Vav promotes differentiation of human tumoral myeloid precursors

被引:23
作者
Bertagnolo, V
Brugnoli, F
Mischiati, C
Sereni, A
Bavelloni, A
Carini, C
Capitani, S
机构
[1] Univ Ferrara, Signal Transduct Unit, Cell Biol Lab, Sect Human Anat,Dept Morphol & Embryol, I-44100 Ferrara, Italy
[2] Univ Ferrara, Dept Biochem & Mol Biol, I-44100 Ferrara, Italy
[3] IOR, Lab Cell Biol & Electron Microscopy, Bologna, Italy
[4] Univ Ferrara, ICSI, MIUR, I-44100 Ferrara, Italy
关键词
Vav; acute promyelocytic leukemia (APL); granulocytic differentiation; all-trans retinoic acid (ATRA); tyrosine phosphorylation;
D O I
10.1016/j.yexcr.2004.12.001
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 ATPA-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. (c) 2004 Elsevier Inc. All rights reserved.
引用
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页码:56 / 63
页数:8
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