Japanese Journal of Clinical Oncology 33:153-160 (2003)
© 2003 Foundation for Promotion of Cancer Research
Molecular Mechanisms of Myelodysplastic Syndrome
Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
ABSTRACT
Myelodysplastic syndrome (MDS) is a family of clonal disorders of hematopoietic stem cells that are characterized by ineffective hematopoiesis and susceptibility to acute myelogenous leukemias and are shown to be strikingly refractory to current therapeutic modalities. A substantial proportion of these complex diseases arises in the setting of exposures to environmental or occupational toxins, including cytotoxic therapy for a prior malignancy or other disorder. The conversion of a normal stem cell into a preleukemic and ultimately leukemic state is a multistep process requiring the accumulation of a number of genetic lesions. At the genomic level, MDS is typified by losses and translocations involving certain key gene segments, with disruption of the normal structure and function of genes that control the balance of proliferation and differentiation of hematopoietic precursors. More than half of the chromosomal abnormalities in MDS comprise deletions of chromosomes 5, 7, 11, 12, 13 and 20. This evidence suggests that as yet unidentified tumor-suppressor genes should have important roles in the molecular mechanisms of MDS. Further molecular approaches to such genetic lesions will identify the relevant tumor-suppressor genes. Over the past years, major signal transduction molecules have been identified and their genetic alterations have been extensively analyzed in both MDS and leukemias. These include receptors for growth factors, RAS signaling molecules, cell cycle regulators and transcription factors. Notable among them are transcription factors that regulate both proliferation and differentiation of hematopoietic stem cells. The disruption of the normal flow of the signal transduction pathways involving these molecules translates into ineffective multilineage hematopoiesis and bone marrow failure. Therefore, MDS provides a fertile testing ground on which we could study the molecular dissection implicated in the multistep leukemogenesis.
FOOTNOTES
+ Abbreviations: AML, acute myelogenous leukemia; CDK, cyclin-dependent kinase; CDKI, cyclin-dependent kinase inhibitor; FISH, fluorescence in situ hybridization; FPD, familial platelet disorder; GAP, GTPase-activating protein; G-CSF, granulocyte colony-stimulating factor; GEP, guanine nucleotide-exchange protein; GM-CSF, granulocyte–macrophage colony-stimulating factor; HDAc, histone deacetylase; HNPCC, hereditary non-polyposis colorectal cancer; IL, interleukin; IRF-1, interferon regulatory factor-1; JMML, juvenile myelomonocytic leukemia; LOH, loss of heterozygosity; MAPK, mitogen-activated protein kinase; M-CSF, macrophage colony-stimulating factor; MDS, myelodysplastic syndrome; MMR, mismatch repair; MSI, microsatellite instability; PDGFR-ß, platelet-derived growth factor receptor-ß; RTK, receptor tyrosine kinase; SSCP, single-strand conformation polymorphism; TGF ß, transforming growth factor ß; TNF
, tumor necrosis factor
For reprints and all correspondence: Hisamaru Hirai, Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Hongo, Tokyo 113-8655, Japan. E-mail: hhirai-tky{at}umin.ac.jp
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