Annals of Hematology

, Volume 87, Issue 10, pp 777–795 | Cite as

Myelodysplastic syndromes: molecular pathogenesis and genomic changes

  • Florian Nolte
  • Wolf-K. Hofmann
Review Article


Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis presenting with peripheral cytopenias in combination with a hyperplastic bone marrow and an increased risk of evolution to acute myeloid leukemia. The classification systems such as the WHO classification mainly rely on morphological criteria and are supplemented by the International Prognostic Scoring System which takes cytogenetical changes into consideration when determining the prognosis of MDS but wide intra-subtype variations do exist. The pathomechanisms causing primary MDS require further work. Development and progression of MDS is suggested to be a multistep alteration to hematopoietic stem cells. Different molecular alterations have been described, affecting genes involved in cell-cycle control, mitotic checkpoints, and growth factor receptors. Secondary signal proteins and transcription factors, which gives the cell a growth advantage over its normal counterpart, may be affected as well. The accumulation of such defects may finally cause the leukemic transformation of MDS.


Angiogenesis Bone marrow stroma cells Cell cycle control Deletion 20q DNA-methylation Gene expression profiling JAK2-mutations Mitochondrial DNA Moleculargenetic changes Myelodysplastic syndrome SNP-analysis 5q-syndrome 


  1. 1.
    Germing U, Strupp C, Kundgen A et al (2004) No increase in age-specific incidence of myelodysplastic syndromes. Haematologica 89:905–910PubMedGoogle Scholar
  2. 2.
    Knudson AG (1996) Hereditary cancer: two hits revisited. J Cancer Res Clin Oncol 122:135–140PubMedCrossRefGoogle Scholar
  3. 3.
    Haase D, Germing U, Schanz J et al (2007) New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood 110:4385–4395PubMedCrossRefGoogle Scholar
  4. 4.
    Krug U, Ganser A, Koeffler HP (2002) Tumor suppressor genes in normal and malignant hematopoiesis. Oncogene 21:3475–3495PubMedCrossRefGoogle Scholar
  5. 5.
    Chen Z, Sandberg AA (2002) Molecular cytogenetic aspects of hematological malignancies: clinical implications. Am J Med Genet 115:130–141PubMedCrossRefGoogle Scholar
  6. 6.
    Hirai H (2002) Molecular pathogenesis of MDS. Int J Hematol 76(Suppl 2):213–221PubMedCrossRefGoogle Scholar
  7. 7.
    List A, Dewald G, Bennett J et al (2006) Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 355:1456–1465PubMedCrossRefGoogle Scholar
  8. 8.
    Pellagatti A, Jadersten M, Forsblom AM et al (2007) Lenalidomide inhibits the malignant clone and up-regulates the SPARC gene mapping to the commonly deleted region in 5q- syndrome patients. Proc Natl Acad Sci U S A 104:11406–11411PubMedCrossRefGoogle Scholar
  9. 9.
    Lehmann S, O’Kelly J, Raynaud S et al (2007) Common deleted genes in the 5q- syndrome: thrombocytopenia and reduced erythroid colony formation in SPARC null mice. Leukemia 21:1931–1936PubMedCrossRefGoogle Scholar
  10. 10.
    Ferraro B, Bepler G, Sharma S, Cantor A, Haura EB (2005) EGR1 predicts PTEN and survival in patients with non-small-cell lung cancer. J Clin Oncol 23:1921–1926PubMedCrossRefGoogle Scholar
  11. 11.
    Ronski K, Sanders M, Burleson JA et al (2005) Early growth response gene 1 (EGR1) is deleted in estrogen receptor-negative human breast carcinoma. Cancer 104:925–930PubMedCrossRefGoogle Scholar
  12. 12.
    Krones-Herzig A, Mittal S, Yule K et al (2005) Early growth response 1 acts as a tumor suppressor in vivo and in vitro via regulation of p53. Cancer Res 65:5133–5143PubMedCrossRefGoogle Scholar
  13. 13.
    Joslin JM, Fernald AA, Tennant TR et al (2007) Haploinsufficiency of EGR1, a candidate gene in the del(5q), leads to the development of myeloid disorders. Blood 110:719–726PubMedCrossRefGoogle Scholar
  14. 14.
    Liu TX, Becker MW, Jelinek J et al (2007) Chromosome 5q deletion and epigenetic suppression of the gene encoding alpha-catenin (CTNNA1) in myeloid cell transformation. Nat Med 13:78–83PubMedCrossRefGoogle Scholar
  15. 15.
    Ebert BL, Pretz J, Bosco J et al (2008) Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. Nature 451:335–339PubMedCrossRefGoogle Scholar
  16. 16.
    Gregorio-King CC, Collier GR, McMillan JS et al (2001) ORP-3, a human oxysterol-binding protein gene differentially expressed in hematopoietic cells. Blood 98:2279–2281PubMedCrossRefGoogle Scholar
  17. 17.
    Lehto M, Mayranpaa MI, Pellinen T et al (2008) The R-Ras interaction partner ORP3 regulates cell adhesion. J Cell Sci 121:695–705PubMedCrossRefGoogle Scholar
  18. 18.
    Heinrichs S, Berman JN, Ortiz TM et al (2005) CD34+ cell selection is required to assess HOXA9 expression levels in patients with myelodysplastic syndrome. Br J Haematol 130:83–86PubMedCrossRefGoogle Scholar
  19. 19.
    Bei L, Lu Y, Eklund EA (2005) HOXA9 activates transcription of the gene encoding gp91Phox during myeloid differentiation. J Biol Chem 280:12359–12370PubMedCrossRefGoogle Scholar
  20. 20.
    Hatano Y, Miura I, Nakamura T et al (1999) Molecular heterogeneity of the NUP98/HOXA9 fusion transcript in myelodysplastic syndromes associated with t(7;11)(p15;p15). Br J Haematol 107:600–604PubMedCrossRefGoogle Scholar
  21. 21.
    Roulston D, Espinosa R III, Stoffel M, Bell GI, Le Beau MM (1993) Molecular genetics of myeloid leukemia: identification of the commonly deleted segment of chromosome 20. Blood 82:3424–3429PubMedGoogle Scholar
  22. 22.
    Bench AJ, Nacheva EP, Hood TL et al (2000) Chromosome 20 deletions in myeloid malignancies: reduction of the common deleted region, generation of a PAC/BAC contig and identification of candidate genes. UK Cancer Cytogenetics Group (UKCCG). Oncogene 19:3902–3913PubMedCrossRefGoogle Scholar
  23. 23.
    Douet-Guilbert N, Basinko A, Morel F et al (2008) Chromosome 20 deletions in myelodysplastic syndromes and Philadelphia-chromosome-negative myeloproliferative disorders: characterization by molecular cytogenetics of commonly deleted and retained regions. Ann Hematol 87(7):537–544PubMedCrossRefGoogle Scholar
  24. 24.
    Saberwal G, Lucas S, Janssen I et al (2004) Increased levels and activity of E2F1 transcription factor in myelodysplastic bone marrow. Int J Hematol 80:146–154PubMedCrossRefGoogle Scholar
  25. 25.
    Saberwal G, Broderick E, Janssen I et al (2003) Involvement of cyclin D1 and E2F1 in intramedullary apoptosis in myelodysplastic syndromes. J Hematother Stem Cell Res 12:443–450PubMedCrossRefGoogle Scholar
  26. 26.
    Gery S, Gombart AF, Fung YK, Koeffler HP (2004) C/EBPepsilon interacts with retinoblastoma and E2F1 during granulopoiesis. Blood 103:828–835PubMedCrossRefGoogle Scholar
  27. 27.
    Beaupre DM, Kurzrock R (1999) RAS and leukemia: from basic mechanisms to gene-directed therapy. J Clin Oncol 17:1071–1079PubMedGoogle Scholar
  28. 28.
    Paquette RL, Landaw EM, Pierre RV et al (1993) N-ras mutations are associated with poor prognosis and increased risk of leukemia in myelodysplastic syndrome. Blood 82:590–599PubMedGoogle Scholar
  29. 29.
    Basu TN, Gutmann DH, Fletcher JA et al (1992) Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients. Nature 356:713–715PubMedCrossRefGoogle Scholar
  30. 30.
    Baxter EJ, Scott LM, Campbell PJ et al (2005) Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365:1054–1061PubMedGoogle Scholar
  31. 31.
    James C, Ugo V, Le Couedic JP et al (2005) A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434:1144–1148PubMedCrossRefGoogle Scholar
  32. 32.
    Jones AV, Kreil S, Zoi K et al (2005) Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood 106:2162–2168PubMedCrossRefGoogle Scholar
  33. 33.
    Renneville A, Quesnel B, Charpentier A et al (2006) High occurrence of JAK2 V617 mutation in refractory anemia with ringed sideroblasts associated with marked thrombocytosis. Leukemia 20:2067–2070PubMedCrossRefGoogle Scholar
  34. 34.
    Szpurka H, Tiu R, Murugesan G et al (2006) Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), another myeloproliferative condition characterized by JAK2 V617F mutation. Blood 108:2173–2181PubMedCrossRefGoogle Scholar
  35. 35.
    Boissinot M, Garand R, Hamidou M, Hermouet S (2006) The JAK2-V617F mutation and essential thrombocythemia features in a subset of patients with refractory anemia with ring sideroblasts (RARS). Blood 108:1781–1782PubMedCrossRefGoogle Scholar
  36. 36.
    Ingram W, Lea NC, Cervera J et al (2006) The JAK2 V617F mutation identifies a subgroup of MDS patients with isolated deletion 5q and a proliferative bone marrow. Leukemia 20:1319–1321PubMedCrossRefGoogle Scholar
  37. 37.
    Remacha AF, Nomdedeu JF, Puget G et al (2006) Occurrence of the JAK2 V617F mutation in the WHO provisional entity: myelodysplastic/myeloproliferative disease, unclassifiable-refractory anemia with ringed sideroblasts associated with marked thrombocytosis. Haematologica 91:719–720PubMedGoogle Scholar
  38. 38.
    Wang SA, Hasserjian RP, Loew JM et al (2006) Refractory anemia with ringed sideroblasts associated with marked thrombocytosis harbors JAK2 mutation and shows overlapping myeloproliferative and myelodysplastic features. Leukemia 20:1641–1644PubMedCrossRefGoogle Scholar
  39. 39.
    Zipperer E, Wulfert M, Germing U, Haas R, Gattermann N (2008) MPL 515 and JAK2 mutation analysis in MDS presenting with a platelet count of more than 500 x 10(9)/l. Ann Hematol 87:413–415PubMedCrossRefGoogle Scholar
  40. 40.
    Kottaridis PD, Gale RE, Frew ME et al (2001) The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 98:1752–1759PubMedCrossRefGoogle Scholar
  41. 41.
    Thiede C, Steudel C, Mohr B et al (2002) Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 99:4326–4335PubMedCrossRefGoogle Scholar
  42. 42.
    Georgiou G, Karali V, Zouvelou C et al (2006) Serial determination of FLT3 mutations in myelodysplastic syndrome patients at diagnosis, follow up or acute myeloid leukaemia transformation: incidence and their prognostic significance. Br J Haematol 134:302–306PubMedCrossRefGoogle Scholar
  43. 43.
    Bacher U, Haferlach T, Kern W, Haferlach C, Schnittger S (2007) A comparative study of molecular mutations in 381 patients with myelodysplastic syndrome and in 4130 patients with acute myeloid leukemia. Haematologica 92:744–752PubMedCrossRefGoogle Scholar
  44. 44.
    Grisendi S, Mecucci C, Falini B, Pandolfi PP (2006) Nucleophosmin and cancer. Nat Rev Cancer 6:493–505PubMedCrossRefGoogle Scholar
  45. 45.
    Falini B, Mecucci C, Tiacci E et al (2005) Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 352:254–266PubMedCrossRefGoogle Scholar
  46. 46.
    Sportoletti P, Grisendi S, Majid SM et al (2008) Npm1 is a haploinsufficient suppressor of myeloid and lymphoid malignancies in the mouse. Blood 111:3859–3862Google Scholar
  47. 47.
    Zhang Y, Zhang M, Yang L, Xiao Z (2007) NPM1 mutations in myelodysplastic syndromes and acute myeloid leukemia with normal karyotype. Leuk Res 31:109–111PubMedCrossRefGoogle Scholar
  48. 48.
    Thiede C, Koch S, Creutzig E et al (2006) Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood 107:4011–4020PubMedCrossRefGoogle Scholar
  49. 49.
    Shiseki M, Kitagawa Y, Wang YH et al (2007) Lack of nucleophosmin mutation in patients with myelodysplastic syndrome and acute myeloid leukemia with chromosome 5 abnormalities. Leuk Lymphoma 48:2141–2144PubMedCrossRefGoogle Scholar
  50. 50.
    Boehrer S, Ades L, Braun T et al (2008) Erlotinib exhibits antineoplastic off-target effects in AML and MDS: a preclinical study. Blood 111:2170–2180PubMedCrossRefGoogle Scholar
  51. 51.
    Ichikawa M, Asai T, Chiba S, Kurokawa M, Ogawa S (2004) Runx1/AML-1 ranks as a master regulator of adult hematopoiesis. Cell Cycle 3:722–724PubMedGoogle Scholar
  52. 52.
    Harada H, Harada Y, Niimi H et al (2004) High incidence of somatic mutations in the AML1/RUNX1 gene in myelodysplastic syndrome and low blast percentage myeloid leukemia with myelodysplasia. Blood 103:2316–2324PubMedCrossRefGoogle Scholar
  53. 53.
    Kitabayashi I, Yokoyama A, Shimizu K, Ohki M (1998) Interaction and functional cooperation of the leukemia-associated factors AML1 and p300 in myeloid cell differentiation. EMBO J 17:2994–3004PubMedCrossRefGoogle Scholar
  54. 54.
    Ohashi H, Tsushita K, Utsumi M et al (2001) Relationship between methylation of the p15 gene and ectopic expression of the EVI-1 gene in myelodysplastic syndromes (MDS). Leukemia 15:990–991PubMedCrossRefGoogle Scholar
  55. 55.
    Nucifora G, Laricchia-Robbio L, Senyuk V (2006) EVI1 and hematopoietic disorders: history and perspectives. Gene 368:1–11PubMedCrossRefGoogle Scholar
  56. 56.
    Russell M, List A, Greenberg P et al (1994) Expression of EVI1 in myelodysplastic syndromes and other hematologic malignancies without 3q26 translocations. Blood 84:1243–1248PubMedGoogle Scholar
  57. 57.
    Zoccola D, Legros L, Cassuto P et al (2003) A discriminating screening is necessary to ascertain EVI1 expression by RT-PCR in malignant cells from the myeloid lineage without 3q26 rearrangement. Leukemia 17:643–645PubMedCrossRefGoogle Scholar
  58. 58.
    Raza A, Buonamici S, Lisak L et al (2004) Arsenic trioxide and thalidomide combination produces multi-lineage hematological responses in myelodysplastic syndromes patients, particularly in those with high pre-therapy EVI1 expression. Leuk Res 28:791–803PubMedCrossRefGoogle Scholar
  59. 59.
    Morishita K, Parganas E, William CL et al (1992) Activation of EVI1 gene expression in human acute myelogenous leukemias by translocations spanning 300–400 kilobases on chromosome band 3q26. Proc Natl Acad Sci U S A 89:3937–3941PubMedCrossRefGoogle Scholar
  60. 60.
    Buonamici S, Li D, Chi Y et al (2004) EVI1 induces myelodysplastic syndrome in mice. J Clin Invest 114:713–719PubMedGoogle Scholar
  61. 61.
    Ikonomi P, Rivera CE, Riordan M et al (2000) Overexpression of GATA-2 inhibits erythroid and promotes megakaryocyte differentiation. Exp Hematol 28:1423–1431PubMedCrossRefGoogle Scholar
  62. 62.
    Sitailo S, Sood R, Barton K, Nucifora G (1999) Forced expression of the leukemia-associated gene EVI1 in ES cells: a model for myeloid leukemia with 3q26 rearrangements. Leukemia 13:1639–1645PubMedCrossRefGoogle Scholar
  63. 63.
    Laricchia-Robbio L, Fazzina R, Li D et al (2006) Point mutations in two EVI1 Zn fingers abolish EVI1-GATA1 interaction and allow erythroid differentiation of murine bone marrow cells. Mol Cell Biol 26:7658–7666PubMedCrossRefGoogle Scholar
  64. 64.
    Chakraborty S, Senyuk V, Sitailo S, Chi Y, Nucifora G (2001) Interaction of EVI1 with cAMP-responsive element-binding protein-binding protein (CBP) and p300/CBP-associated factor (P/CAF) results in reversible acetylation of EVI1 and in co-localization in nuclear speckles. J Biol Chem 276:44936–44943PubMedCrossRefGoogle Scholar
  65. 65.
    Liu Y, Chen L, Ko TC, Fields AP, Thompson EA (2006) Evi1 is a survival factor which conveys resistance to both TGFbeta- and taxol-mediated cell death via PI3K/AKT. Oncogene 25:3565–3575PubMedCrossRefGoogle Scholar
  66. 66.
    Lai JL, Preudhomme C, Zandecki M et al (1995) Myelodysplastic syndromes and acute myeloid leukemia with 17p deletion. An entity characterized by specific dysgranulopoiesis and a high incidence of P53 mutations. Leukemia 9:370–381PubMedGoogle Scholar
  67. 67.
    Herman JG, Baylin SB (2003) Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349:2042–2054PubMedCrossRefGoogle Scholar
  68. 68.
    Nakamaki T, Bartram C, Seriu T et al (1997) Molecular analysis of the cyclin-dependent kinase inhibitor genes, p15, p16, p18 and p19 in the myelodysplastic syndromes. Leuk Res 21:235–240PubMedCrossRefGoogle Scholar
  69. 69.
    Quesnel B, Guillerm G, Vereecque R et al (1998) Methylation of the p15(INK4b) gene in myelodysplastic syndromes is frequent and acquired during disease progression. Blood 91:2985–2990PubMedGoogle Scholar
  70. 70.
    Uchida T, Kinoshita T, Nagai H et al (1997) Hypermethylation of the p15INK4B gene in myelodysplastic syndromes. Blood 90:1403–1409PubMedGoogle Scholar
  71. 71.
    Aggerholm A, Holm MS, Guldberg P, Olesen LH, Hokland P (2006) Promoter hypermethylation of p15INK4B, HIC1, CDH1, and ER is frequent in myelodysplastic syndrome and predicts poor prognosis in early-stage patients. Eur J Haematol 76:23–32PubMedCrossRefGoogle Scholar
  72. 72.
    Hopfer O, Komor M, Koehler IS et al (2007) DNA methylation profiling of myelodysplastic syndrome hematopoietic progenitor cells during in vitro lineage-specific differentiation. Exp Hematol 35:712–723PubMedCrossRefGoogle Scholar
  73. 73.
    Silverman LR, Demakos EP, Peterson BL et al (2002) Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 20:2429–2440PubMedCrossRefGoogle Scholar
  74. 74.
    Daskalakis M, Nguyen TT, Nguyen C et al (2002) Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2′-deoxycytidine (decitabine) treatment. Blood 100:2957–2964PubMedCrossRefGoogle Scholar
  75. 75.
    Fenrick R, Hiebert SW (1998) Role of histone deacetylases in acute leukemia. J Cell Biochem Suppl 30–31:194–202Google Scholar
  76. 76.
    Kuendgen A, Strupp C, Aivado M et al (2004) Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid. Blood 104:1266–1269PubMedCrossRefGoogle Scholar
  77. 77.
    Kuendgen A, Knipp S, Fox F et al (2005) Results of a phase 2 study of valproic acid alone or in combination with all-trans retinoic acid in 75 patients with myelodysplastic syndrome and relapsed or refractory acute myeloid leukemia. Ann Hematol 84(Suppl 1):61–66PubMedCrossRefGoogle Scholar
  78. 78.
    Cheson BD, Bennett JM, Kantarjian H et al (2000) Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood 96:3671–3674PubMedGoogle Scholar
  79. 79.
    Blum W, Klisovic RB, Hackanson B et al (2007) Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J Clin Oncol 25:3884–3891PubMedCrossRefGoogle Scholar
  80. 80.
    Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B et al (2006) Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia. Blood 108:3271–3279PubMedCrossRefGoogle Scholar
  81. 81.
    Gattermann N, Retzlaff S, Wang YL et al (1996) A heteroplasmic point mutation of mitochondrial tRNALeu(CUN) in non-lymphoid haemopoietic cell lineages from a patient with acquired idiopathic sideroblastic anaemia. Br J Haematol 93:845–855PubMedCrossRefGoogle Scholar
  82. 82.
    Gattermann N, Retzlaff S, Wang YL et al (1997) Heteroplasmic point mutations of mitochondrial DNA affecting subunit I of cytochrome c oxidase in two patients with acquired idiopathic sideroblastic anemia. Blood 90:4961–4972PubMedGoogle Scholar
  83. 83.
    Gattermann N, Wulfert M, Junge B et al (2004) Ineffective hematopoiesis linked with a mitochondrial tRNA mutation (G3242A) in a patient with myelodysplastic syndrome. Blood 103:1499–1502PubMedCrossRefGoogle Scholar
  84. 84.
    Reddy PL, Shetty VT, Dutt D et al (2002) Increased incidence of mitochondrial cytochrome c-oxidase gene mutations in patients with myelodysplastic syndromes. Br J Haematol 116:564–575PubMedCrossRefGoogle Scholar
  85. 85.
    Shin MG, Kajigaya S, Levin BC, Young NS (2003) Mitochondrial DNA mutations in patients with myelodysplastic syndromes. Blood 101:3118–3125PubMedCrossRefGoogle Scholar
  86. 86.
    Rieger K, Marinets O, Fietz T et al (2005) Mesenchymal stem cells remain of host origin even a long time after allogeneic peripheral blood stem cell or bone marrow transplantation. Exp Hematol 33:605–611PubMedCrossRefGoogle Scholar
  87. 87.
    Awaya N, Rupert K, Bryant E, Torok-Storb B (2002) Failure of adult marrow-derived stem cells to generate marrow stroma after successful hematopoietic stem cell transplantation. Exp Hematol 30:937–942PubMedCrossRefGoogle Scholar
  88. 88.
    Soenen-Cornu V, Tourino C, Bonnet ML et al (2005) Mesenchymal cells generated from patients with myelodysplastic syndromes are devoid of chromosomal clonal markers and support short- and long-term hematopoiesis in vitro. Oncogene 24:2441–2448PubMedCrossRefGoogle Scholar
  89. 89.
    Alvi S, Shaher A, Shetty V et al (2001) Successful establishment of long-term bone marrow cultures in 103 patients with myelodysplastic syndromes. Leuk Res 25:941–954PubMedCrossRefGoogle Scholar
  90. 90.
    Simmons PJ, Przepiorka D, Thomas ED, Torok-Storb B (1987) Host origin of marrow stromal cells following allogeneic bone marrow transplantation. Nature 328:429–432PubMedCrossRefGoogle Scholar
  91. 91.
    Flores-Figueroa E, Gutierrez-Espindola G, Montesinos JJ, Arana-Trejo RM, Mayani H (2002) In vitro characterization of hematopoietic microenvironment cells from patients with myelodysplastic syndrome. Leuk Res 26:677–686PubMedCrossRefGoogle Scholar
  92. 92.
    Flores-Figueroa E, Arana-Trejo RM, Gutierrez-Espindola G, Perez-Cabrera A, Mayani H (2005) Mesenchymal stem cells in myelodysplastic syndromes: phenotypic and cytogenetic characterization. Leuk Res 29:215–224PubMedCrossRefGoogle Scholar
  93. 93.
    Blau O, Hofmann WK, Baldus CD et al (2007) Chromosomal aberrations in bone marrow mesenchymal stroma cells from patients with myelodysplastic syndrome and acute myeloblastic leukemia. Exp Hematol 35:221–229PubMedCrossRefGoogle Scholar
  94. 94.
    Aguayo A, Kantarjian H, Manshouri T et al (2000) Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. Blood 96:2240–2245PubMedGoogle Scholar
  95. 95.
    Keith T, Araki Y, Ohyagi M et al (2007) Regulation of angiogenesis in the bone marrow of myelodysplastic syndromes transforming to overt leukaemia. Br J Haematol 137:206–215PubMedCrossRefGoogle Scholar
  96. 96.
    Stifter G, Heiss S, Gastl G, Tzankov A, Stauder R (2005) Over-expression of tumor necrosis factor-alpha in bone marrow biopsies from patients with myelodysplastic syndromes: relationship to anemia and prognosis. Eur J Haematol 75:485–491PubMedCrossRefGoogle Scholar
  97. 97.
    Campioni D, Punturieri M, Bardi A et al (2004) “In vitro” evaluation of bone marrow angiogenesis in myelodysplastic syndromes: a morphological and functional approach. Leuk Res 28:9–17PubMedCrossRefGoogle Scholar
  98. 98.
    Raza A, Candoni A, Khan U et al (2004) Remicade as TNF suppressor in patients with myelodysplastic syndromes. Leuk Lymphoma 45:2099–2104PubMedCrossRefGoogle Scholar
  99. 99.
    Stasi R, Amadori S (2002) Infliximab chimaeric anti-tumour necrosis factor alpha monoclonal antibody treatment for patients with myelodysplastic syndromes. Br J Haematol 116:334–337PubMedGoogle Scholar
  100. 100.
    Roboz GJ, Giles FJ, List AF et al (2006) Phase 1 study of PTK787/ZK 222584, a small molecule tyrosine kinase receptor inhibitor, for the treatment of acute myeloid leukemia and myelodysplastic syndrome. Leukemia 20:952–957PubMedCrossRefGoogle Scholar
  101. 101.
    Mohamedali A, Gaken J, Twine NA et al (2007) Prevalence and prognostic significance of allelic imbalance by single nucleotide polymorphism analysis in low risk myelodysplastic syndromes. Blood 110:3365–3373Google Scholar
  102. 102.
    Hofmann WK, de Vos S, Komor M et al (2002) Characterization of gene expression of CD34 + cells from normal and myelodysplastic bone marrow. Blood 100:3553–3560PubMedCrossRefGoogle Scholar
  103. 103.
    Miyazato A, Ueno S, Ohmine K et al (2001) Identification of myelodysplastic syndrome-specific genes by DNA microarray analysis with purified hematopoietic stem cell fraction. Blood 98:422–427PubMedCrossRefGoogle Scholar
  104. 104.
    Lee YT, Miller LD, Gubin AN et al (2001) Transcription patterning of uncoupled proliferation and differentiation in myelodysplastic bone marrow with erythroid-focused arrays. Blood 98:1914–1921PubMedCrossRefGoogle Scholar
  105. 105.
    Schoch C, Kohlmann A, Schnittger S et al (2002) Acute myeloid leukemias with reciprocal rearrangements can be distinguished by specific gene expression profiles. Proc Natl Acad Sci U S A 99:10008–10013PubMedCrossRefGoogle Scholar
  106. 106.
    Alizadeh AA, Eisen MB, Davis RE et al (2000) Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403:503–511PubMedCrossRefGoogle Scholar
  107. 107.
    Mauro C, Pacifico F, Lavorgna A et al (2006) ABIN-1 binds to NEMO/IKKgamma and co-operates with A20 in inhibiting NF-kappaB. J Biol Chem 281:18482–18488PubMedCrossRefGoogle Scholar
  108. 108.
    Zhang S, Fukushi M, Hashimoto S et al (2002) A new ERK2 binding protein, Naf1, attenuates the EGF/ERK2 nuclear signaling. Biochem Biophys Res Commun 297:17–23PubMedCrossRefGoogle Scholar
  109. 109.
    Casas S, Nagy B, Elonen E et al (2003) Aberrant expression of HOXA9, DEK, CBL and CSF1R in acute myeloid leukemia. Leuk Lymphoma 44:1935–1941PubMedCrossRefGoogle Scholar
  110. 110.
    Suh ER, Ha CS, Rankin EB, Toyota M, Traber PG (2002) DNA methylation down-regulates CDX1 gene expression in colorectal cancer cell lines. J Biol Chem 277:35795–35800PubMedCrossRefGoogle Scholar
  111. 111.
    Grewal T, Evans R, Rentero C et al (2005) Annexin A6 stimulates the membrane recruitment of p120GAP to modulate Ras and Raf-1 activity. Oncogene 24:5809–5820PubMedCrossRefGoogle Scholar
  112. 112.
    Gou D, Wang J, Gao L et al (2004) Identification and functional analysis of a novel human KRAB/C2H2 zinc finger gene ZNF300. Biochim Biophys Acta 1676:203–209PubMedGoogle Scholar
  113. 113.
    Kaddu S, Zenahlik P, Beham-Schmid C, Kerl H, Cerroni L (1999) Specific cutaneous infiltrates in patients with myelogenous leukemia: a clinicopathologic study of 26 patients with assessment of diagnostic criteria. J Am Acad Dermatol 40:966–978PubMedCrossRefGoogle Scholar
  114. 114.
    Wirtenberger M, Tchatchou S, Hemminki K et al (2006) Associations of genetic variants in the estrogen receptor coactivators PPARGC1A, PPARGC1B and EP300 with familial breast cancer. Carcinogenesis 27:2201–2208PubMedCrossRefGoogle Scholar
  115. 115.
    Srivastava S, Barrett JN, Moraes CT (2007) PGC-1alpha/beta upregulation is associated with improved oxidative phosphorylation in cells harboring nonsense mtDNA mutations. Hum Mol Genet 16:993–1005PubMedCrossRefGoogle Scholar
  116. 116.
    Lierman E, Lahortiga I, Van Miegroet H et al (2007) The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. Haematologica 92:27–34PubMedCrossRefGoogle Scholar
  117. 117.
    Gorello P, La Starza R, Brandimarte L et al (2008) A PDGFRB-positive acute myeloid malignancy with a new t(5;12)(q33;p13.3) involving the ERC1 gene. Leukemia 22:216–218PubMedCrossRefGoogle Scholar
  118. 118.
    Tokita K, Maki K, Tadokoro J et al (2007) Chronic idiopathic myelofibrosis expressing a novel type of TEL-PDGFRB chimaera responded to imatinib mesylate therapy. Leukemia 21:190–192PubMedCrossRefGoogle Scholar
  119. 119.
    Monma F, Nishii K, Lorenzo F et al (2006) Molecular analysis of PDGFRalpha/beta genes in core binding factor leukemia with eosinophilia. Eur J Haematol 76:18–22PubMedCrossRefGoogle Scholar
  120. 120.
    Grand FH, Burgstaller S, Kuhr T et al (2004) p53-Binding protein 1 is fused to the platelet-derived growth factor receptor beta in a patient with a t(5;15)(q33;q22) and an imatinib-responsive eosinophilic myeloproliferative disorder. Cancer Res 64:7216–7219PubMedCrossRefGoogle Scholar
  121. 121.
    Kulkarni S, Heath C, Parker S et al (2000) Fusion of H4/D10S170 to the platelet-derived growth factor receptor beta in BCR-ABL-negative myeloproliferative disorders with a t(5;10)(q33;q21). Cancer Res 60:3592–3598PubMedGoogle Scholar
  122. 122.
    Sanz L, Diaz-Meco MT, Nakano H, Moscat J (2000) The atypical PKC-interacting protein p62 channels NF-kappaB activation by the IL-1-TRAF6 pathway. EMBO J 19:1576–1586PubMedCrossRefGoogle Scholar
  123. 123.
    Zhao Y, Qin S, Atangan LI et al (2004) Casein kinase 1alpha interacts with retinoid X receptor and interferes with agonist-induced apoptosis. J Biol Chem 279:30844–30849PubMedCrossRefGoogle Scholar
  124. 124.
    Itoh S, Kim HW, Nakagawa O et al (2008) Novel role of antioxidant-1 (atox1) as a copper dependent transcription factor involved in cell proliferation. J Biol Chem 283:9157–9167Google Scholar
  125. 125.
    Yu YP, Yu G, Tseng G et al (2007) Glutathione peroxidase 3, deleted or methylated in prostate cancer, suppresses prostate cancer growth and metastasis. Cancer Res 67:8043–8050PubMedCrossRefGoogle Scholar
  126. 126.
    Lee OJ, Schneider-Stock R, McChesney PA et al (2005) Hypermethylation and loss of expression of glutathione peroxidase-3 in Barrett's tumorigenesis. Neoplasia 7:854–861PubMedCrossRefGoogle Scholar
  127. 127.
    Fuster MM, Wang L, Castagnola J et al (2007) Genetic alteration of endothelial heparan sulfate selectively inhibits tumor angiogenesis. J Cell Biol 177:539–549PubMedCrossRefGoogle Scholar
  128. 128.
    Yuan K, Chung LW, Siegal GP, Zayzafoon M (2007) alpha-CaMKII controls the growth of human osteosarcoma by regulating cell cycle progression. Lab Invest 87:938–950PubMedCrossRefGoogle Scholar
  129. 129.
    Backs J, Backs T, Bezprozvannaya S, McKinsey TA, Olson EN (2008) Histone deacetylase 5 acquires calcium/calmodulin-dependent kinase II responsiveness by oligomerization with histone deacetylase 4. Mol Cell Biol 28(10):3437–3445PubMedCrossRefGoogle Scholar
  130. 130.
    Liu AM, Wong YH (2005) Activation of nuclear factor {kappa}B by somatostatin type 2 receptor in pancreatic acinar AR42J cells involves G{alpha}14 and multiple signaling components: a mechanism requiring protein kinase C, calmodulin-dependent kinase II, ERK, and c-Src. J Biol Chem 280:34617–34625PubMedCrossRefGoogle Scholar
  131. 131.
    McClellan KA, Slack RS (2007) Specific in vivo roles for E2Fs in differentiation and development. Cell Cycle 6:2917–2927PubMedGoogle Scholar
  132. 132.
    Black AR, Azizkhan-Clifford J (1999) Regulation of E2F: a family of transcription factors involved in proliferation control. Gene 237:281–302PubMedCrossRefGoogle Scholar
  133. 133.
    Mizuno S, Chijiwa T, Okamura T et al (2001) Expression of DNA methyltransferases DNMT1, 3A, and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia. Blood 97:1172–1179PubMedCrossRefGoogle Scholar
  134. 134.
    Tadokoro Y, Ema H, Okano M, Li E, Nakauchi H (2007) De novo DNA methyltransferase is essential for self-renewal, but not for differentiation, in hematopoietic stem cells. J Exp Med 204:715–722PubMedCrossRefGoogle Scholar
  135. 135.
    Suzuki M, Yamada T, Kihara-Negishi F et al (2006) Site-specific DNA methylation by a complex of PU.1 and Dnmt3a/b. Oncogene 25:2477–2488PubMedCrossRefGoogle Scholar
  136. 136.
    Evans R, Naber C, Steffler T et al (2008) Aurora A kinase RNAi and small molecule inhibition of Aurora kinases with VE-465 induce apoptotic death in multiple myeloma cells. Leuk Lymphoma 49:559–569PubMedCrossRefGoogle Scholar
  137. 137.
    Wittmann T, Wilm M, Karsenti E, Vernos I (2000) TPX2, A novel xenopus MAP involved in spindle pole organization. J Cell Biol 149:1405–1418PubMedCrossRefGoogle Scholar
  138. 138.
    Eckerdt F, Eyers PA, Lewellyn AL, Prigent C, Maller JL (2008) Spindle pole regulation by a discrete Eg5-interacting domain in TPX2. Curr Biol 18:519–525PubMedCrossRefGoogle Scholar
  139. 139.
    Ries C, Loher F, Zang C, Ismair MG, Petrides PE (1999) Matrix metalloproteinase production by bone marrow mononuclear cells from normal individuals and patients with acute and chronic myeloid leukemia or myelodysplastic syndromes. Clin Cancer Res 5:1115–1124PubMedGoogle Scholar
  140. 140.
    Travaglino E, Benatti C, Malcovati L et al (2008) Biological and clinical relevance of matrix metalloproteinases 2 and 9 in acute myeloid leukaemias and myelodysplastic syndromes. Eur J Haematol 80:216–226PubMedCrossRefGoogle Scholar
  141. 141.
    LeCouter JE, Kablar B, Hardy WR et al (1998) Strain-dependent myeloid hyperplasia, growth deficiency, and accelerated cell cycle in mice lacking the Rb-related p107 gene. Mol Cell Biol 18:7455–7465PubMedGoogle Scholar
  142. 142.
    Balciunaite E, Spektor A, Lents NH et al (2005) Pocket protein complexes are recruited to distinct targets in quiescent and proliferating cells. Mol Cell Biol 25:8166–8178PubMedCrossRefGoogle Scholar
  143. 143.
    Clark AJ, Doyle KM, Humbert PO (2004) Cell-intrinsic requirement for pRb in erythropoiesis. Blood 104:1324–1326PubMedCrossRefGoogle Scholar
  144. 144.
    Walkley CR, Orkin SH (2006) Rb is dispensable for self-renewal and multilineage differentiation of adult hematopoietic stem cells. Proc Natl Acad Sci U S A 103:9057–9062PubMedCrossRefGoogle Scholar
  145. 145.
    Allen TC, Granville LA, Cagle PT et al (2007) Expression of glutathione S-transferase pi and glutathione synthase correlates with survival in early stage non-small cell carcinomas of the lung. Hum Pathol 38:220–227PubMedCrossRefGoogle Scholar
  146. 146.
    Lu J, Chew EH, Holmgren A (2007) Targeting thioredoxin reductase is a basis for cancer therapy by arsenic trioxide. Proc Natl Acad Sci U S A 104:12288–12293PubMedCrossRefGoogle Scholar
  147. 147.
    Fok JY, Ekmekcioglu S, Mehta K (2006) Implications of tissue transglutaminase expression in malignant melanoma. Mol Cancer Ther 5:1493–1503PubMedCrossRefGoogle Scholar
  148. 148.
    Ai L, Kim WJ, Demircan B et al (2008) The transglutaminase 2 gene (TGM2), a potential molecular marker for chemotherapeutic drug sensitivity, is epigenetically silenced in breast cancer. Carcinogenesis 29:510–518PubMedCrossRefGoogle Scholar
  149. 149.
    Horowitz A, Tkachenko E, Simons M (2002) Fibroblast growth factor-specific modulation of cellular response by syndecan-4. J Cell Biol 157:715–725PubMedCrossRefGoogle Scholar
  150. 150.
    Chen Q, Sivakumar P, Barley C et al (2007) Potential role for heparan sulfate proteoglycans in regulation of transforming growth factor-beta (TGF-beta) by modulating assembly of latent TGF-beta-binding protein-1. J Biol Chem 282:26418–26430PubMedCrossRefGoogle Scholar
  151. 151.
    Gupta P, Oegema TR Jr, Brazil JJ et al (1998) Structurally specific heparan sulfates support primitive human hematopoiesis by formation of a multimolecular stem cell niche. Blood 92:4641–4651PubMedGoogle Scholar
  152. 152.
    Charnaux N, Brule S, Hamon M et al (2005) Syndecan-4 is a signaling molecule for stromal cell-derived factor-1 (SDF-1)/ CXCL12. FEBS J 272:1937–1951PubMedCrossRefGoogle Scholar
  153. 153.
    Drzeniek Z, Stocker G, Siebertz B et al (1999) Heparan sulfate proteoglycan expression is induced during early erythroid differentiation of multipotent hematopoietic stem cells. Blood 93:2884–2897PubMedGoogle Scholar
  154. 154.
    Chendrimada TP, Finn KJ, Ji X et al (2007) MicroRNA silencing through RISC recruitment of eIF6. Nature 447:823–828PubMedCrossRefGoogle Scholar
  155. 155.
    Lee SK, Kim HJ, Kim JW, Lee JW (1999) Steroid receptor coactivator-1 and its family members differentially regulate transactivation by the tumor suppressor protein p53. Mol Endocrinol 13:1924–1933PubMedCrossRefGoogle Scholar
  156. 156.
    Lutz T, Stoger R, Nieto A (2006) CHD6 is a DNA-dependent ATPase and localizes at nuclear sites of mRNA synthesis. FEBS Lett 580:5851–5857PubMedCrossRefGoogle Scholar
  157. 157.
    Surapureddi S, Yu S, Bu H et al (2002) Identification of a transcriptionally active peroxisome proliferator-activated receptor alpha -interacting cofactor complex in rat liver and characterization of PRIC285 as a coactivator. Proc Natl Acad Sci U S A 99:11836–11841PubMedCrossRefGoogle Scholar
  158. 158.
    Golay J, Broccoli V, Borleri GM et al (1997) Redundant functions of B-Myb and c-Myb in differentiating myeloid cells. Cell Growth Differ 8:1305–1316PubMedGoogle Scholar
  159. 159.
    Sala A (2005) B-MYB, a transcription factor implicated in regulating cell cycle, apoptosis and cancer. Eur J Cancer 41:2479–2484PubMedCrossRefGoogle Scholar
  160. 160.
    Grassilli E, Salomoni P, Perrotti D, Franceschi C, Calabretta B (1999) Resistance to apoptosis in CTLL-2 cells overexpressing B-Myb is associated with B-Myb-dependent bcl-2 induction. Cancer Res 59:2451–2456PubMedGoogle Scholar
  161. 161.
    Muller-Tidow C, Wang W, Idos GE et al (2001) Cyclin A1 directly interacts with B-myb and cyclin A1/cdk2 phosphorylate B-myb at functionally important serine and threonine residues: tissue-specific regulation of B-myb function. Blood 97:2091–2097PubMedCrossRefGoogle Scholar
  162. 162.
    Kim YK, Furic L, Parisien M et al (2007) Staufen1 regulates diverse classes of mammalian transcripts. EMBO J 26:2670–2681PubMedCrossRefGoogle Scholar
  163. 163.
    Nerlov C (2007) The C/EBP family of transcription factors: a paradigm for interaction between gene expression and proliferation control. Trends Cell Biol 17:318–324PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  1. 1.Department of Hematology and OncologyUniversity Hospital Benjamin FranklinBerlinGermany

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