The myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem cells. Typically there is peripheral pancytopenia despite a hypercellular bone marrow. It is generally considered that this phenomenon is due to apoptosis of hematopoietic bone marrow cells, resulting in ineffective hematopoiesis. Typically, morphological examination of the bone marrow shows trilineage dysplasia and the molecular lesions occur in pluripotent hematopoietic precursors; the myeloid, monocytic, erythroid, and megakaryocytic lineages are all affected. There is susceptibility to progression to acute myelogenous leukemia (AML), and the patients are often refractory to current therapeutic modalities. There is accumulating evidence suggesting that there is a multistep process with abnormalities in genes for cell cycle control, growth factor receptors, RAS signaling molecules, and transcription factors. A good proportion of all chromosome abnormalities in MDS involve deletions of chromosomes 5, 7, 11, 12, 13 or 20. This provides circumstantial evidence that tumor suppressor genes play an important role in MDS.

It is helpful to consider the molecular genetic model emerging for AML, which is essentially based on two classes of mutations acting together to give rise to AML. The class I mutations provide a proliferative and/or survival signal to hematopoi-etic progenitors. These include activating point mutations in receptor tyrosine kinases such as FLT3 and c-KIT. Class II mutations are those targeting hematopoietic transcription factors and serve primarily to impair differentiation and subsequent apoptosis. This model may be directly applicable to a small proportion of MDS cases such as those with balanced translocations, although it seems unlikely to be more generally applicable to MDS. Figure 8.1 shows a proposed model for genetic progression of MDS to AML which will be refined over the next few years as new insights are gained from micro-array gene expression and other studies.

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