c-mplExpression in Hematologic Disorders

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Abstract
The c-mpl gene encodes a member of the hematopoietic cytokine receptor superfamily. This gene was discovered through the study of a murine retrovirus which induces an acute myeloproliferative syndrome in mice. MPLV (for myeloproliferative leukemia virus) has transduced a truncated and constitutively activated form of the c-mpl receptor chain. The c-mpl ligand is unknown, but recent data indicate that it could specifically regulate thrombocytopoiesis. This review focuses on the expression of the c-mpl gene in a large series of human hematopoietic pathologies by Northern blot analysis. Barely detectable transcript levels were detected in normal bone marrow (BM) and in BM samples from chronic myeloproliferative disorders, plasmocytoma, Burkitt lymphoma or acute lymphoid leukemia. In contrast, high levels of c-mpl expression were detected in 45% of acute myeloid leukemia (AML). No correlation was found between c-mpl expression and the French-American-British classification subtype of AML. However c-mpl expression correlated with CD34 expression, and unfavorable cytogenetic abnormalities, defining a subgroup of AML with a low rate of complete remission. In myelodysplasia, c-mpl expression was elevated in 44% of chronic myelomonocytic leukemia (CMML), 42% of refractory anemia with excess myeloblasts (RAEB), and RAEB in transformation to acute leukemia (RAEBt), but not in refractory anemia (RA) and RA with ringed sideroblasts (RARS). In CMML, there was no correlation between c-mpl expression and any prognostic factor tested, nor with the course of the disease. The biologic significance of c-mpl expression in RAEB and RAEBt is probably different. In fact, a significant correlation was observed between c-mpl, CD34, and the megakaryocyte glycoprotein IIb (GPIIb) expression, and the presence of dysmegakaryopoiesis. Moreover, a subgroup of patients of particular poor prognosis, with an increased risk of secondary leukemia, may be defined by the following phenotype: c-mpl+, CD34+, GpIIb+. In AML, RAEB, and RAEBt, c-mpl expression seems to reflect the expansion of a CD34 positive blast cell population. Molecular cloning of the c-mpl ligand and functional characterization of the c-mpl receptor in AML cells will provide further understanding of its role in the growth of blast cells.

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