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