Molecular mechanisms of myelodysplastic syndrome

Japanese Journal of Clinical Oncology

Volumn 33, Issue 4, 2003, Pages 153-160

  Hirai, Hisamaru ^a  

^a UNIVERSITY OF TOKYO   (Japan)

Author keywords

Chromosomal abnormality; Genetic lesion; Myelodysplastic syndrome

Indexed keywords

5 AZA 2' DEOXYCYTIDINE; FLT3 LIGAND; GROWTH FACTOR; PROTEIN P53; RAS PROTEIN; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR RUNX1; TUMOR SUPPRESSOR PROTEIN;

ACUTE GRANULOCYTIC LEUKEMIA; BONE MARROW DEPRESSION; CANCER SUSCEPTIBILITY; CELL CYCLE REGULATION; CELL DIFFERENTIATION; CELL PROLIFERATION; CHROMOSOME 11; CHROMOSOME 12; CHROMOSOME 13; CHROMOSOME 20; CHROMOSOME 7; CHROMOSOME ABERRATION; CHROMOSOME DELETION 13; CHROMOSOME DELETION 5; ENVIRONMENTAL EXPOSURE; GENE DISRUPTION; GENE MUTATION; GENE TRANSLOCATION; GENOMICS; HEMATOPOIESIS; HEMATOPOIETIC STEM CELL; HUMAN; MALIGNANT TRANSFORMATION; MOLECULAR MECHANICS; MYELODYSPLASTIC SYNDROME; OCCUPATIONAL EXPOSURE; PROTEIN FUNCTION; PROTEIN STRUCTURE; REVIEW; SIGNAL DETECTION; SIGNAL TRANSDUCTION; STRUCTURE ANALYSIS; BLOOD; CHROMOSOME DELETION; GENETICS; LEUKEMIA; PATHOLOGY; PHYSIOLOGY; TUMOR SUPPRESSOR GENE;

CHROMOSOME ABERRATIONS; CHROMOSOME DELETION; GENES, TUMOR SUPPRESSOR; HEMATOPOIESIS; HEMATOPOIETIC STEM CELLS; HUMANS; LEUKEMIA; MYELODYSPLASTIC SYNDROMES; TRANSLOCATION, GENETIC;

EID: 0038470905     PISSN: 03682811     EISSN: 14653621     Source Type: Journal    
DOI: 10.1093/jjco/hyg037     Document Type: Review

References (81)

1. Gersuk GM, Beckham C, Loken MR, Kiener P, Anderson JE, Farrand A, et al. A role for tumour necrosis factor-alpha, Fas and Fas-Ligand in marrow failure associated with myelodysplastic syndrome. Br J Haematol 1998;103:176-88.
2. Raza A, Gezer S, Mundle S, Gao XZ, Alvi S, Borok R, et al. Apoptosis in bone marrow biopsy samples involving stromal and hematopoietic cells in 50 patients with myelodysplastic syndromes. Blood 1995;86:268-76.
3. Shetty V, Mundle S, Alvi S, Showel M, Broady-Robinson L, Dar S, et al. Measurement of apoptosis, proliferation and three cytokines in 46 patients with myelodysplastic syndromes. Leukemia Res 1996;20:891-900.
4. Haase D, Feuring-Buske M, Schafer C, Schoch C, Troff C, Gahn B, et al. Cytogenetic analysis of CD34+ subpopulations in AML and MDS characterized by the expression of CD38 and CD117. Leukemia 1997;11:674-9.
5. Loeb LA. Cancer cells exhibit a mutator phenotype. Adv Cancer Res 1998;72:25-56.
6. Arzimanoglou II, Gilbert F, Barber HR. Microsatellite instability in human solid tumors. Cancer 1998;82:1808-20.
7. Third MIC Cooperative Group Study. Recommendations for a morphologic, immunologic and cytogenetic (MIC) working classification of the primaty and therapy-related myelodysplastic disorders. Cancer Genet Cytogenet 1988;32:1-10.
8. Mecucci C. Molecular features of primary MDS with cytogenetic changes. Leukemia Res 1998;22:293-302.
9. Van den Berghe H, Vermaelen K, Mecucci C, Barbieri D, Tricot G. The 5q- anomaly. Cancer Genet Cytogenet 1985;17:189-255.
10. Boultwood J, Lewis S, Wainscoat JS. The 5q- syndrome. Blood 1994;84: 3253-60.
11. Boultwood J, Rack K, Kelly S, Madden J, Sakaguchi AY, Wang LM, et al. Loss of both CSF1R (FMS) alleles in patients with myelodysplasia and a chromosome 5 deletion. Proc Natl Acad Sci USA 1991;88:6176-80.
12. Willman CL, Sever CE, Pallavicini MG, Harada H, Tanaka N, Slovak ML, et al. Deletion of IRF-1, mapping to chromosome 5q31.1, in human leukemia and preleukemic myelodysplasia. Science 1993;259:968-71.
13. Lezon-Geyda K, Najfeld V, Johnson EM. Deletions of PURA, at 5q31 and PURB, at 7p13, in myelodysplastic syndrome and progression to acute myelogenous leukemia. Leukemia 2001;15:954-62.
14. Yoneda-Kato N, Look AT, Kirstein MN, Valentine MB, Raimondi SC, Cohen KJ, et al. The t(3;5)(q25.1;q34) of myelodysplastic syndrome and acute myeloid leukemia produces a novel fusion gene, NPM-MLF1. Oncogene 1996;12:265-75.
15. Borkhardt A, Bojesen S, Haas OA, Fuchs U, Bartelheimer D, Loncarevic IF, et al. The human GRAF gene is fused to MLL in a unique t(5;11)(q31; q23) and both alleles are disrupted in three cases of myelodysplastic syndrome/acute myeloid leukemia with a deletion 5q. Proc Natl Acad Sci USA 2000;97:9168-73.
16. Yagasaki F, Jinnai I, Yoshida S, Yokoyama Y, Matsuda A, Kusumoto S, et al. Fusion of TEL/ETV6 to a novel ACS2 in myelodysplastic syndrome and acute myelogenous leukemia with t(5;12)(q31;p13). Genes Chromosom Cancer 1999;26:192-202.
17. Jaju RJ, Fidler C, Haas OA, Strickson AJ, Watkins F, Clark K, et al. A novel gene, NSD1, is fused to NUP98 in the t(5;11)(q35;p15.5) in de novo childhood acute myeloid leukemia. Blood 2001;98:1264-7.
18. Johnson EJ, Scherer SW, Osborne L, Tsui LC, Oscier D, Mould S, et al. Molecular definition of a narrow interval at 7q22.1 associated with myelodysplasia. Blood 1996;87:3579-86.
19. Kratz CP, Emerling BM, Bonifas J, Wang W, Green ED, Beau MM, et al. Genomic structure of the PIK3CG gene on chromosome band 7q22 and evaluation as a candidate myeloid tumor suppressor. Blood 2002;99: 372-4.
20. Side L, Taylor B, Cayouette M, Conner E, Thompson P, Luce M, et al. Homozygous inactivation of the NF1 gene in bone marrow cells from children with neurofibromatosis type 1 and malignant myeloid disorders. N Engl J Med 1997;336:1713-20.
21. Stephenson J, Lizhen H, Mufti GJ. Possible co-existence of RAS activation and monosomy 7 in the leukaemic transformation of myelodysplastic syndromes. Leukemia Res 1995;19:741-8.
22. Luna-Fineman S, Shannon KM, Lange BJ. Childhood monosomy 7: epidemiology, biology and mechanistic implications. Blood 1995;85: 1985-99.
23. Asimakopoulos FA, Holloway TL, Nacheva EP, Scott MA, Fenaux P, Green AR. Detection of chromosome 20q deletions in bone marrow metaphases but not peripheral blood granulocytes in patients with myeloproliferative disorders or myelodysplastic syndromes. Blood 1996;87: 1561-70.
24. Asimakopoulos FA, Green AR. Deletions of chromosome 20q and the pathogenesis of myeloproliferative disorders. Br J Haematol 1996;95: 219-26.
25. La Starza R, Wlodarska I, Aventin A, Falzetti D, Crescenzi B, Martelli MF, et al. Molecular delineation of 13q deletion boundaries in 20 patients with myeloid malignancies. Blood 1998;91:231-7.
26. Mecucci C, Van Orshoven A, Vermaelen K, Michaux JL, Tricot G, Louwagie A, et al. 11q- chromosome is associated with abnormal iron stores in myelodysplastic syndromes. Cancer Genet Cytogenet 1987;27: 39-44.
27. Hoglund M, Johansson B, Pedersen-Bjergaard J, Marynen P, Mitelman F. Molecular characterization of 12p abnormalities in hematologic malignancies: Deletion of KIP1, rearrangement of TEL and amplification of CCND2. Blood 1996;87:324-30.
28. Golub TR, Barker GF, Lovett M, Gilliland DG. Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell 1994;77:307-16.
29. Wlodarska I, Mecucci C, Marynen P, Guo C, Franckx D, La Starza R, et al. TEL gene is involved in myelodysplastic syndromes with either the typical t(5;12)(q33;p13) translocation or its variant t(10;12)(q24;p13). Blood 1995;85:2848-52.
30. Carroll M, Tomasson MH, Barker GF, Golub TR, Gilliland DG. The TEL/ platelet-derived growth factor beta receptor (PDGF beta R) fusion in chronic myelomonocytic leukemia is a transforming protein that self-associates and activates PDGF beta R kinase-dependent signaling pathways. Proc Natl Acad Sci USA 1996;93:14845-50.
31. Apperley JF, Gardembas M, Melo JV, Russell-Jones R, Bain BJ, Baxter EJ, et al. Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. New Engl J Med 2002;347:481-7.
32. Salomon-Nguyen F, Della-Valle V, Mauchauffe M, Busson-Le Coniat M, Ghysdael J, Berger R, et al. The t(1;12)(q21;p13) translocation of human acute myeloblastic leukemia results in a TEL-ARNT fusion. Proc Natl Acad Sci USA 2000;97:6757-62.
33. Buijs A, Sherr S, van Baal S, van Bezouw S, van der Plas D, Geurts van Kessel A, et al. Translocation (12;22) (p13;q11) in myeloproliferative disorders results in fusion of the ETS-like TEL gene on 12p13 to the MN1 gene on 22q11. Oncogene 1995;10:1511-9.
34. Raynaud SD, Baens M, Grosgeorge J, Rodgers K, Reid CD, Dainton M, et al. Fluorescence in situ hybridization analysis of t(3;12)(q26;p13): A recurring chromosomal abnormality involving the TEL gene (ETV6) in myelodysplastic syndromes. Blood 1996;88:682-9.
35. Yagasaki F, Jinnai I, Yoshida S, Yokoyama Y, Matsuda A, Kusumoto S, et al. Fusion of TEL/ETV6 to a novel ACS2 in myelodysplastic syndrome and acute myelogenous leukemia with t(5;12)(q31;p13). Genes Chromosom Cancer 1999;26:192-202.
36. Ayton PM, Cleary ML. Molecular mechanism of leukemogenesis mediated by MLL fusion proteins. Oncogene 2001;20:5695-707.
37. Mitani K, Kanda Y, Ogawa S, Tanaka T, Inazawa J, Yazaki Y, et al. Cloning of several species of MLL/MEN chimeric cDNAs in myeloid leukemia with t(11;19)(q23;p13.1) translocation. Blood 1995;85:2017-24.
38. 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 1997;89:3945-50.
39. Caligiuri MA, Strout MP, Schichman SA, Mrozek K, Arthur DC, Herzig GP, et al. Partial tandem duplication of ALL1 as a recurrent molecular defect in acute myeloid leukemia with trisomy 11. Cancer Res 1996;56: 1418-25.
40. Radu A, Blobel G, Moore MS. Identification of a protein complex that is required for nuclear protein import and mediates docking of import substrate to distinct nucleoporins. Proc Natl Acad Sci USA 1995;92:1769-73.
41. Nakamura T, Largaespada DA, Lee MP, Johnson LA, Ohyashiki K, Toyama K, et al. Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemia. Nature Genet 1996;12:154-8.
42. Raza-Egilmez SZ, Jani-Sait SN, Grossi M, Higgins MJ, Shows TB, Aplan PD. NUP98-HOXD13 gene fusion in therapy-related acute myelogenous leukemia. Cancer Res 1998;58:4269-73.
43. Nishiyama M, Arai Y, Tsunematsu Y, Kobayasbi H, Asami K, Yabe M, et al. 11p15 translocations involving the NUP98 gene in childhood therapy-related acute myeloid leukemia/myelodysplastic syndrome. Genes Chromosom Cancer 1999;26:215-20.
44. Ahuja HG, Felix CA, Aplan PD. The t(11;20)(p15;q11) chromosomal translocation associated with therapy-related myelodysplastic syndrome results in an NUP98-TOP1 fusion. Blood 1999;94:3258-61.
45. Arai Y, Hosoda F, Kobayashi H, Arai K, Hayashi Y, Kamada N, et al. The inv(11)(p15q22) chromosome translocation of de novo and therapy-related myeloid malignancies results in fusion of the nucleoporin gene, NUP98, with the putative RNA helicase gene, DDX10. Blood 1997;89: 3936-44.
46. Soekarman D, von Lindern M, Daenen S, de Jong B, Fonatsch C, Heinze B, et al. The translocation (6;9) (p23;q34) shows consistent rearrangement of two genes and defines a myeloproliferative disorder with specific clinical features. Blood 1992;79:2990-7.
47. Boer J, Bonten-Surtel J, Grosveld G. Overexpression of the nucleoporin CAN/NUP214 induces growth arrest, nucleocytoplasmic transport defects and apoptosis. Mol Cell Biol 1998;18:1236-47.
48. Jotterand Bellomo M, Parlier V, Muhlematter D, Grob JP, Beris P. Three new cases of chromosome 3 rearrangement in bands q21 and q26 with abnormal thrombopoiesis bring further evidence to the existence of a 3q21q26 syndrome. Cancer Genet Cytogenet 1992;59:138-60.
49. Suzukawa K, Parganas E, Gajjar A, Abe T, Takahashi S, Tani K, et al. Identification of a breakpoint cluster region 3′ of the ribophorin I gene at 3q21 associated with the transcriptional activation of the EVI1 gene in acute myelogenous leukemias with inv(3)(q21q26). Blood 1994;84: 2681-8.
50. Mochizuki N, Shimizu S, Nagasawa T, Tanaka H, Taniwaki M, Yokota J, et al. A novel gene, MEL1, mapped to 1p36.3 is highly homologous to the MDS1/EVI1 gene and is transcriptionally activated in t(1;3)(p36;q21)-positive leukemia cells. Blood 2000;96:3209-14.
51. Mitani K, Ogawa S, Tanaka T, Miyoshi H, Kurokawa M, Mano H, et al. Generation of the AML1-EVI-1 fusion gene in the t(3;21)(q26;q22) causes blastic crisis in chronic myelocytic leukemia. EMBO J 1994;13: 504-10.
52. Kurokawa M, Mitani K, Irie K, Matsuyama T, Takahashi T, Chiba S, et al. The oncoprotein Evi-1 represses TGF-beta signalling by inhibiting Smad3. Nature 1998;394:92-6.
53. Izutsu K, Kurokawa M, Imai Y, Maki K, Mitani K, Hirai H. The corepressor CtBP interacts with Evi-1 to repress transforming growth factor beta signaling. Blood 2001;97:2815-22.
54. Marshall MS. Ras target proteins in eukaryotic cells. FASEB J 1995;9: 1311-8.
55. Hirai H, Kobayashi Y, Mano H, Hagiwara K, Maru Y, Omine M, et al. A point mutation at codon 13 of the N-ras oncogene in myelodysplastic syndrome. Nature 1987;327:430-2.
56. Paquette RL, Landaw EM, Pierre RV, Kahan J, Lubbert M, Lazcano O, et al. N-ras mutations are associated with poor prognosis and increased risk of leukemia in myelodysplastic syndrome. Blood 1993;82:590-9.
57. Hirai H, Okada M, Mizoguchi H, Mano H, Kobayashi Y, Nishida J, et al. Relationship between an activated N-ras oncogene and chromosomal abnormality during leukemic progression from myelodysplastic syndrome. Blood 1988;71:256-8.
58. Yokota S, Kiyoi H, Nakao M, Iwai T, Misawa S, Okuda T, et al. Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines. Leukemia 1997;11:1605-9.
59. Horiike S, Yokota S, Nakao M, Iwai T, Sasai Y, Kaneko H, et al. Tandem duplications of the FLT3 receptor gene are associated with leukemic transformation of myelodysplasia. Leukemia 1997;11:1442-6.
60. Sugimoto K, Hirano N, Toyoshima H, Chiba S, Mano H, Takaku F, et al. Mutations of the p53 gene in myelodysplastic syndrome (MDS) and MDS-derived leukemia. Blood 1993;81:3022-6.
61. Song WJ, Sullivan MG, Legare RD, Hutchings S, Tan X, Kufrin D, et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nature Genet 1999;23: 166-75.
62. Osato M, Asou N, Abdalla E, Hoshino K, Yamasaki H, Okubo T, et al. Biallelic and heterozygous point mutations in the runt domain of the AML1/PEBP2alphaB gene associated with myeloblastic leukemias. Blood 1999;93:1817-24.
63. Preudhomme C, Warot-Loze D, Roumier C, Grardel-Duflos N, Garand R, Lai JL, et al. High incidence of biallelic point mutations in the Runt domain of the AML1/PEBP2 alpha B gene in Mo acute myeloid leukemia and in myeloid malignancies with acquired trisomy 21. Blood 2000;96: 2862-9.
64. Imai Y, Kurokawa M, Izutsu K, Hangaishi A, Takeuchi K, Maki K, et al. Mutations of the AML1 gene in myelodysplastic syndrome and their functional implications in leukemogenesis. Blood 2000;96:3154-60.
65. Pabst T, Mueller BU, Zhang P, Radomska HS, Narravula S, Schnittger S, et al. Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia. Nature Genet 2001;27:263-70.
66. Gombart AF, Hofmann WK, Kawano S, Takeuchi S, Krug U, Kwok SH, et al. Mutations in the gene encoding the transcription factor CCAAT/enhancer binding protein alpha in myelodysplastic syndromes and acute myeloid leukemias. Blood 2002;99:1332-40.
67. Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science 1994;264:436-9.
68. Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K, Carson DA. Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature 1994;368:753-6.
69. Hannon GJ, Beach D. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature 1994;371:257-61.
70. Ogawa S, Hangaishi A, Miyawaki S. Hirosawa S, Miura Y, Takeyama K, et al. Loss of the cyclin-dependent kinase 4-inhibitor (CDK4I; p16; MTS1) gene is frequent in and highly specific to lymphoid tumors in human hematopoietic malignancies. Blood 1995;86:1548-56.
71. Herman JG, Jen J, Merlo A, Baylin SB. Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B. Cancer Res 1996;56:722-7.
72. Uchida T, Kinoshita T, Nagai H, Nakahara Y, Saito H, Hotta T, et al. Hypermethylation of the p15INK4B gene in myelodysplastic syndromes. Blood 1997;90:1403-9.
73. Quesnel B, Guillerm G, Vereecque R, Wattel E, Preudhomme C, Bauters F, et al. Methylation of the p15(INK4b) gene in myelodysplastic syndromes is frequent and acquired during disease progression. Blood 1998; 91:2985-90.
74. Wijermans P, Lubbert M, Verhoef G, Bosly A, Ravoet C, Andre M, et al. Low-dose 5-aza-2′-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: A multicenter phase II study in elderly patients. J Clin Oncol 2000;18:956-62.
75. Lubbert M, Wijermans P, Kunzmann R, Verhoef G, Bosly A, Ravoet C, et al. Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with the DNA methylation inhibitor 5-aza-2′-deoxycytidine. Br J Haematol 2001;114:349-57.
76. Bos JL. Ras oncogenes in human cancer: A review. Cancer Res 1989;49: 4682-9.
77. Deng C, Zhang P, Harper JW, Elledge SJ, Leder P. Mice lacking p21CIP1/ WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell 1995;82:675-84.
78. Okuda T, van Deursen J, Hiebert SW, Grosveld G, Downing JR. AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 1996;84:321-30.
79. Wang Q, Stacy T, Miller JD, Lewis AF, Gu TL, Huang X, et al. The CBFbeta subunit is essential for CBFalpha2 (AML1) function in vivo. Cell 1996;87:697-708.
80. Collins SJ, Ulmer J, Purton LE, Darlington G. Multipotent hematopoietic cell lines derived from C/EBPalpha(-/-) knockout mice display granulocyte macrophage-cobony-stimulating factor, granulocyte-colony-stimulating factor and retinoic acid-induced granulocytic differentiation. Blood 2001;98:2382-8.
81. Wang LC, Swat W, Fujiwara Y, Davidson L, Visvader J, Kuo F, et al. The TEL/ETV6 gene is required specifically for hematopoiesis in the bone marrow. Genes Dev 1998;12:2392-402.