Skip to main content
SpringerLink
Log in

Current Treatment Options: Impact of Cytogenetics on the Course of Myelodysplasia

  • Chronic Leukemia
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

The heterogeneity of myelodysplastic syndromes (MDS) has driven the search for unifying biologic and clinical features that would stratify patients into distinct prognostic and therapeutic subgroups. Cytogenetics has been shown to impact the course of myelodysplasia. Despite the presence of non-random cytogenetic abnormalities in ∼50% of MDS patients, it is significant that only a proportion of metaphases may contain the abnormality. Clonality studies however show that the karyotypically normal metaphases are still part of the MDS clone. This would suggest that the chromosomal abnormality may not be the initiating lesion in MDS, and that the gross karyotypic changes represent clonal evolution in a genetically unstable population. Yet, as will be described below, specific cytogenetic abnormalities are associated with clinically and biologically distinct forms of the disease, most notable in the response of del(5q) patients to lenalidomide. One possible explanation for the appearance of non-random mutational events could relate to the interaction of MDS cells with their microenvironment. Whatever the initiating lesion in the MDS stem cell, the end result is a clonal expansion where the marrow becomes populated by the monoclonal progeny of this cell. Interaction of these cells with a microenvironment which has been shown to be rich in pro-apoptotic cytokines such as tumor necrosis factor alpha (TNFa), leads to increased genetic instability. Hypoxia mediated decrease in DNA repair enzymes could further accelerate mutational events culminating in accumulation of multiple chromosomal abnormalities. Some of these chromosomal changes are associated with increased sensitivity to specific drugs. Lenalidomide has shown a high degree of efficacy in MDS patients with del(5q), although the target for the drug is unknown since a small but significant subset of MDS patients without del(5q) abnormality also respond to the drug. In contrast, the molecular target for imatinib mesylate is known; mutations in tyrosine kinase receptor family of genes found in patients with t(5;12) and del(4q12) make these individuals sensitive to the drug. Patients with isolated trisomy 8 have an immune component to the disease phenotype which can be targeted by cyclosporine and or anti-thymocyte globulin (ATG), especially in the presence of a PNH (paroxysmal nocturnal hemoglobinurea) clone. In the absence of these specific cytogenetic abnormalities described above, the two FDA approved hypomethylating agents 5 azacytidine and decitabine should be considered as therapeutic alternatives.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: •Of importance ••Of major importance

  1. Bennett JM, Catovsky D, Daniel MT, et al (1982) Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51(2):189–199

    PubMed  CAS  Google Scholar 

  2. Harris NL, Jaffe ES, Diebold J, et al. (1999) The World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues. Report of the Clinical Advisory Committee meeting, Airlie House, Virginia, November 1997. Ann Oncol 10(12):1419–1432

    Article  PubMed  CAS  Google Scholar 

  3. Yunis JJ, Lobell M, Arnesen MA, Oken MM, et al (1988) Refined chromosome study helps define prognostic subgroups in most patients with primary myelodysplastic syndrome and acute myelogenous leukaemia. Br J Haematol 68:189–194

    PubMed  CAS  Google Scholar 

  4. Morel P, Hebbar M, Lai J-L, A, et al (1993) Cytogenetic analysis has strong independent prognostic value in de novo myelodysplastic syndromes and can be incorporated in a new scoring system: a report on 408 cases. Leukemia 7:1315–1323

    PubMed  CAS  Google Scholar 

  5. Parlier V, Van Melle G, Berise P, PM, et al (1995) Prediction of 18-month survival in patients with primary myelodysplastic syndrome: a regression model and a scoring system based on the combination of chromosome findings and the Bournemouth score. Cancer Genet Cytogenet 81:158–165

    Article  PubMed  CAS  Google Scholar 

  6. Jotterand M, Parlier V (1996) Diagnostic and prognostic significance of cytogenetics in adult primary myelodysplastic syndromes. Leuk Lymphoma 23:253–266

    PubMed  CAS  Google Scholar 

  7. Greenberg P, Cox C, LeBeau MM, Fenaux P, et al (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079–2088

    PubMed  CAS  Google Scholar 

  8. Vallespi T, Imbert M, Mecucci C, Preudhomme C, et al (1998) Diagnosis, classification and cytogenetics of myelodysplastic syndromes. Haematologica 83:258–275

    Article  PubMed  CAS  Google Scholar 

  9. Morel P, Hebbar M, Lai JL, et al (1993) Cytogenetic analysis has strong independent prognostic value in de novo myelodysplastic syndromes and can be incorporated in a new scoring system: a report on 408 cases. Leukemia 7:1315–1323

    PubMed  CAS  Google Scholar 

  10. Pedersen-Bjergaard J, Philip P, Larsen SO, et al (1990) Chromosome aberrations and prognostic factors in therapy-related myelodysplasia and acute nonlymphocytic leukemia. Blood 76:1083-1891

    PubMed  CAS  Google Scholar 

  11. Giagounidis AAN, Germing U, Aul C (2006) Biologic and prognostic significance of chromosome 5q deletions in myeloid malignancies. Clin Cancer Res 12:5–10.

    Article  PubMed  CAS  Google Scholar 

Recent review of the del(5q) in myeloid diseases.

  1. Jaju RJ, Boultwood J, Oliver FJ, et al (1998) Molecular cytogenetic delineation of the critical deleted region in the del(5q) syndrome. Genes Chromosomes Cancer 22:251–256

    Article  PubMed  CAS  Google Scholar 

  2. Nagarajan L (1995) Molecular analysis of the del(5q) chromosome. Leuk Lymphoma 17:361–366

    PubMed  CAS  Google Scholar 

  3. Look AT: Oncogenic transcription factors in the human acute leukemias. Science 1997, 278: 1059–1106.

    Google Scholar 

  4. Marriott JB, Muller G, Stirling D, Dalgleish AG (2001) Immunotherapeutic and antitumour potential of thalidomide analogues. Expert Opin Biol Ther 1(4):675–682

    Article  PubMed  CAS  Google Scholar 

  5. List A, Kurtin S, Roe DJ, et al (2005) Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 352:549–557.

    Article  PubMed  CAS  Google Scholar 

This is the first report of the efficacy of lenalidomide in treatment of del(5q) MDS.

  1. List A, Dewald G, Bennett J, et al. (2006) Myelodysplastic Syndrome-003 Study Investigators. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 355(14):1456–1465

    Article  PubMed  CAS  Google Scholar 

  2. Ebert BL, Galili N, Tamayo P, et al.: An erythroid differentiation gene expression signature predicts response to Lenalidomide in myelodysplasia. Am Soc Hematol, Abstract #2668 Blood 2006, 108(11).

  3. Liang H, Fairman J, Claxton DF, et al.: Molecular anatomy of chromosome 7q deletions in myeloid neoplasms: evidence for multiple critical loci. Proc Natl Acad Sci USA 1998, 95: 3781–3785.

    Google Scholar 

  4. Smith SM, Le Beau MM, Huo D, et al (2003) Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series. Blood 102:43–52

    Article  PubMed  CAS  Google Scholar 

  5. Luna-Fineman S, Shannon KM, Atwater SK, et al (1999) Myelodysplastic and myeloproliferative disorders of childhood: a Study of 167 Patients. Blood 93:459–466

    PubMed  CAS  Google Scholar 

  6. Kardos G, Baumann I, Passmore SJ, et al (2003) Refractory anemia in childhood: a retrospective analysis of 67 patients with particular reference to monosomy 7. Blood 102:1997–2003

    Article  PubMed  CAS  Google Scholar 

  7. Aktas D, Tuncbilek E (2006) Myelodysplastic syndrome associated with monosomy 7 in childhood: a retrospective study. Cancer Genet Cytogenet 171(1):72–75

    Article  PubMed  CAS  Google Scholar 

  8. van Lom K, Hagemeijer A, Smit E, et al (1995) Cytogenetic clonality analysis in myelodysplastic syndromes: monosomy 7 can be demonstrated in the myeloid and in the lymphoid lineage. Leukemia 9(11):1818–1821

    PubMed  Google Scholar 

  9. Sevilla J, Querol S, Molines A, et al (2006) Transient donor cell-derived myelodysplastic syndrome with monosomy 7 after unrelated cord blood transplantation. Eur J Haematol 77(3):259–263

    Article  PubMed  Google Scholar 

  10. Pedersen-Bjergaard J, Christiansen DH, Desta F, Andersen MK (2006) Alternative genetic pathways and cooperating genetic abnormalities in the pathogenesis of therapy-related myelodysplasia and acute myeloid leukemia. Leukemia 20:1943–1949

    Article  PubMed  CAS  Google Scholar 

  11. Sloand EM, Mainwaring L, Fuhrer M, et al (2005) Preferential suppression of trisomy 8 compared with normal hematopoietic cell growth by autologous lymphocytes in patients with trisomy 8 myelodysplastic syndrome. Blood 106(3):841-851

    Article  PubMed  CAS  Google Scholar 

  12. Sole F, Espinet B, Sanz G, Cervera J, et al (2000) Incidence, characterization and prognostic significance of chromosomal abnormalities in 640 patients with primary myelodysplastic syndromes. Br J Haematol 108:346–356

    Article  PubMed  CAS  Google Scholar 

  13. Sloand EM, Pfannes L, Chen G, et al.: CD34 cells from trisomy 8 MDS patients express early apoptotic markers but avoid programmed cell death by upregulation of anti-apoptotic proteins. Blood 2006, Nov 7; [Epub ahead of print].

This study shows a mechanism by which MDS cells with trisomy 8 escape apoptosis despite the presence of trisomy 8 specific cytotoxic T cells.

  1. Březinová J, Zemanova Z, Ransdorfová S, et al (2005) Prognostic significance of del(20q) in patients with hematological malignancies. Cancer Genet Cytogenet 160(2):188–192

    Article  PubMed  Google Scholar 

  2. Wattel E, Lai JL, Hebbar M, Preudhomme C, et al (1993) 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 17(11):921–926

    Article  PubMed  CAS  Google Scholar 

  3. Liu YC, Ito Y, Hsiao HH, et al (2006) Risk factor analysis in myelodysplastic syndrome patients with del(20q): prognosis revisited. Cancer Genet Cytogenet 171(1):9–16

    Article  PubMed  CAS  Google Scholar 

  4. Chen B, Zhao WL, Jin J, et al (2005) Clinical and cytogenetic features of 508 Chinese patients with myelodysplastic syndrome and comparison with those in Western countries. Leukemia 19:767–775

    Article  PubMed  CAS  Google Scholar 

  5. Matsushima T, Handa H, Yokohama A, et al.: Prevalence and clinical characteristics of myelodysplastic syndrome with bone marrow eosinophilia or basophilia. Blood 2003, 101(9):3386–3390. [Epub 2002]

    Google Scholar 

  6. Cools J, DeAngelo DJ, Gotlib J, et al (2003) A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 348(13):1201–1214. This is the first report of the molecular target of imatinib in HES.

    Article  PubMed  CAS  Google Scholar 

This is the first report of the molecular target of imatinib in HES

  1. Schaller JL, Burkland GA: Case report: rapid and complete control of idiopathic hypereosinophilia with imatinib mesylate. MedGenMed 2001, 3:9

    Google Scholar 

  2. Gleich GJ, Leiferman KM, Pardanani A, et al (2002) Treatment of hypereosinophilic syndrome with imatinib mesylate. Lancet 359:1577–1578

    Article  PubMed  CAS  Google Scholar 

  3. Ault P, Cortes J, Koller C, Kaled ES, Kantarjian H (2002) Response of idiopathic hypereosinophilic syndrome to treatment with imatinib mesylate. Leuk Res 26:881–884

    Article  PubMed  CAS  Google Scholar 

  4. Cortes J, Ault P, Koller C, et al (2003) Efficacy of imatinib mesylate in the treatment of idiopathic hypereosinophilic syndrome. Blood 101:4714–4716

    Article  PubMed  CAS  Google Scholar 

  5. Gotlib J (2005) Molecular Classification and Pathogenesis of Eosinophilic Disorders: 2005 Update. Acta Haematol. 114(1):7-25

    Article  PubMed  CAS  Google Scholar 

  6. Jovanovic J, Score J, Waghorn K,et al.: Low-dose imatinib mesylate leads to rapid induction of major molecular responses and achievement of complete molecular remission in FIP1L1-PDGFRA positive chronic eosinophilic leukemia. Blood 2007 Feb 13; [Epub ahead of print]

This study describes the efficacy of low-dose imatinib in FIP1L1-PDGFRA positive chronic eosinophilic leukemia.

  1. Berkowicz M, Rosner E, Rechavi G, et al (1991) Atypical chronic myelomonocytic leukemia with eosinophilia and translocation (5;12). A new association. Cancer Genet Cytogenet 51(2):277–278

    Article  PubMed  CAS  Google Scholar 

  2. Golub TR, Barker GF, Lovett M, Gilliland DG (1994) Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell 77:307–316

    Article  PubMed  CAS  Google Scholar 

  3. Carroll M, Tomasson MH, Barker GF, et al.: 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(25):14845–14850.

    Article  PubMed  CAS  Google Scholar 

  4. Yoon SY, Tefferi A, Li CY (2000) Cellular distribution of platelet-derived growth factor, transforming growth factor-beta, basic fibroblast growth factor, and their receptors in normal bone marrow. Acta Hematol 104:151–157

    Article  CAS  Google Scholar 

  5. Ross TS, Bernard OA, Berger R, Gilliland DG (1998) Fusion of Huntingtin interacting protein 1 to platelet-derived growth factor beta receptor (PDGFbetaR) in chronic myelomonocytic leukemia with t(5;7)(q33;q11.2). Blood 91:4419-4426

    PubMed  CAS  Google Scholar 

  6. 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 60:3529-3598

    Google Scholar 

  7. Magnusson MK, Meade KE, Brown KE, et al (2001) Rabaptin-5 is a novel fusion partner to platelet-derived growth factor beta receptor in chronic myelomonocytic leukemia. Blood 98:2518-2525

    Article  PubMed  CAS  Google Scholar 

  8. Abe A, Emi N, Tanimoto M, et al (1997) Fusion of the platelet-derived growth factor receptor beta to a novel gene CEV14 in acute myelogenous leukemia after clonal evolution. Blood 90:4271-4277

    PubMed  CAS  Google Scholar 

  9. Wlodarska I, Mecucci C, Marynen P, et al (1995) 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. 85(10):2848–2852

    PubMed  CAS  Google Scholar 

  10. Odero MD, Vizmanos JL, Roman JP, et al (2002) A novel gene, MDS2, is fused to ETV6/TEL in a t(1;12)(p36.1;p13) in a patient with myelodysplastic syndrome. Genes Chromosomes Cancer 35(1):11–19

    Article  PubMed  CAS  Google Scholar 

  11. Apperley JF, Gardembas M, Melo JV, et al (2002) Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. N Engl J Med 347:481–487

    Article  PubMed  CAS  Google Scholar 

  12. Cortes J, Giles F, O’Brien S, et al.: Results of imatinib mesylate therapy in patients with refractory or recurrent acute myeloid leukemia, high-risk myelodysplastic syndrome, and myeloproliferative disorders. Cancer 2003, 97:2760–2766.

    Article  PubMed  CAS  Google Scholar 

Therapeutic efficacy of imatinib lmited to those patients with a mutated tyrosine kinase gene.

  1. Raza A, Lisak L, Dutt D, et al (2001) Gleevec (imatinib mesylate) in 16 patients with Chronic Myelomonocytic leukemia (CMMoL) (abstract). Blood 98:273b.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Radhey Khanna MDS Center, Division of Hematology, University of Massachusetts Medical Center, 364 Plantation Street, Worcester, MA, 01605, USA

    Naomi Galili Ph.D., Jan Cerny M.D. & Azra Raza M.D.

Authors
  1. Naomi Galili Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jan Cerny M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Azra Raza M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Azra Raza M.D..

Rights and permissions

Reprints and permissions

About this article

Cite this article

Galili, N., Cerny, J. & Raza, A. Current Treatment Options: Impact of Cytogenetics on the Course of Myelodysplasia. Curr. Treat. Options in Oncol. 8, 117–128 (2007). https://doi.org/10.1007/s11864-007-0017-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11864-007-0017-1

Keywords

Search

Navigation