Defective megakaryocytic development in myelodysplastic syndromes

Megakaryocytic proliferation and differentiation is typically abnormal in p atients with myelodysplastic syndromes (MDS). The underlying mechanisms for this finding are not known, but may involve defects at the level of the th rombopoietin-receptor (c-mpl) or post-receptor signaling pathways in megaka ryocyte progenitor cells. Premature apoptosis of the bone marrow cells and inhibitory effects of cytokines such as tumor necrosis factor alpha have be en implicated as contributing to altered megakaryopoiesis in MDS, but their significance remains unclear. The availability of thrombopoietin (TPO) has facilitated more detailed analysis of megakaryocytic biology using several experimental in-vitro systems. However numerous studies have shown that th e developmental abnormalities of MDS megakaryocytes could not be corrected by TPO, Increasing investigations are being extended to the evaluation of s ignal transduction pathways of c-mpl both in cell lines and human hematopoi etic cells in order to identify the molecular mechanisms responsible for th e defective megakaryocytic development in MDS.