Acute promyelocytic leukemia (APL) is the M3 subtype of acute myeloid leukemias, characterized by hyperproliferation of progenitors that are committed to terminal differentiation into granulocytes. Despite recent clinical studies using arsenic trioxide, anthracyclines and anti-CD33 monoclonal antibodies, all-trans retinoic acid (ATRA)-based therapy represents, until today, the standard cure of APL patients. Studies on both APL blasts and APL-derived cell lines have elucidated that the treatment with ATRA promotes the completion of their maturation to neutrophils throughout a complex network that includes the degradation of the PML/RAR-alpha fusion protein and the activation of RAR-alpha-mediated gene transcription. Even if the underlying mechanism by which ATRA interacts with its receptor located on specific DNA sequences is well known, the events mediated by the ATRA target genes, able to elicit the integrated signaling networks that promote maturation of tumoral promyelocytes, are currently studied to identify specific targets for new therapies of APL. Stemming from the above reported consideration, the proposed review will focus on the possible role of the multidomain protein Vav1 as a target molecule in treatment of APL. This proposal arises from evidences demonstrating that, in addition to promote the acquisition of a mature phenotype by normal hematopoietic cells, Vav1 is a crucial molecule in the completion of the differentiation program to neutrophils of APL-derived cells induced by ATRA. Indeed, it was demonstrated that the down-modulation of Vav1 prevents, and the Vav1 over-expression potentiates, the ability of ATRA to induce the acquisition of a mature phenotype by tumoral promyelocytes.

Vav1: a key player in aginist-induced differentiation of promyelocytes from Acute Myeloid leukemia (APL).

BERTAGNOLO, Valeria;BRUGNOLI, Federica;CAPITANI, Silvano
2011

Abstract

Acute promyelocytic leukemia (APL) is the M3 subtype of acute myeloid leukemias, characterized by hyperproliferation of progenitors that are committed to terminal differentiation into granulocytes. Despite recent clinical studies using arsenic trioxide, anthracyclines and anti-CD33 monoclonal antibodies, all-trans retinoic acid (ATRA)-based therapy represents, until today, the standard cure of APL patients. Studies on both APL blasts and APL-derived cell lines have elucidated that the treatment with ATRA promotes the completion of their maturation to neutrophils throughout a complex network that includes the degradation of the PML/RAR-alpha fusion protein and the activation of RAR-alpha-mediated gene transcription. Even if the underlying mechanism by which ATRA interacts with its receptor located on specific DNA sequences is well known, the events mediated by the ATRA target genes, able to elicit the integrated signaling networks that promote maturation of tumoral promyelocytes, are currently studied to identify specific targets for new therapies of APL. Stemming from the above reported consideration, the proposed review will focus on the possible role of the multidomain protein Vav1 as a target molecule in treatment of APL. This proposal arises from evidences demonstrating that, in addition to promote the acquisition of a mature phenotype by normal hematopoietic cells, Vav1 is a crucial molecule in the completion of the differentiation program to neutrophils of APL-derived cells induced by ATRA. Indeed, it was demonstrated that the down-modulation of Vav1 prevents, and the Vav1 over-expression potentiates, the ability of ATRA to induce the acquisition of a mature phenotype by tumoral promyelocytes.
2011
9789533077895
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/2321617
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