Myelodysplastic Syndromes: Pathophysiology

Leukemias: Principles and Practice of Therapy

Volumn , Issue , 2011, Pages 77-86

  Gore, Steve D ^a   Warlick, Erica ^b  

^a JOHNS HOPKINS UNIVERSITY   (United States)

^b UNIVERSITY OF MINNESOTA MEDICAL SCHOOL   (United States)

Author keywords

Apoptosis; Epigenetic modulation; Myelodysplastic syndromes; Pathogenesis

Indexed keywords

EID: 84875960868     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9781444327359.ch6     Document Type: Chapter

References (99)

1. Gerritsen WR, Donohue J, Bauman J, et al. Clonal analysis of myelodysplastic syndrome: monosomy 7 is expressed in the myeloid lineage, but not in the lymphoid lineage as detected by fluorescent in situ hybridization. Blood 1992; 80 : 217-24.
2. Kibbelaar RE, van Kamp H, Dreef EJ, et al. Combined immunophenotyping and DNA in situ hybridization to study lineage involvement in patients with myelodysplastic syndromes. Blood 1992; 79: 1823-8.
3. Kroef MJ, Fibbe WE, Mout R, et al. Myeloid but not lymphoid cells carry the 5q deletion: polymerase chain reaction analysis of loss of heterozygosity using mini-repeat sequences on highly purified cell fractions. Blood 1993; 81: 1849-54.
4. Saitoh K, Miura I, Takahashi N, Miura AB. Fluorescence in situ hybridization of progenitor cells obtained by fluorescence - activated cell sorting for the detection of cells affected by chromosome abnormality trisomy 8 in patients with myelodysplastic syndromes. Blood 1998; 92: 2886-92.
5. Nilsson L, Astrand-Grundstrom I, Arvidsson I, et al. Isolation and characterization of hematopoietic progenitor/stem cells in 5q-deleted myelodysplastic syndromes: evidence for involvement at the hematopoietic stem cell level. Blood 2000; 96 : 2012-21.
6. Nilsson L, Astrand-Grundstrom I, Anderson K, et al. Involvement and functional impairment of the CD34(+)CD38(-) Thy-1(+) hematopoietic stem cell pool in myelodysplastic syndromes with trisomy 8. Blood 2002; 100: 259-67.
7. Nilsson L, Eden P, Olsson E, et al. The molecular signature of MDS stem cells supports a stem-cell origin of 5q myelodysplastic syndromes. Blood 2007; 110: 3005-14.
8. Pasqualetti P, Festuccia V, Acitelli P, Collacciani A, Giusti A, Casale R. Tobacco smoking and risk of haematological malignancies in adults: a case-control study. Br J Haematol 1997 ; 97: 659-62.
9. Ido M, Nagata C, Kawakami N, et al. A case-control study of myelodysplastic syndromes among Japanese men and women. Leuk Res 1996; 20: 727-31.
10. Mundle S, Allampallam K, Aftab Rashid K, et al. Presence of activation-related m-RNA for EBV and CMV in the bone marrow of patients with myelodysplastic syndromes. Cancer Lett 2001; 164: 197-205.
11. Dalamaga M, Petridou E, Cook FE, Trichopoulos D. Risk factors for myelodysplastic syndromes: a case-control study in Greece. Cancer Causes Control 2002; 13: 603-8.
12. Kuang S, Liang W. Clinical analysis of 43 cases of chronic benzene poisoning. Chem Biol Interact 2005; 129-35: 153-4.
13. Aksoy M, Dincol K, Erdem S, Dincol G. Acute leukemia due to chronic exposure to benzene. Am J Med 1972; 52 : 160-6.
14. Yin SN, Hayes RB, Linet MS, et al. A cohort study of cancer among benzene-exposed workers in China: overall results. Am J Ind Med 1996; 29: 227-35.
15. Hiraku Y, Kawanishi S. Oxidative DNA damage and apoptosis induced by benzene metabolites. Cancer Res 1996; 56: 5172-8.
16. Yardley-Jones A, Anderson D, Parke DV. The toxicity of benzene and its metabolism and molecular pathology in human risk assessment. B r J Ind Med 1991; 48: 437-44.
17. Smith MT. The mechanism of benzene-induced leukemia: a hypothesis and speculations on the causes of leukemia. Environ Health Perspect 1996; 104 (Suppl. 6): 1219-25.
18. Rothman N, Haas R, Hayes RB, et al. Benzene induces gene - duplicating but not gene-inactivating mutations at the glycophorin A locus in exposed humans. Proc Natl Acad Sci U S A 1995; 92: 4069-73.
19. Aul C, Bowen DT, Yoshida Y. Pathogenesis, etiology and epidemiology of myelodysplastic syndromes. Haematologica 1998 ; 83: 71-86.
20. Catenacci DV, Schiller GJ. Myelodysplasic syndromes: a comprehensive review. Blood Rev 2005; 19: 301-19.
21. Mufti GJ. Pathobiology, classification, and diagnosis of myelodysplastic syndrome. Best Pract Res Clin Haematol 2004; 17 : 543-57.
22. Pedersen-Bjergaard J, Philip P, Larsen SO, et al. Therapy-related myelodysplasia and acute myeloid leukemia. Cytogenetic characteristics of 115 consecutive cases and risk in seven cohorts of patients treated intensively for malignant diseases in the Copenhagen series. Leukemia 1993; 7: 1975-86.
23. Rund D, Ben-Yehuda D. Therapy-related leukemia and myelodysplasia: evolving concepts of pathogenesis and treatment. Hematology 2004; 9: 179-87.
24. Pedersen-Bjergaard J, Andersen MK, Christiansen DH, Nerlov C. Genetic pathways in therapy-related myelodysplasia and acute myeloid leukemia. Blood 2002; 99: 1909-12.
25. Moloney WC. Radiogenic leukemia revisited. Blood 1987; 70 : 905-8.
26. Hirai H. Molecular mechanisms of myelodysplastic syndrome. Jpn J Clin Oncol 2003; 33: 153-60.
27. Look AT. Molecular Pathogenesis of MDS. Hematology Am Soc Hematol Educ Program 2005: 156-60.
28. Nimer SD. Clinical management of myelodysplastic syndromes with interstitial deletion of chromosome 5q. J Clin Oncol 2006 Jun; 24: 2576-82.
29. Olney HJ, Le Beau MM. The cytogenetics of myelodysplastic syndromes. B est Pract Res Clin Haematol 2001; 14: 479-95.
30. Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89: 2079-88.
31. Haase D, Germing U, Schanz J, et al. New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood 2007; 110: 4385-95.
32. Jary L, Mossafa H, Fourcade C, Genet P, Pulik M, Flandrin G. The 17p-syndrome:a distinct myelodysplastic syndrome entity? Leuk Lymphoma 1997; 25: 163-8.
33. Fairman J, Chumakov I, Chinault AC, Nowell PC, Nagarajan L. Physical mapping of the minimal region of loss in 5q-chromosome. Proc Natl Acad Sci U S A 1995; 92 : 7406-10.
34. Zhao N, Stoffel A, Wang PW, et al. Molecular delineation of the smallest commonly deleted region of chromosome 5 in malignant myeloid diseases to 1-1.5 Mb and preparation of a PAC - based physical map. Proc Natl Acad Sci U S A 1997; 94 : 6948-53.
35. Jaju RJ, Boultwood J, Oliver FJ, et al. Molecular cytogenetic delineation of the critical deleted region in the 5q-syndrome. Genes Chromosomes Cancer 1998; 22: 251-6.
36. Horrigan SK, Arbieva ZH, Xie HY, et al. Delineation of a minimal interval and identification of 9 candidates for a tumor suppressor gene in malignant myeloid disorders on 5q31. Blood 2000; 95: 2372-7.
37. Le Beau MM, Espinosa R, 3rd, Neuman WL, et al. Cytogenetic and molecular delineation of the smallest commonly deleted region of chromosome 5 in malignant myeloid diseases. Proc Natl Acad Sci U S A 1993; 90: 5484-8.
38. Boultwood J, Fidler C, Strickson AJ, et al. Transcription mapping of the 5q-syndrome critical region: cloning of two novel genes and sequencing, expression, and mapping of a further six novel cDNAs. Genomics 2000 15; 66: 26-34.
39. Vallespi T, Imbert M, Mecucci C, Preudhomme C, Fenaux P. Diagnosis, classification, and cytogenetics of myelodysplastic syndromes. H aematologica 1998; 83: 258-75.
40. Wattel E, Lai JL, Hebbar M, et al. De novo myelodysplastic syndrome (MDS) with deletion of the long arm of chromosome 20:a subtype of MDS with distinct hematological and prognostic features? Leuk Res 1993; 17: 921-6.
41. Davis MP, Dewald GW, Pierre RV, Hoagland HC. Hematologic manifestations associated with deletions of the long arm of chromosome 20. Cancer Genet Cytogenet 1984; 12: 63-71.
42. Asimakopoulos FA, Green AR. Deletions of chromosome 20q and the pathogenesis of myeloproliferative disorders. Br J Haematol 1996; 95: 219-26.
43. Liang H, Fairman J, Claxton DF, Nowell PC, Green ED, Nagarajan L. Molecular anatomy of chromosome 7q deletions in myeloid neoplasms: evidence for multiple critical loci. Proc Natl Acad Sci U S A 1998; 95: 3781-5.
44. Pasquali F, Bernasconi P, Casalone R, et al. Pathogenetic significance of " pure " monosomy 7 in myeloproliferative disorders. Analysis of 14 cases. Hum Genet 1982; 62: 40-51.
45. Le Beau MM, Espinosa R, 3rd, Davis EM, Eisenbart JD, Larson RA, Green ED. Cytogenetic and molecular delineation of a region of chromosome 7 commonly deleted in malignant myeloid diseases. Blood 1996; 88: 1930-5.
46. Ebert BL, Pretz J, Bosco J, et al. Identification of RPS14 as a 5q-syndrome gene by RNA interference screen. Nature 2008; 451: 335-9.
47. Pedersen-Bjergaard J, Andersen MK, Andersen MT, Christiansen DH. Genetics of therapy-related myelodysplasia and acute myeloid leukemia. Leukemia 2008; 22: 240-8.
48. Chen CY, Lin LI, Tang JL, et al. RUNX1 gene mutation in primary myelodysplastic syndrome-the mutation can be detected early at diagnosis or acquired during disease progression and is associated with poor outcome. Br J Haematol 2007; 139: 405-14.
49. Herman JG, Civin CI, Issa JP, Collector MI, Sharkis SJ, Baylin SB. Distinct patterns of inactivation of p15INK4B and p16INK4A characterize the major types of hematological malignancies. Cancer Res 1997; 57: 837-41.
50. Quesnel B, Guillerm G, Vereecque R, et al. Methylation of the p15(INK4b) gene in myelodysplastic syndromes is frequent and acquired during disease progression. Blood 1998; 91: 2985-90.
51. Leone G, Teofili L, Voso MT, Lubbert M. DNA methylation and demethylating drugs in myelodysplastic syndromes and secondary leukemias. Haematologica 2002; 87: 1324-41.
52. Aggerholm A, Holm MS, Guldberg P, Olesen LH, Hokland P. Promoter hypermethylation of p15INK4B, HIC1, CDH1, and ER is frequent in myelodysplastic syndrome and predicts poor prognosis in early-stage patients. Eur J Haematol 2006; 76: 23-32.
53. Christiansen DH, Andersen MK, Pedersen-Bjergaard J. Methylation of p15INK4B is common, is associated with deletion of genes on chromosome arm 7q and predicts a poor prognosis in therapy-related myelodysplasia and acute myeloid leukemia. L eukemia 2003; 17: 1813-19.
54. Dhodapkar M, Grill J, Lust JA. Abnormal regional hypermethylation of the calcitonin gene in myelodysplastic syndromes. Leuk Res 1995; 19: 719-26.
55. Wu S, Xie G, Bai R, Wang Y, Zhu P. Semi-quantitative study of calcitonin gene methylation in myelodysplastic syndrome. Chin Med J (Engl) 1998; 111: 690-3.
56. Bai R, Wu S, Zhu P, Xue H, Xu Y, Qin X. Quantitative study of calcitonin gene methylation in myelodysplastic syndromes. Zhonghua Xue Ye Xue Za Zhi 1997; 18: 17-20.
57. Li G, Zou D, Bai R. Clinical significance of human calcitonin and gene-related peptide in the serum of myelodysplastic syndromes patients. Zhonghua Xue Ye Xue Za Zhi 1999; 20: 79-81.
58. Wu SJ, Yao M, Chou WC, et al. Clinical implications of SOCS1 methylation in myelodysplastic syndrome. Br J Haematol 2006; 135: 317-23.
59. Johan MF, Bowen DT, Frew ME, Goodeve AC, Reilly JT. Aberrant methylation of the negative regulators RASSFIA, SHP-1 and SOCS-1 in myelodysplastic syndromes and acute myeloid leukemia. Br J Haematol 2005; 129: 60-5.
60. Boumber YA, Kondo Y, Chen X, et al. RIL, a LIM gene on 5q31, is silenced by methylation in cancer and sensitizes cancer cells to apoptosis. Cancer Res 2007; 67: 1997-2005.
61. Haggarty SJ, Koeller KM, Wong JC, Grozinger CM, Schreiber SL. Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proc Natl Acad Sci U S A 2003; 100: 4389-94.
62. Wolf D, Rodova M, Miska EA, Calvet JP, Kouzarides T. Acetylation of beta-catenin by CREB-binding protein (CBP). J Biol Chem 2002; 277: 25562-7.
63. Bannister AJ, Miska EA, Gorlich D, Kouzarides T. Acetylation of importin-alpha nuclear import factors by CBP/p300. Curr Biol 2000; 10: 467-70.
64. Cohen HY, Lavu S, Bitterman KJ, et al. Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. M ol Cell 2004; 13: 627-38.
65. Morgan MA, Reuter CW. Molecularly targeted therapies in myelodysplastic syndromes and acute myeloid leukemia s. Ann Hematol 2006; 85: 139-63.
66. Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK. Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer 2001; 1: 194-202.
67. Johnstone RW, Licht JD. Histone deacetylase inhibitors in cancer therapy: is transcription the primary target? Cancer Cell 2003; 4: 13-18.
68. Parker JE, Mufti GJ. Ineffective haemopoiesis and apoptosis in myelodysplastic syndromes. Br J Haematol 1998; 101: 220-30.
69. Parker JE, Mufti GJ, Rasool F, Mijovic A, Devereux S, Pagliuca A. The role of apoptosis, proliferation, and the Bcl-2-related proteins in the myelodysplastic syndromes and acute myeloid leukemia secondary to MDS. Blood 2000; 96: 3932-8.
70. Rajapaksa R, Ginzton N, Rott LS, Greenberg PL. Altered oncoprotein expression and apoptosis in myelodysplastic syndrome marrow cells. Blood 1996; 88: 4275-87.
71. Sawanobori M, Yamaguchi S, Hasegawa M, et al. Expression of TNF receptors and related signaling molecules in the bone marrow from patients with myelodysplastic syndromes. Leuk Res 2003; 27: 583-91.
72. Kitagawa M, Saito I, Kuwata T, et al. Overexpression of tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma by bone marrow cells from patients with myelodysplastic syndromes . Leukemia 1997; 11: 2049-54.
73. Hsu H, Huang J, Shu HB, Baichwal V, Goeddel DV. TNF - dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex. Immunity 1996; 4: 387-96.
74. Hsu H, Xiong J, Goeddel DV. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell 1995; 81: 495-504.
75. Katsoulidis E, Li Y, Yoon P, et al. Role of the p38 mitogen - activated protein kinase pathway in cytokine-mediated hematopoietic suppression in myelodysplastic syndromes. Cancer Res 2005; 65: 9029-37.
76. Navas TA, Mohindru M, Estes M, et al. Inhibition of overactivated p38 MAPK can restore hematopoiesis in myelodysplastic syndrome progenitors. Blood 2006; 108: 4170-7.
77. Raza A, Mundle S, Shetty V, et al. Novel insights into the biology of myelodysplastic syndromes: excessive apoptosis and the role of cytokines. Int J Hematol 1996; 63: 265-78.
78. Flores-Figueroa E, Gutierrez-Espindola G, Montesinos JJ, Arana-Trejo RM, Mayani H. In vitro characterization of hemat opoietic microenvironment cells from patients with myelodysplastic syndrome. Leuk Res 2002; 26: 677-86.
79. Wetzler M, Kurzrock R, Estrov Z, Estey E, Talpaz M. Cytokine expression in adherent layers from patients with myelodysplastic syndrome and acute myelogenous leukemia. Leuk Res 1995; 19: 23-34.
80. Deeg HJ, Beckham C, Loken MR, et al. Negative regulators of hemopoiesis and stroma function in patients with myelodysplastic syndrome. Leuk Lymphoma 2000; 37: 405-14.
81. Koike M, Ishiyama T, Tomoyasu S, Tsuruoka N. Spontaneous cytokine overproduction by peripheral blood mononuclear cells from patients with myelodysplastic syndromes and aplastic anemia. Leuk Res 1995; 19: 639-44.
82. Aggarwal BB. Nuclear factor-kappaB: the enemy within. Cancer Cell 2004; 6: 203-8.
83. Braun T, Carvalho G, Coquelle A, et al. NF-kappaB constitutes a potential therapeutic target in high-risk myelodysplastic syndrome . Blood 2006; 107: 1156-65.
84. Bouscary D, De Vos J, Guesnu M, et al. Fas/Apo-1 (CD95) expression and apoptosis in patients with myelodysplastic syndromes . Leukemia 1997; 11: 839-45.
85. Claessens YE, Bouscary D, Dupont JM, et al. In vitro proliferation and differentiation of erythroid progenitors from patients with myelodysplastic syndromes: evidence for Fas-dependent apoptosis. B lood 2002; 99: 1594-601.
86. Estey EH. Modulation of angiogenesis in patients with myelodysplastic syndrome. Best Pract Res Clin Haematol 2004; 17: 623-39.
87. Aguayo A, Kantarjian H, Manshouri T, et al. Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. Blood 2000; 96: 2240-5.
88. Brunner B, Gunsilius E, Schumacher P, Zwierzina H, Gastl G, Stauder R. Blood levels of angiogenin and vascular endothelial growth factor are elevated in myelodysplastic syndromes and in acute myeloid leukemia. J Hematother Stem Cell Res 2002; 11: 119-25.
89. Zorat F, Shetty V, Dutt D, et al. The clinical and biological effects of thalidomide in patients with myelodysplastic syndromes. Br J Haematol 2001; 115: 881-94.
90. Wimazal F, Krauth MT, Vales A, et al. Immunohistochemical detection of vascular endothelial growth factor (VEGF) in the bone marrow in patients with myelodysplastic syndromes: correlation between VEGF expression and the FAB category. Leuk Lymphoma 2006; 47: 451-60.
91. Pruneri G, Bertolini F, Soligo D, et al. Angiogenesis in myelodysplastic syndromes. Br J Cancer 1999; 81: 1398-401.
92. Korkolopoulou P, Apostolidou E, Pavlopoulos PM, et al. Prognostic evaluation of the microvascular network in myelodysplastic syndromes. Leukemia 2001; 15: 1369-76.
93. Marisavljevic D, Kraguljac N, Rolovic Z. Immunologic abnormalities in myelodysplastic syndromes: clinical features and characteristics of the lymphoid population. Med Oncol 2006; 23: 385-92.
94. Billstrom R, Johansson H, Johansson B, Mitelman F. Immune - mediated complications in patients with myelodysplastic syndromes-clinical and cytogenetic features. Eur J Haematol 1995; 55: 42-8.
95. Epperson DE, Nakamura R, Saunthararajah Y, Melenhorst J, Barrett AJ. Oligoclonal T cell expansion in myelodysplastic syn- drome: evidence for an autoimmune process. Leuk Res 2001; 25: 1075-83.
96. Molldrem JJ, Jiang YZ, Stetler-Stevenson M, Mavroudis D, Hensel N, Barrett AJ. Haematological response of patients with myelodysplastic syndrome to antithymocyte globulin is associated with a loss of lymphocyte-mediated inhibition of CFU-GM and alterations in T-cell receptor Vbeta profiles. Br J Haematol 1998; 102: 1314-22.
97. Melenhorst JJ, Eniafe R, Follmann D, Nakamura R, Kirby M, Barrett AJ. Molecular and flow cytometric characterization of the CD4 and CD8 T-cell repertoire in patients with myelodysplastic syndrome. Br J Haematol 2002; 119: 97-105.
98. Kiladjian JJ, Bourgeois E, Lobe I, et al. Cytolytic function and survival of natural killer cells are severely altered in myelodysplastic syndromes. Leukemia 2006; 20: 463-70.
99. Epling-Burnette PK, Bai F, Painter JS, et al. Reduced natural killer (NK) function associated with high-risk myelodysplastic syndrome (MDS) and reduced expression of activating NK receptors. Blood 2007; 109: 4816-24.