VAV1 NEL DIFFERENZIAMENTO MONOCITO/MACROFAGICO DI PRECURSORI MIELOIDI TUMORALI

Vav1 is a critical signal transducer for the development and function of normal hematopoietic cells, in which it regulates the acquisition of maturation-related properties, including adhesion, motility, and phagocytosis. In addition, Vav1is a key player in the ATRAinduced completion of the differentiation program of tumoral myeloid precursors derived from APL, in which it promotes the acquisition of a mature phenotype by playing multiple functions at both cytoplasmic and nuclear levels. Here we investigate the possible role of Vav1 in the differentiation of leukemic precursors to monocytes/macrophages. Tumoral promyelocytes in which Vav1was negatively modulated were induced to differentiate along the monocytic/macrophagic lineage with ATRA and PMA and monitored for their maturation-related properties. We found that Vav1 is crucial for the phenotypical differentiation of tumoral myeloid precursors to monocytes/macrophages, in terms of CD11b expression, adhesion capability and cell morphology. Confocal analysis revealed that Vav1 may synergize with actin in modulating nuclear morphology of PMA-treated adherent cells. Moreover, Electrophoretic Mobility Shift Assays indicated that Vav1 and the transcription factor PU.1 are recruited to CD11b promoter, suggesting that the two proteins cooperate to regulate the expression of the surface antigen CD11b. The reported results constitute the first evidence thatVav1 plays a crucial role in the maturation of tumoral myeloid precursors to monocytes/macrophages. Since Vav1 is also critical for the maturation of leukemic promyelocytes along the granulocytic lineage, our data highlight the key role for this protein during the completion of the differentiation program of tumoral myeloid cells along the various hematopoietic lineages and suggest that Vav1 is a common target for developing future treatment strategies for the diverse subtypes of myeloid leukemias.