Myelodysplastic Syndrome

MDS is a clonal multipotent hematopoietic stem cell disorder characterized by both clinically and morphologically ineffective hematopoiesis. Clinically, MDS represents a condition of bone marrow failure, usually of the elderly (primary MDS), or of patients previously exposed to prior chemotherapy, or radiation, or both (secondary MDS). The correlation of the biology of this clonal disorder with its clinical presentation of cytope-nias is varied, ranging from an incidental mild anemia stable for years to a rapidly evolving leukemia.

Clonality of MDS was first verified by glucose 6-phos-phatase-dehydrogenase (G6PD) isoenzyme studies.155 Furthermore, several studies using X-linked restriction fragment length polymorphism (LFRP)156 demonstrated that MDS arises from a multipotent stem cell with the potential for both myeloid and lymphoid differentiation.

Bone marrow failure in MDS is a result of ineffective hematopoiesis rather than a lack of hematopoietic activity. Recent studies implicate extensive apoptosis as the explanation of the paradoxical observation of marrow hyperplasia but peripheral cytopenia.157 High levels of TNF-a were found to correlate with high levels of apoptosis.158 Both precursor and terminally differentiated cells in MDS often have functional defects (i.e., decreased sensitivity to erythropoietin in red cell precursors, decreased MPO, and microbicidal activity in neutrophils, and functional defects in platelets). Among these, neu-tropenia or neutrophil dysfunction accounts for the primary clinical manifestation of MDS in terms of an increased risk for infection, which is the leading cause of death in MDS.

Certain chromosomal abnormalities are common in MDS, especially loss or gain of all or parts of chromosomes 5,7, 8, and 20.159 Recently, a number of MDS cases associated with 11q23 abnormalities have been reported.124

By definition MDS is characterized by hypercellular marrow with bi- or trilineage dyplasia. Single line dysplasia of the ery-throid, granulocytic, or megakaryocytic precursors has become recognized with increased frequency and is captured in the WHO proposals and listed under MDS, Unclassified, when the blast percentage is less than 5. The bone marrow cellularity at diagnosis was assessed in different stem cell disorders by our group.160 The estimation of bone marrow cellularity for each group was used both with and without age adjustment, based on normal marrow biopsies. The age-corrected data disclosed that of all patients with chronic myeloproliferative disorders (CMPD), 63 percent of patients with AML and only 35 percent of patients with MDS had hypercellular bone marrow according to their age. Our study suggests that in terms of bone mar row cellularity, MDS is quite different from AML and CMPDs, and appears to have a different proliferative capacity.

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