Advertisement

International Journal of Hematology

, Volume 82, Issue 1, pp 9–20 | Cite as

Molecular Pathogenesis of MLL-Associated Leukemias

  • Mariko Eguchi
  • Minenori Eguchi-Ishimae
  • Mel Greaves
Article

Abstract

Chromosome translocations disrupting theMLL gene are associated with various hematologic malignancies but are particularly common in infant and secondary therapy-related acute leukemias. The normal MLL-encoded protein is an essential component of a supercomplex with chromatin-modulating activity conferred by histone acetylase and methyltransferase activities, and the protein plays a key role in the developmental regulation of gene expression, includingHox gene expression. In leukemia, this function is subverted by breakage, recombination, and the formation of chimeric fusion with one of many alternative partners. SuchMLL translocations result in the replacement of the C-terminal functional domains of MLL with those of a fusion partner, yielding a newly formed MLL chimeric protein with an altered function that endows hematopoietic progenitors with self-renewing and leukemogenic activity. This potent impact of the MLL chimera can be attributed to one of 2 kinds of activity of the fusion partner: direct transcriptional transactivation or dimerization/oligomerization. Key unresolved issues currently being addressed include the set of target genes forMLL fusions, the stem cell of origin for the leukemias, the role of additional secondary mutations, and the origins or etiology of theMLL gene fusions themselves. Further elaboration of the biology ofMLL gene-associated leukemia should lead to novel and specific therapeutic strategies.

Key words

MLL gene Histone methylation/acetylation Hematopoietic stem cells Mouse models Short latency 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Rabbitts TH. Chromosomal translocations in human cancer.Nature. 1994;372:143–149.PubMedGoogle Scholar
  2. 2.
    Look AT. Oncogenic transcription factors in the human acute leukemias.Science. 1997;278:1059–1064.PubMedGoogle Scholar
  3. 3.
    Cimino G, Moir DT, Canaani O, et al. Cloning of ALL-1, the locus involved in leukemias with the t(4;11)(q21;q23), t(9;11)(p22;q23), and t(11;19)(q23;p13) chromosome translocations.Cancer Res. 1991;51:6712–6714.PubMedGoogle Scholar
  4. 4.
    Ziemin-van der Poel S, McCabe NR, Gill HJ, et al. Identification of a gene, MLL, that spans the breakpoint in 11q23 translocations associated with human leukemias.Proc Natl Acad Sci USA. 1991; 88:10735–10739.Google Scholar
  5. 5.
    Tkachuk DC, Kohler S, Cleary ML. Involvement of a homolog ofDrosophila trithorax by 11q23 chromosomal translocations in acute leukemias.Cell. 1992;71:691–700.PubMedGoogle Scholar
  6. 6.
    Djabali M, Selleri L, Parry P, Bower M, Young BD, Evans GA. A trithorax-like gene is interrupted by chromosome 11q23 trans- locations in acute leukaemias.Nat Genet. 1992;2:113–118.PubMedGoogle Scholar
  7. 7.
    Rowley JD. The role of chromosome translocations in leukemogenesis.Semin Hematol. 1999;36:59–72.PubMedGoogle Scholar
  8. 8.
    DiMartino JF, Cleary ML.MLL rearrangements in haematological malignancies: lessons from clinical and biological studies.Br J Haematol. 1999;106:614–626.PubMedGoogle Scholar
  9. 9.
    Biondi A, Cimino G, Pieters R, Pui CH. Biological and therapeutic aspects of infant leukemia.Blood. 2000;96:24–33.PubMedGoogle Scholar
  10. 10.
    Felix CA. Secondary leukemias induced by topoisomerase-targeted drugs.Biochim Biophys Acta. 1998;1400:233–255.PubMedGoogle Scholar
  11. 11.
    Gu Y, Nakamura T, Alder H, et al. The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related toDrosophila trithorax, to the AF-4 gene.Cell. 1992;71:701–708.PubMedGoogle Scholar
  12. 12.
    Yu BD, Hess JL, Horning SE, Brown GA, Korsmeyer SJ. Altered Hox expression and segmental identity in Mll-mutant mice.Nature. 1995;378:505–508.PubMedGoogle Scholar
  13. 13.
    Yu BD, Hanson RD, Hess JL, Horning SE, Korsmeyer SJ. MLL, a mammalian trithorax-group gene, functions as a transcriptional maintenance factor in morphogenesis.Proc Natl Acad Sci USA. 1998;95:10632–10636.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Hsieh JJ, Cheng EH, Korsmeyer SJ. Taspase1: a threonine aspartase required for cleavage of MLL and properHOX gene expression.Cell. 2003;115:293–303.PubMedGoogle Scholar
  15. 15.
    Nakamura T, Mori T, Tada S, et al. ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation.Mol Cell. 2002;10:1119–1128.PubMedGoogle Scholar
  16. 16.
    Yokoyama A, Kitabayashi I, Ayton PM, Cleary ML, Ohki M. Leukemia proto-oncoprotein MLL is proteolytically processed into 2 fragments with opposite transcriptional properties.Blood. 2002;100:3710–3718.PubMedGoogle Scholar
  17. 17.
    Hsieh JJ, Ernst P, Erdjument-Bromage H, Tempst P, Korsmeyer SJ. Proteolytic cleavage of MLL generates a complex of N- and C-terminal fragments that confers protein stability and sub- nuclear localization.Mol Cell Biol. 2003;23:186–194.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Zeleznik-Le NJ, Harden AM, Rowley JD. 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. 1994;91:10610–10614.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Broeker PL, Harden A, Rowley JD, Zeleznik-Le N. The mixed lineage leukemia (MLL) protein involved in 11q23 translocations contains a domain that binds cruciform DNA and scaffold attachment region (SAR) DNA.Curr Top Microbiol Immunol. 1996;211:259–2688.PubMedGoogle Scholar
  20. 20.
    Aravind L, Landsman D. AT-hook motifs identified in a wide variety of DNA-binding proteins.Nucleic Acids Res. 1998;26:4413–44211.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Xia Z-B, Anderson M, Diaz MO, Zeleznik-Le NJ. 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. 2003;100:8342–8347.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Cross SH, Meehan RR, Nan X, Bird A. A component of the transcriptional repressor MeCP1 shares a motif with DNA methyl- transferase and HRX proteins.Nat Genet. 1997;16:256–259.PubMedGoogle Scholar
  23. 23.
    Fuks F, Burgers WA, Brehm A, Hughes-Davies L, Kouzarides T. DNA methyltransferase Dnmt1 associates with histone deacetylase activity.Nat Genet. 2000;24:88–91.PubMedGoogle Scholar
  24. 24.
    Birke M, Schreiner S, Garcia-Cuellar MP, Mahr K, Titgemeyer F, Slany RK. The MT domain of the proto-oncoprotein MLL binds to CpG-containing DNA and discriminates against methylation.Nucleic Acids Res. 2002;30:958–965.PubMedPubMedCentralGoogle 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;24:10470–10478.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Fair K, Anderson M, Bulanova E, Mi H, Tropschug M, Diaz MO. Protein interactions of the MLL PHD fingers modulate MLL target gene regulation in human cells.Mol Cell Biol. 2001;21:3589–35977.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Diaz MO, Koonce MA. Cyp33-MLL interaction modulates human HOX gene expression and chromatin structure [abstract].Blood. 2004;104:319a.Google Scholar
  28. 28.
    Ernst P, Wang J, Huang M, Goodman RH, Korsmeyer SJ. MLL and CREB bind cooperatively to the nuclear coactivator CREB- binding protein.Mol Cell Biol. 2001;21:2249–2258.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Milne TA, Briggs SD, Brock HW, et al. MLL targets SET domain methyltransferase activity toHox gene promoters.Mol Cell. 2002; 10:1107–1117.PubMedGoogle Scholar
  30. 30.
    Prasad R, Zhadanov AB, Sedkov Y, et al. Structure and expression pattern of humanALR, a novel gene with strong homology to ALL-1 involved in acute leukemia and toDrosophila trithorax.Oncogene. 1997;15:549–560.PubMedPubMedCentralGoogle Scholar
  31. 31.
    FitzGerald KT, Diaz MO.MLL2: a new mammalian member of thetrx/MLL family of genes.Genomics. 1999;59:187–192.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Huntsman DG, Chin SF, Muleris M, et al.MLL2, the second human homolog of theDrosophila trithorax gene, maps to 19q13.1 and is amplified in solid tumor cell lines.Oncogene. 1999;18:7975–79844.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Tan YC, Chow VT. Novel human HALR (MLL3) gene encodes a protein homologous to ALR and to ALL-1 involved in leukemia, and maps to chromosome 7q36 associated with leukemia and developmental defects.Cancer Detect Prev. 2001;25:454–469.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Ruault M, Brun ME, Ventura M, Roizes G, De Sario A.MLL3, a new human member of theTRX/MLL gene family, maps to 7q36, a chromosome region frequently deleted in myeloid leukaemia.Gene. 2002;284:73–81.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Emerling BM, Bonifas J, Kratz CP, et al.MLL5, a homolog ofDrosophila trithorax located within a segment of chromosome band 7q22 implicated in myeloid leukemia.Oncogene. 2002;21:4849–48544.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Deng LW, Chiu I, Strominger JL. MLL 5 protein forms intranuclear foci, and overexpression inhibits cell cycle progression.Proc Natl Acad Sci USA. 2004;101:757–762.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Yokoyama A, Wang Z, Wysocka J, et al. Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulateHox gene expression.Mol Cell Biol. 2004;24:5639–56499.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Milne TA, Martin ME, Slany RK, Hess JL. Leukemogenic MLL fusion proteins promote MLL association with HOX loci resulting in persistent expression [abstract].Blood. 2004;104:114a.Google Scholar
  39. 39.
    Milne TA, Hughes CM, Lloyd R, et al. Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors.Proc Natl Acad Sci USA.2005;102:749–754.Google Scholar
  40. 40.
    Hughes CM, Rozenblatt-Rosen O, Milne TA, et al. Menin associates with a trithorax family histone methyltransferase complex and with theHoxc8 locus.Mol Cell. 2004;13:587–597.PubMedGoogle Scholar
  41. 41.
    Hess JL, Yu BD, Li B, Hanson R, Korsmeyer SJ. Defects in yolk sac hematopoiesis in Mll-null embryos.Blood. 1997;90:1799–1806.PubMedGoogle Scholar
  42. 42.
    Yagi H, Deguchi K, Aono A, Tani Y, Kishimoto T, Komori T. Growth disturbance in fetal liver hematopoiesis of Mll-mutant mice.Blood. 1998;92:108–117.PubMedGoogle Scholar
  43. 43.
    Ernst P, Fisher JK, Avery W, Wade S, Foy D, Korsmeyer SJ. Definitive hematopoiesis requires the mixed-lineage leukemia gene.Dev Cell. 2004;6:437–443.PubMedGoogle Scholar
  44. 44.
    Ayton PM, Cleary ML. Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins.Oncogene. 2001;20:5695–5707.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Collins EC, Rabbitts TH. The promiscuousMLL gene links chromosomal translocations to cellular differentiation and tumour tropism.Trends Mol Med. 2002;8:436–442.PubMedGoogle Scholar
  46. 46.
    Eguchi M, Eguchi-Ishimae M, Greaves M. The role of theMLL gene in infant leukemia.Int J Hematol. 2003;78:390–401.PubMedGoogle Scholar
  47. 47.
    Bohlander SK. Fusion genes in leukemia: an emerging network.Cytogenet Cell Genet. 2000;91:52–56.PubMedGoogle Scholar
  48. 48.
    Slape C, Aplan PD. The role of NUP98 gene fusions in hematologic malignancy.Leuk Lymphoma. 2004;45:1341–1350.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Joh T, Yamamoto K, Kagami Y, et al. Chimeric MLL products with a Ras binding cytoplasmic protein AF6 involved in t(6;11) (q27;q23) leukemia localize in the nucleus.Oncogene. 1997;15:1681–16877.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Yano T, Nakamura T, Blechman J, et al. Nuclear punctate distribution of ALL-1 is conferred by distinct elements at the N terminus of the protein.Proc Natl Acad Sci USA. 1997;94:7286–7291.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Eguchi M, Eguchi-Ishimae M, Greaves M. The small oligomerization domain of gephyrin converts MLL to an oncogene.Blood. 2004;103:3876–3882.PubMedGoogle Scholar
  52. 52.
    Liu H, Chen B, Xiong H, et al. Functional contribution of EEN to leukemogenic transformation by MLL-EEN fusion protein.Oncogene. 2004;23:3385–3394.PubMedGoogle Scholar
  53. 53.
    Dobson CL, Warren AJ, Pannell R, et al. TheMll-AF9 gene fusion in mice controls myeloproliferation and specifies acute myeloid leukaemogenesis.EMBO J. 1999;18:3564–3574.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Lavau C, Szilvassy SJ, Slany R, Cleary ML. Immortalization and leukemic transformation of a myelomonocytic precursor by retrovirally transduced HRX-ENL.EMBO J. 1997;16:4226–4237.PubMedPubMedCentralGoogle Scholar
  55. 55.
    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;85:853–861.PubMedGoogle Scholar
  56. 56.
    Forster A, Pannell R, Drynan LF, et al. Engineering de novo reciprocal chromosomal translocations associated withMll to replicate primary events of human cancer.Cancer Cell. 2003;3:449–458.PubMedGoogle Scholar
  57. 57.
    Dobson CL, Warren AJ, Pannell R, Forster A, Rabbitts TH. Tumorigenesis in mice with a fusion of the leukaemia oncogeneMll and the bacteriallacZ gene.EMBO J. 2000;19:843–851.PubMedPubMedCentralGoogle Scholar
  58. 58.
    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;18:122–1299.PubMedPubMedCentralGoogle Scholar
  59. 59.
    DiMartino JF, Miller T, Ayton PM, et al. A carboxy-terminal domain of ELL is required and sufficient for immortalization of myeloid progenitors by MLL-ELL.Blood. 2000;96:3887–3893.PubMedGoogle Scholar
  60. 60.
    Lavau C, Luo RT, Du C, Thirman MJ. Retrovirus-mediated gene transfer of MLL-ELL transforms primary myeloid progenitors and causes acute myeloid leukemias in mice.Proc Natl Acad Sci USA. 2000;97:10984–10989.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Luo RT, Lavau C, Du C, et al. The elongation domain of ELL is dispensable but its ELL-associated factor 1 interaction domain is essential for MLL-ELL-induced leukemogenesis.Mol Cell Biol. 2001;21:5678–5687.PubMedPubMedCentralGoogle Scholar
  62. 62.
    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;99:3780–3785.PubMedGoogle Scholar
  63. 63.
    So CW, Cleary ML. MLL-AFX requires the transcriptional effector domains of AFX to transform myeloid progenitors and trans- dominantly interfere with forkhead protein function.Mol Cell Biol. 2002;22:6542–6552.PubMedPubMedCentralGoogle Scholar
  64. 64.
    So CW, Cleary ML. Common mechanism for oncogenic activation of MLL by forkhead family proteins.Blood. 2003;101:633–639.PubMedGoogle Scholar
  65. 65.
    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;19:4655–46644.PubMedPubMedCentralGoogle Scholar
  66. 66.
    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.PubMedGoogle Scholar
  67. 67.
    Fuchs U, Rehkamp G, Haas OA, et al. The human formin-binding protein 17 (FBP17) interacts with sorting nexin, SNX2, and is an MLL-fusion partner in acute myelogeneous leukemia.Proc Natl Acad Sci USA. 2001;98:8756–8761.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Strehl S, Borkhardt A, Slany R, Fuchs UE, Konig M, Haas OA. The humanLASP1 gene is fused toMLL in an acute myeloid leukemia with t(11;17)(q23;q21).Oncogene. 2003;22:157–160.PubMedPubMedCentralGoogle Scholar
  69. 69.
    So CW, Wong P, Lin M, Cleary ML. Disease models and transformation mechanisms mediated by MLL-AF4 family oncoproteins in human leukemia [abstract].Blood. 2004;104:136a.Google Scholar
  70. 70.
    Zeisig BB, Schreiner S, Garcia-Cuellar MP, Slany RK. Transcriptional activation is a key function encoded by MLL fusion partners.Leukemia. 2003;17:359–365.PubMedGoogle Scholar
  71. 71.
    Martin ME, Milne TA, Bloyer S, et al. Dimerization of MLL fusion proteins immortalizes hematopoietic cells.Cancer Cell. 2003;4:197–2077.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Jacobson RH, Zhang XJ, DuBose RF, Matthews BW. Three- dimensional structure of beta-galactosidase fromE. coli. Nature. 1994;369:761–766.PubMedGoogle Scholar
  73. 73.
    Minucci S, Maccarana M, Cioce M, et al. Oligomerization of RAR and AML1 transcription factors as a novel mechanism of oncogenic activation.Mol Cell. 2000;5:811–820.PubMedGoogle Scholar
  74. 74.
    Hayashi Y. The molecular genetics of recurring chromosome abnormalities in acute myeloid leukemia.Semin Hematol. 2000;37:368–3800.PubMedGoogle Scholar
  75. 75.
    Cairns BR, Henry NL, Kornberg RD. TFG/TAF30/ANC1, a component of the yeast SWI/SNF complex that is similar to the leukemogenic proteins ENL and AF-9.Mol Cell Biol. 1996;16:3308–3316.PubMedPubMedCentralGoogle Scholar
  76. 76.
    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;23:2942–2952.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Debernardi S, Bassini A, Jones LK, et al. The MLL fusion partner AF10 binds GAS41, a protein that interacts with the human SWI/ SNF complex.Blood. 2002;99:275–281.PubMedGoogle Scholar
  78. 78.
    Garcia-Cuellar MP, Schreiner SA, Birke M, Hamacher M, Fey GH, Slany RK. 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. 2000;19:1744–1751.PubMedGoogle Scholar
  79. 79.
    Burgering BM, Kops GJ. Cell cycle and death control: long live Forkheads.Trends Biochem Sci. 2002;27:352–360.PubMedGoogle Scholar
  80. 80.
    Shilatifard A, Lane WS, Jackson KW, Conaway RC, Conaway JW. An RNA polymerase II elongation factor encoded by the human ELL gene.Science. 1996;271:1873–1876.PubMedGoogle Scholar
  81. 81.
    Maki K, Mitani K, Yamagata T, et al. Transcriptional inhibition of p53 by the MLL/MEN chimeric protein found in myeloid leukemia.Blood. 1999;93:3216–3224.PubMedGoogle Scholar
  82. 82.
    Wiederschain D, Kawai H, Gu J, Shilatifard A, Yuan ZM. Molecular basis of p53 functional inactivation by the leukemic protein MLL-ELL.Mol Cell Biol. 2003;23:4230–4246.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Yam JW, Jin DY, So CW, Chan LC. Identification and characterization of EBP, a novel EEN binding protein that inhibits Ras signaling and is recruited into the nucleus by the MLL-EEN fusion protein.Blood. 2004;103:1445–1453.PubMedGoogle Scholar
  84. 84.
    Owens BM, Hawley RG.HOX and non-HOX homeobox genes in leukemic hematopoiesis.Stem Cells. 2002;20:364–379.PubMedGoogle Scholar
  85. 85.
    Pineault N, Helgason CD, Lawrence HJ, Humphries RK. Differential expression ofHox, Meis1, andPbx1 genes in primitive cells throughout murine hematopoietic ontogeny.Exp Hematol. 2002; 30:49–57.PubMedGoogle Scholar
  86. 86.
    Fidanza V, Melotti P, Yano T, et al. Double knockout of the ALL-1 gene blocks hematopoietic differentiation in vitro.Cancer Res. 1996;56:1179–1183.PubMedGoogle Scholar
  87. 87.
    Ernst P, Mabon M, Davidson AJ, Zon LI, Korsmeyer SJ. AnMll- dependent Hox program drives hematopoietic progenitor expansion.Curr Biol. 2004;14:2063–2069.PubMedGoogle Scholar
  88. 88.
    Armstrong SA, Staunton JE, Silverman LB, et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia.Nat Genet. 2002;30:41–47.PubMedGoogle Scholar
  89. 89.
    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;1:133–143.PubMedGoogle Scholar
  90. 90.
    Ferrando AA, Armstrong SA, Neuberg DS, et al. Gene expression signatures in MLL-rearranged T-lineage and B-precursor acute leukemias: dominance ofHOX dysregulation.Blood. 2003;102:262–2688.PubMedGoogle Scholar
  91. 91.
    Rozovskaia T, Ravid-Amir O, Tillib S, et al. Expression profiles of acute lymphoblastic and myeloblastic leukemias with ALL-1 rearrangements.Proc Natl Acad Sci USA. 2003;100:7853–7858.PubMedPubMedCentralGoogle Scholar
  92. 92.
    Tsutsumi S, Taketani T, Nishimura K, et al. Two distinct gene expression signatures in pediatric acute lymphoblastic leukemia with MLL rearrangements.Cancer Res. 2003;63:4882–4887.PubMedGoogle Scholar
  93. 93.
    Ross ME, Zhou X, Song G, et al. Classification of pediatric acute lymphoblastic leukemia by gene expression profiling.Blood. 2003; 102:2951–2959.PubMedGoogle Scholar
  94. 94.
    Ross ME, Mahfouz R, Onciu M, et al. Gene expression profiling of pediatric acute myelogenous leukemia.Blood. 2004;104:3679–3687.PubMedGoogle Scholar
  95. 95.
    Ayton PM, Cleary ML. Transformation of myeloid progenitors by MLL oncoproteins is dependent onHoxa7 andHoxa9.Genes Dev. 2003;17:2298–2307.PubMedPubMedCentralGoogle Scholar
  96. 96.
    Zeisig BB, Milne T, Garcia-Cuellar MP, et al.Hoxa9 andMeis1 are key targets for MLL-ENL-mediated cellular immortalization.Mol Cell Biol. 2004;24:617–628.PubMedPubMedCentralGoogle Scholar
  97. 97.
    Wang J, Iwasaki H, Krivtsov A, et al. Conditional MLL-CBP targets GMP and models therapy-related myeloproliferative disease.EMBO J. 2005;24:368–381.PubMedPubMedCentralGoogle Scholar
  98. 98.
    Nakamura T, Largaespada DA, Shaughnessy JD Jr, Jenkins NA, Copeland NG. Cooperative activation ofHoxa andPbx1 -related genes in murine myeloid leukaemias.Nat Genet. 1996;12:149–153.PubMedGoogle Scholar
  99. 99.
    Kroon E, Krosl J, Thorsteinsdottir U, Baban S, Buchberg AM, Sauvageau G.Hoxa9 transforms primary bone marrow cells through specific collaboration withMeis1a but notPbx1b.EMBO J. 1998;17:3714–3725.PubMedPubMedCentralGoogle Scholar
  100. 100.
    Thorsteinsdottir U, Kroon E, Jerome L, Blasi F, Sauvageau G. Defining roles forHOX andMEIS1 genes in induction of acute myeloid leukemia.Mol Cell Biol. 2001;21:224–234.PubMedPubMedCentralGoogle Scholar
  101. 101.
    So CW, Karsunky H, Wong P, Weissman IL, Cleary ML. Leukemic transformation of hematopoietic progenitors by MLL-GAS7 in the absence ofHoxa7 orHoxa9.Blood. 2004;103:3192–3199.PubMedGoogle Scholar
  102. 102.
    Kumar AR, Hudson WA, Chen W, Nishiuchi R, Yao Q, Kersey JH.Hoxa9 influences the phenotype but not the incidence ofMll-AF9 fusion gene leukemia.Blood. 2004;103:1823–1828.PubMedGoogle Scholar
  103. 103.
    Greaves MF, Chan LC, Furley AJ, Watt SM, Molgaard HV. Lineage promiscuity in hemopoietic differentiation and leukemia.Blood. 1986;67:1–11.PubMedGoogle Scholar
  104. 104.
    EnverT, Greaves M. Loops, lineage, and leukemia.Cell. 1998;94:9–12.Google Scholar
  105. 105.
    Hu M, Krause D, Greaves M, et al. Multilineage gene expression precedes commitment in the hemopoietic system.Genes Dev. 1997; 11:774–785.PubMedGoogle Scholar
  106. 106.
    Miyamoto T, Iwasaki H, Reizis B, et al. Myeloid or lymphoid promiscuity as a critical step in hematopoietic lineage commitment.Dev Cell. 2002;3:137–147.PubMedGoogle Scholar
  107. 107.
    Ridge SA, Cabrera ME, Ford AM, et al. Rapid intraclonal switch of lineage dominance in congenital leukaemia with a MLL gene rearrangement.Leukemia. 1995;9:2023–2026.PubMedGoogle Scholar
  108. 108.
    Cumano A, Paige CJ, Iscove NN, Brady G. Bipotential precursors of B cells and macrophages in murine fetal liver.Nature. 1992;356:612–6155.PubMedGoogle Scholar
  109. 109.
    Hotfilder M, Rottgers S, Rosemann A, et al. Leukemic stem cells in childhood high-risk ALL/t(9;22) and t(4;11) are present in primitive lymphoid-restricted CD34+CD19- cells.Cancer Res. 2005;65:1442–14499.PubMedGoogle Scholar
  110. 110.
    Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell.Nat Med. 1997;3:730–737.PubMedPubMedCentralGoogle Scholar
  111. 111.
    Warner JK, Wang JC, Hope KJ, Jin L, Dick JE. Concepts of human leukemic development.Oncogene. 2004;23:7164–7177.PubMedPubMedCentralGoogle Scholar
  112. 112.
    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;3:161–171.PubMedGoogle Scholar
  113. 113.
    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;17:3029–3035.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Manaia A, Lemarchandel V, Klaine M, et al. Lmo2 and GATA-3 associated expression in intraembryonic hemogenic sites.Development. 2000;127:643–653.PubMedGoogle Scholar
  115. 115.
    Bertrand JY, Giroux S, Golub R, et al. Characterization of purified intraembryonic hematopoietic stem cells as a tool to define their site of origin.Proc NatlAcad Sci USA. 2005;102:134–139.Google Scholar
  116. 116.
    Rabbitts TH. Chromosomal translocation master genes, mouse models and experimental therapeutics.Oncogene. 2001;20:5763–57777.PubMedGoogle Scholar
  117. 117.
    Gilliland DG. Molecular genetics of human leukemias: new insights into therapy.Semin Hematol. 2002;39:6–11.PubMedGoogle Scholar
  118. 118.
    Greaves MF, Wiemel J. Origins of chromosome translocations in childhood leukaemia.Nat Rev Cancer. 2003;3:639–649.PubMedGoogle Scholar
  119. 119.
    Tsuzuki S, Seto M, Greaves M, Enver T. Modeling first-hit functions of the t(12;21)TEL-AML1 translocation in mice.Proc Natl Acad Sci USA. 2004;101:8443–8448.PubMedPubMedCentralGoogle Scholar
  120. 120.
    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;98:10398–10403.PubMedPubMedCentralGoogle Scholar
  121. 121.
    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;1:63–74.Google Scholar
  122. 122.
    Castilla LH, Garrett L, Adya N, et al. The fusion geneCbfb- MYH11 blocks myeloid differentiation and predisposes mice to acute myelomonocytic leukaemia.Nat Genet. 1999;23:144–146.PubMedGoogle Scholar
  123. 123.
    Ford AM, Bennett CA, Price CM, Bruin MC, Van WeringER, Greaves M. Fetal origins of theTEL-AML1 fusion gene in identical twins with leukemia.Proc Natl Acad Sci USA. 1998;95:4584–45888.PubMedPubMedCentralGoogle Scholar
  124. 124.
    Wiemels JL, Ford AM, Van WeringER, Postma A, Greaves M. Protracted and variable latency of acute lymphoblastic leukemia afterTEL-AML1 gene fusion in utero.Blood. 1999;94:1057–1062.PubMedGoogle Scholar
  125. 125.
    Ford AM, Ridge SA, Cabrera ME, et al. In utero rearrangements in the trithorax-related oncogene in infant leukaemias.Nature. 1993;363:358–360.PubMedGoogle Scholar
  126. 126.
    Gale KB, Ford AM, Repp R, et al. Backtracking leukemia to birth: identification of clonotypic gene fusion sequences in neonatal blood spots.Proc Natl Acad Sci USA. 1997;94:13950–13954.PubMedPubMedCentralGoogle Scholar
  127. 127.
    Maia AT, Koechling J, Corbett R, Metzler M, Wiemels JL, Greaves M. Protracted postnatal natural histories in childhood leukemia.Genes Chromosomes Cancer. 2004;39:335–340.PubMedGoogle Scholar
  128. 128.
    Greaves MF. Infant leukaemia biology, aetiology and treatment.Leukemia. 1996;10:372–377.PubMedGoogle Scholar
  129. 129.
    Megonigal MD, Cheung NK, Rappaport EF, et al. Detection of leukemia-associatedMLL-GAS7 translocation early during chemotherapy with DNA topoisomerase II inhibitors.Proc Natl Acad Sci USA. 2000;97:2814–2819.PubMedPubMedCentralGoogle Scholar
  130. 130.
    Rowley JD, Olney HJ. International workshop on the relationship of prior therapy to balanced chromosome aberrations in therapy- related myelodysplastic syndromes and acute leukemia: overview report.Genes Chromosomes Cancer. 2002;33:331–345.PubMedGoogle Scholar
  131. 131.
    Abe R, Ryan D, Cecalupo A, Cohen H, Sandberg AA. Cytogenetic findings in congenital leukemia: case report and review of the literature.Cancer Genet Cytogenet. 1983;9:139–144.PubMedGoogle Scholar
  132. 132.
    Horstmann M, Argyriou-Tirita A, Borkhardt A, et al.MLL/ENL fusion in congenital acute lymphoblastic leukemia with a unique t(11;18;19).Cancer Genet Cytogenet. 1996;88:103–109.PubMedGoogle Scholar
  133. 133.
    Borkhardt A, Wilda M, Fuchs U, Gortner L, Reiss I. Congenital leukaemia after heavy abuse of permethrin during pregnancy.Arch Dis Child Fetal Neonatal Ed. 2003;88:F436-F437.PubMedPubMedCentralGoogle Scholar
  134. 134.
    Hunger SP, McGavran L, Meltesen L, Parker NB, Kassenbrock CK, Bitter MA. Oncogenesisin utero: fetal death due to acute myelogenous leukaemia with anMLL translocation.Br J Haematol. 1998; 103:539–542.PubMedGoogle Scholar
  135. 135.
    Greaves MF, Maia AT, Wiemels JL, Ford AM. Leukemia in twins: lessons in natural history.Blood. 2003;102:2321–2333.PubMedGoogle Scholar
  136. 136.
    Harrison CJ, Cuneo A, Clark R, et al. Ten novel 11q23 chromosomal partner sites: European 11q23 Workshop participants.Leukemia. 1998;12:811–822.PubMedGoogle Scholar
  137. 137.
    Moorman AV, Hagemeijer A, Charrin C, Rieder H, Secker-Walker LM. The translocations, t(11;19)(q23;p13.1) and t(11;19) (q23;p13.3): a cytogenetic and clinical profile of 53 patients. European 11q23 Workshop participants.Leukemia. 1998;12:805–810.PubMedGoogle Scholar
  138. 138.
    Armstrong SA, Kung AL, Mabon ME, et al. Inhibition of FLT3 in MLL: validation of a therapeutic target identified by gene expression based classification.Cancer Cell. 2003;3:173–183.PubMedGoogle Scholar
  139. 139.
    Taketani T, Taki T, Sugita K, et al.FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL withMLL rearrangements and pediatric ALL with hyperdiploidy.Blood. 2003;103:1085–1088.PubMedGoogle Scholar
  140. 140.
    Schulte CE, Lindern MV, Steinlein P, Beug H, Wiedemann LM. MLL-ENL cooperates with SCF to transform primary avian multipotent cells.EMBO J. 2002;21:4297–4306.PubMedPubMedCentralGoogle Scholar
  141. 141.
    Haupt Y, Bath ML, Harris AW, Adams JM. bmi-1 transgene induces lymphomas and collaborates with myc in tumorigenesis.Oncogene. 1993;8:3161–3164.PubMedGoogle Scholar
  142. 142.
    Alkema MJ, Jacobs H, van LohuizenM, Berns A. Pertubation of B and T cell development and predisposition to lymphomagenesis in Emu Bmi1 transgenic mice require the Bmi1 RING finger.Oncogene. 1997;15:899–910.PubMedGoogle Scholar
  143. 143.
    Johnson JJ, Chen W, Hudson W, et al. Prenatal and postnatal myeloid cells demonstrate stepwise progression in the pathogenesis of MLL fusion gene leukemia.Blood. 2003;101:3229–3235.PubMedGoogle Scholar
  144. 144.
    Mikkers H, Berns A. Retroviral insertional mutagenesis: tagging cancer pathways.Adv Cancer Res. 2003;88:53–99.PubMedGoogle Scholar
  145. 145.
    Ross JA, Potter JD, Reaman GH, Pendergrass TW, Robison LL. Maternal exposure to potential inhibitors of DNA topoisomerase II and infant leukemia (United States): a report from the Children’s Cancer Group.Cancer Causes Control. 1996;7:581–590.PubMedGoogle Scholar
  146. 146.
    Greaves MF. Aetiology of acute leukaemia.Lancet. 1997;349:344–3499.PubMedGoogle Scholar
  147. 147.
    Alexander FE,Patheal SL, Biondi A, et al. Transplacental chemical exposure and risk of infant leukemia withMLL gene fusion.Cancer Res. 2001;61:2542–2546.PubMedGoogle Scholar
  148. 148.
    Wiemels JL, Pagnamenta A, Taylor GM, Eden OB, Alexander FE, Greaves MF. A lack of a functional NAD(P)H:quinone oxidore- ductase allele is selectively associated with pediatric leukemias that have MLL fusions: United Kingdom Childhood Cancer Study Investigators.Cancer Res. 1999;59:4095–4099.PubMedGoogle Scholar
  149. 149.
    Aplan PD, Chervinsky DS, Stanulla M, Burhans WC. Site-specific DNA cleavage within the MLL breakpoint cluster region induced by topoisomerase II inhibitors.Blood. 1996;87:2649–2658.PubMedGoogle Scholar
  150. 150.
    Stanulla M, Wang J, Chervinsky DS, Thandla S, Aplan PD. DNA cleavage within the MLL breakpoint cluster region is a specific event which occurs as part of higher-order chromatin fragmentation during the initial stages of apoptosis.Mol Cell Biol. 1997;17:4070–40799.PubMedPubMedCentralGoogle Scholar
  151. 151.
    Sim SP, Liu LF. Nucleolytic cleavage of the mixed lineage leukemia breakpoint cluster region during apoptosis.J Biol Chem. 2001;276:31590–315955.PubMedGoogle Scholar
  152. 152.
    Ishii E, Eguchi M, Eguchi-Ishimae M, et al. In vitro cleavage of the MLL gene by topoisomerase II inhibitor (etoposide) in normal cord and peripheral blood mononuclear cells.Int J Hematol. 2002; 76:74–79.PubMedGoogle Scholar
  153. 153.
    Blanco JG, Edick MJ, Relling MV. Etoposide induces chimericMll gene fusions.FASEB J. 2004;18:173–175.PubMedPubMedCentralGoogle Scholar
  154. 154.
    Libura J, Slater DJ, Felix CA, Richardson C. Therapy-related acute myeloid leukemia-like MLL rearrangements are induced by etoposide in primary human CD34+ cells and remain stable after clonal expansion.Blood. 2005;105:2124–2131.PubMedPubMedCentralGoogle Scholar
  155. 155.
    Caslini C, Shilatifard A, Yang L, Hess JL. The amino terminus of the mixed lineage leukemia protein (MLL) promotes cell cycle arrest and monocytic differentiation.Proc Natl Acad Sci USA. 2000;97:2797–2802.PubMedPubMedCentralGoogle Scholar
  156. 156.
    Muyrers-Chen I, Rozovskaia T, Lee N, et al. Expression of leukemic MLL fusion proteins inDrosophila affects cell cycle control and chromosome morphology.Oncogene. 2004;23:8639–8648.PubMedPubMedCentralGoogle Scholar
  157. 157.
    Caslini C, Serna A, Rossi V, Introna M, Biondi A. Modulation of cell cycle by graded expression of MLL-AF4 fusion oncoprotein.Leukemia. 2004;18:1064–1071.PubMedPubMedCentralGoogle Scholar
  158. 158.
    Adler HT, Chinery R, Wu DY, et al. Leukemic HRX fusion proteins inhibit GADD34-induced apoptosis and associate with the GADD34 and hSNF5/INI1 proteins.Mol Cell Biol. 1999;19:7050–70600.PubMedPubMedCentralGoogle Scholar
  159. 159.
    Oguchi K, Takagi M, Tsuchida R, et al. Missense mutation and defective function of ATM in a childhood acute leukemia patient with MLL gene rearrangement.Blood. 2003;101:3622–3627.PubMedPubMedCentralGoogle Scholar
  160. 160.
    Dierov J, Dierova R, Carroll M. BCR/ABL translocates to the nucleus and disrupts an ATR-dependent intra-S phase checkpoint.Cancer Cell. 2004;5:275–285.PubMedPubMedCentralGoogle Scholar
  161. 161.
    Smith MT, Wang Y, Skibola CF, et al. Low NAD(P)H:quinone oxidoreductase activity is associated with increased risk of leukemia withMLL translocations in infants and children.Blood. 2002;100:4590–45933.PubMedGoogle Scholar
  162. 162.
    Felix CA, Walker AH, Lange BJ, et al. Association ofCYP3A4 genotype with treatment-related leukemia.Proc Natl Acad Sci USA. 1998;95:13176–13181.PubMedPubMedCentralGoogle Scholar
  163. 163.
    Asher G, Lotem J, Kama R, Sachs L, Shaul Y. NQO1 stabilizes p53 through a distinct pathway.Proc Natl Acad Sci USA. 2002;99:3099–31044.PubMedPubMedCentralGoogle Scholar
  164. 164.
    Mikkola HK, Fujiwara Y, Schlaeger TM, Traver D, Orkin SH. Expression of CD41 marks the initiation of definitive hematopoiesis in the mouse embryo.Blood. 2003;101:508–516.PubMedGoogle Scholar
  165. 165.
    Luo RT, Kebriaei P, Kaberlein JJ, Thirman MJ. Cooperating mutations are necessary for the development of AML in Mll-ELL knock-in mice [abstract].Blood. 2002;100:136a.Google Scholar

Copyright information

© The Japanese Society of Hematology 2005

Authors and Affiliations

  • Mariko Eguchi
    • 1
  • Minenori Eguchi-Ishimae
    • 1
  • Mel Greaves
    • 1
  1. 1.Section of Haemato-Oncology, Institute of Cancer ResearchChester Beatty LaboratoriesLondonUK

Personalised recommendations