrance, A. M. et al. Mll partial tandem duplication induces aberrant Hox expression in vivo via specific epigenetic alterations. J. Clin. Invest. 116, 2707–2716 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Dobson, C. L., Warren, A. J., Pannell, R., Forster, A. & Rabbitts, T. H. Tumorigenesis in mice with a fusion of the leukaemia oncogene Mll and the bacterial lacZ gene. EMBO J. 19, 843–851 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Bernard, O. A., Mauchauffe, M., Mecucci, C., Van den Berghe, H. & Berger, R. A novel gene, AF-1p, fused to HRX in t(1;11)(p32;q23), is not related to AF-4, AF-9 nor ENL. Oncogene 9, 1039–1045 (1994).

    CAS  PubMed  Google Scholar 

  75. Megonigal, M. D. et al. Detection of leukemia-associated MLL-GAS7 translocation early during chemotherapy with DNA topoisomerase II inhibitors. Proc. Natl Acad. Sci. USA 97, 2814–2819 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Slany, R. K. When epigenetics kills: MLL fusion proteins in leukemia. Hematol. Oncol. 23, 1–9 (2005).

    CAS  PubMed  Google Scholar 

  77. Shilatifard, A., Lane, W. S., Jackson, K. W., Conaway, R. C. & Conaway, J. W. An RNA polymerase II elongation factor encoded by the human ELL gene. Science 271, 1873–1876 (1996).

    CAS  PubMed  Google Scholar 

  78. Simone, F. et al. EAF1, a novel ELL-associated factor that is delocalized by expression of the MLL-ELL fusion protein. Blood 98, 201–209 (2001).

    CAS  PubMed  Google Scholar 

  79. Garcia-Cuellar, M. P. et al. ENL, the MLL fusion partner in t(11;19), binds to the c-Abl interactor protein 1 (ABI1) that is fused to MLL in t(10;11)+. Oncogene 19, 1744–1751 (2000).

    CAS  PubMed  Google Scholar 

  80. Prasad, R. et al. Domains with transcriptional regulatory activity within the ALL1 and AF4 proteins involved in acute leukemia. Proc. Natl Acad. Sci. USA 92, 12160–12164 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. So, C. W. & Cleary, M. L. MLL-AFX requires the transcriptional effector domains of AFX to transform myeloid progenitors and transdominantly interfere with forkhead protein function. Mol. Cell Biol. 22, 6542–6552 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Erfurth, F., Hemenway, C. S., de Erkenez, A. C. & Domer, P. H. MLL fusion partners AF4 and AF9 interact at subnuclear foci. Leukemia 18, 92–102 (2004).

    CAS  PubMed  Google Scholar 

  83. Okada, Y. et al. hDOT1L links histone methylation to leukemogenesis. Cell 121, 167–178 (2005). Identifies a unique function of an MLL fusion (MLL–AF10). The recruitment of the H3K79 methyltransferase DOT1L by AF10 is necessary for transformation.

    CAS  PubMed  Google Scholar 

  84. Guenther, M. G., Levine, S. S., Boyer, L. A., Jaenisch, R. & Young, R. A. A chromatin landmark and transcription initiation at most promoters in human cells. Cell 130, 77–88 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Lachner, M., O'Sullivan, R. J. & Jenuwein, T. An epigenetic road map for histone lysine methylation. J. Cell Sci. 116, 2117–2124 (2003).

    CAS  PubMed  Google Scholar 

  86. Zhang, W., Xia, X., Reisenauer, M. R., Hemenway, C. S. & Kone, B. C. Dot1a-AF9 complex mediates histone H3 Lys-79 hypermethylation and repression of ENaCα in an aldosterone-sensitive manner. J. Biol. Chem. 281, 18059–18068 (2006).

    CAS  PubMed  Google Scholar 

  87. Bitoun, E., Oliver, P. L. & Davies, K. E. The mixed-lineage leukemia fusion partner AF4 stimulates RNA polymerase II transcriptional elongation and mediates coordinated chromatin remodeling. Hum. Mol. Genet. 16, 92–106 (2007).

    CAS  PubMed  Google Scholar 

  88. Zeisig, D. T. et al. The eleven-nineteen-leukemia protein ENL connects nuclear MLL fusion partners with chromatin. Oncogene 24, 5525–5532 (2005).

    CAS  PubMed  Google Scholar 

  89. So, C. W. et al. The interaction between EEN and Abi-1, two MLL fusion partners, and synaptojanin and dynamin: implications for leukaemogenesis. Leukemia 14, 594–601 (2000).

    CAS  PubMed  Google Scholar 

  90. Cozzio, A. et al. Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes Dev. 17, 3029–3035 (2003). Demonstrates direct transformation of committed myeloid progenitors by an MLL fusion. This finding suggests that cells incapable of self renewal can be transformed by certain oncogenes.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Na Nakorn, T., Traver, D., Weissman, I. L. & Akashi, K. Myeloerythroid-restricted progenitors are sufficient to confer radioprotection and provide the majority of day 8 CFU.-S. J. Clin. Invest. 109, 1579–1585 (2002).

    PubMed  PubMed Central  Google Scholar 

  92. Huntly, B. J. et al. MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell 6, 587–596 (2004).

    CAS  PubMed  Google Scholar 

  93. Miller, C. T., Maves, L. & Kimmel, C. B. moz regulates Hox expression and pharyngeal segmental identity in zebrafish. Development 131, 2443–2461 (2004).

    CAS  PubMed  Google Scholar 

  94. Deguchi, K. et al. MOZ-TIF2-induced acute myeloid leukemia requires the MOZ nucleosome binding motif and TIF2-mediated recruitment of CBP. Cancer Cell 3, 259–271 (2003).

    CAS  PubMed  Google Scholar 

  95. Dick, J. E. & Lapidot, T. Biology of normal and acute myeloid leukemia stem cells. Int. J. Hematol. 82, 389–396 (2005).

    CAS  PubMed  Google Scholar 

  96. Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).

    CAS  PubMed  Google Scholar 

  97. Bonnet, D. & Dick, J. E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Med. 3, 730–737 (1997).

    CAS  PubMed  Google Scholar 

  98. Passegue, E., Wagers, A. J., Giuriato, S., Anderson, W. C. & Weissman, I. L. Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates. J. Exp. Med. 202, 1599–1611 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Krivtsov, A. V. et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 442, 818–822 (2006).

    CAS  PubMed  Google Scholar 

  100. Somervaille, T. C. & Cleary, M. L. Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. Cancer Cell 10, 257–268 (2006).

    CAS  PubMed  Google Scholar 

  101. Kroon, E. et al. Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b. EMBO J. 17, 3714–3725 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Griffin, J. D. & Lowenberg, B. Clonogenic cells in acute myeloblastic leukemia. Blood 68, 1185–1195 (1986).

    CAS  PubMed  Google Scholar 

  103. Opferman, J. T. et al. Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells. Science 307, 1101–1104 (2005).

    CAS  PubMed  Google Scholar 

  104. Terskikh, A. V., Miyamoto, T., Chang, C., Diatchenko, L. & Weissman, I. L. Gene expression analysis of purified hematopoietic stem cells and committed progenitors. Blood 102, 94–101 (2003).

    CAS  PubMed  Google Scholar 

  105. Scharenberg, C. W., Harkey, M. A. & Torok-Storb, B. The ABCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors. Blood 99, 507–512 (2002).

    CAS  PubMed  Google Scholar 

  106. Yilmaz, O. H. et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441, 475–482 (2006).

    CAS  PubMed  Google Scholar 

  107. Krause, D. S., Lazarides, K., von Andrian, U. H. & Van Etten, R. A. Requirement for CD44 in homing and engraftment of BCR-ABL-expressing leukemic stem cells. Nature Med. 12, 1175–1180 (2006).

    CAS  PubMed  Google Scholar 

  108. Deshpande, A. J. 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 10, 363–374 (2006).

    CAS  PubMed  Google Scholar 

  109. Jin, L., Hope, K. J., Zhai, Q., Smadja-Joffe, F. & Dick, J. E. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nature Med. 12, 1167–1174 (2006).

    PubMed  Google Scholar 

  110. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006). A landmark paper demonstrating the ability to induce cellular reprogramming from fibroblasts to ES cells with a limited number of genes.

    CAS  PubMed  Google Scholar 

  111. Okita, K., Ichisaka, T. & Yamanaka, S. Generation of germline-competent induced pluripotent stem cells. Nature 448, 313–317 (2007).

    CAS  PubMed  Google Scholar 

  112. Wernig, M. et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448, 318–324 (2007).

    CAS  PubMed  Google Scholar 

  113. Ducasse, M. & Brown, M. A. Epigenetic aberrations and cancer. Mol. Cancer 5, 60 (2006).

    PubMed  PubMed Central  Google Scholar 

  114. Feinberg, A. P. Phenotypic plasticity and the epigenetics of human disease. Nature 447, 433–440 (2007).

    CAS  PubMed  Google Scholar 

  115. Esteller, M. Cancer epigenomics: DNA methylomes and histone-modification maps. Nature Rev. Genet. 8, 286–298 (2007).

    CAS  PubMed  Google Scholar 

  116. Francis, N. J., Kingston, R. E. & Woodcock, C. L. Chromatin compaction by a polycomb group protein complex. Science 306, 1574–1577 (2004).

    CAS  PubMed  Google Scholar 

  117. Papp, B. & Muller, J. Histone trimethylation and the maintenance of transcriptional ON and OFF states by trxG and PcG proteins. Genes Dev. 20, 2041–2054 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Schuettengruber, B., Chourrout, D., Vervoort, M., Leblanc, B. & Cavalli, G. Genome regulation by polycomb and trithorax proteins. Cell 128, 735–745 (2007).

    CAS  PubMed  Google Scholar 

  119. De Braekeleer, M., Morel, F., Le Bris, M. J., Herry, A. & Douet-Guilbert, N. The MLL gene and translocations involving chromosomal band 11q23 in acute leukemia. Anticancer Res. 25, 1931–1944 (2005).

    CAS  PubMed  Google Scholar 

  120. Fair, K. et al. Protein interactions of the MLL PHD fingers modulate MLL target gene regulation in human cells. Mol. Cell Biol. 21, 3589–3597 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Cheung, N., Chan, L. C., Thompson, A., Cleary, M. L. & Eric So, C. W. Protein arginine-methyltransferase-dependent oncogenesis. Nature Cell Biol. 23 September 2007 [Epub ahead of print].

    Google Scholar 

Download references

Acknowledgements

We would like to thank members of the Armstrong laboratory for helpful comments and Elise Porter for administrative assistance. We recognize that there are a number of aspects of MLL-mediated biology that we were unable to cover in this Review, and direct readers to a number of recent reviews that cover other aspects of this interesting topic. We apologize to those that we have been unable to reference owing to space constraints.

Author information

Authors and Affiliations

  1. Division of Haematology/Oncology, Department of Pediatric Oncology, Children's Hospital, and Harvard Medical School, Boston, 02115, Massachusetts, USA

    Andrei V. Krivtsov & Scott A. Armstrong

Authors
  1. Andrei V. Krivtsov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Scott A. Armstrong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Scott A. Armstrong.

Related links

Related links

FURTHER INFORMATION

Scott A. Armstrong's homepage

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Glossary

Biphenotypic leukaemia

An acute leukaemia where leukaemic blasts express both myeloid and lymphoid antigens such as CD14 and CD19, respectively. Normally, such cells are not found in haematopoietic organs.

Immunophenotype

A combination of cell surface antigens recognized by fluorescent-dye-labelled antibodies that are used to define a specific cell type.

Aorta–gonad–mesonephros region

A region in the mouse embryo that is believed to be the origin of definitive haematopoiesis and where the first definitive haematopoietic stem cell appears to develop.

Breakpoint cluster region

A region on a chromosome that is a frequent site of involvement in interchromosomal translocations.

Nuclear matrix

A protein matrix that provides a scaffold for nuclear organization and to which chromatin is attached.

Cyclophilin

An enzyme with peptidyl prolyl isomerase activity, which catalyses the isomerization of peptide bonds from trans to cis form at proline residues and facilitates protein folding.

Self renewal

The ability of a cell to replicate such that it produces at least one progeny cell that retains all of the developmental and proliferative potential of the mother cell. A self-renewing division can produce either two cells with all properties of the mother cell or one cell with all properties of the mother cell and one cell that is more differentiated.

Granulocyte macrophage progenitor

(GMP). A progenitor cell in bone marrow that can give rise to terminally differentiated monocytes, macrophages, and neutrophils, but not other haematopoietic cells such as megakaryocytes, red blood cells, B or T natural killer cells, or dendritic cells. GMPs are incapable of self renewal.

BCR-ABL

A leukaemogenic fusion protein that is a result of reciprocal translocation between chromosome 9 and chromosome 22. The 5′ section of BCR from chromosome 9 is fused to most of the proto-oncogene ABL from chromosome 22.

Rapamycin

An immunosuppressive drug that inhibits mammalian target of rapamycin (mTOR). Rapamycin and other mTOR inhibitors are being assessed as potential therapeutics in a number of cancers, including leukaemias.

PTEN

Mutations in the PTEN tumour suppressor are found in many common human tumour types, including glioma, endometrial adenocarcinoma, melanoma and prostate adenocarcinoma.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Krivtsov, A., Armstrong, S. MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer 7, 823–833 (2007). https://doi.org/10.1038/nrc2253

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2253

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing