Apoptosis In

Apoptosis may carry the explanation for the paradoxical observation of peripheral cytopenias and a normo- or hypercellular bone marrow in MDS.49,12 Evidence of apoptosis in MDS is supported by various techniques. Apoptosis was first observed by electron microscopic examination of the bone marrow in MDS patients. Evidence of apoptosis was also shown by biochemical techniques, in situ methods, and flow cyto-metric studies.12

Apoptosis seems to be greater in the early stages of MDS and decreases as MDS progresses and transforms to AML. Flow cytometric studies revealed that the proportion of CD34+ cells in G1-DNA phase is higher in early MDS. Also, the ratio of c-Myc (a pro-apoptotic gene) to BCL 2 (an anti-apoptotic gene) decreases as MDS progresses to AML.50 It is controversial whether apoptosis is restricted to CD34+ progenitors, or whether it also includes mature cells.12

Several mechanisms can explain the observation of excessive apoptosis in MDS. The MDS clone itself may carry an intrinsic liability for apoptosis due to altered gene functions and expression; however, there is a lack of correlation between cytogenetic abnormalities and apoptosis, suggesting that the phenomenon is not only restricted to the MDS clone.5152 Increased apoptosis in MDS could also be secondary to inhibitory cytokines (mainly TNF-a) that can induce apoptosis and may affect both the MDS clone and normal cells.53 54 Increased expression of FAS ligand (CD 95 cell surface protein) in MDS bone marrow cells could also be one of the mechanisms contributing to apop-tosis.55 Other potential mechanisms include cell cycle abnormalities and mithochondrial abnormalities leading to increased apoptosis. Mutations of mitochondr-ial DNA may also impair iron metabolism, contributing to sideroblastic anemia.12

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