Vav promotes differentiation of human tumoral myeloid precursors.
Vav is one of the genetic markers that correlate with the differentiation of hematopoietic cells. In T and B cells, it appears crucial for both development and functions, while, in non-lymphoid hematopoietic cells, Vav seems not involved in cell maturation, but rather in the response of mature cells to agonist-dependent proliferation and phagocytosis. We have previously demonstrated that the amount and the tyrosine phosphorylation of Vav are up-regulated in both whole cells and nuclei of tumoral promyelocytes induced to granulocytic maturation by ATRA and that tyrosine-phosphorylated Vav does not display any ATRA-induced GEF activity but contributes to the regulation of PI 3-K activity. In this study, we report that Vav accumulates in nuclei of ATRA-treated APL-derived cells and that the down-modulation of Vav prevents differentiation of tumoral promyelocytes, indicating that it is a key molecule in ATRA-dependent myeloid maturation. On the other hand, the overexpression of Vav induces an increased expression of surface markers of granulocytic differentiation without affecting the maturation-related changes of the nuclear morphology. Consistent with an effect of Vav on the transcriptional machinery, array profiling shows that the inhibition of the Syk-dependent tyrosine phosphorylation of Vav reduces the number of ATRA-induced genes. Our data support the unprecedented notion that Vav plays crucial functions in the maturation process of myeloid cells, and suggest that Vav can be regarded as a potential target for the therapeutic treatment of myeloproliferative disorders.
Bertagnolo
Valeria
V
Signal Transduction Unit-Laboratory of Cell Biology, Section of Human Anatomy, Department of Morphology and Embryology, University of Ferrara, Via Fossato di Mortara, 66, 44100 Ferrara, Italy.
Brugnoli
Federica
F
Mischiati
Carlo
C
Sereni
Alessia
A
Bavelloni
Alberto
A
Carini
Cinzia
C
Capitani
Silvano
S
D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006098:Granulocytes / Q000502:physiology; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D023461:Myeloid Progenitor Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051567:Proto-Oncogene Proteins c-vav; D034741:RNA, Small Interfering / Q000235:genetics; D013267:Stilbenes / Q000494:pharmacology; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D034741:RNA, Small Interfering; D013267:Stilbenes; C496618:VAV1 protein, human; D014212:Tretinoin; C041525:3,3',4,5'-tetrahydroxystilbene; D011505:Protein-Tyrosine Kinases