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Vav1 is a crucial molecule in monocytic/macrophagic differentiation of myeloid leukemia-derived cells

Abstract

Vav1 is a critical signal transducer for both the development and function of normal hematopoietic cells, in which it regulates the acquisition of maturation-related properties, including adhesion, motility, and phagocytosis. Vav1 is also important for the agonist-induced maturation of acute promyelocytic leukemia (APL)-derived promyelocytes, in which it promotes the acquisition of a mature phenotype by playing multiple functions at both cytoplasmic and nuclear levels. We investigated the possible role of Vav1 in the differentiation of leukemic precursors to monocytes/macrophages. Tumoral promyelocytes in which Vav1 was negatively modulated were induced to differentiate into monocytes/macrophages with phorbol-12-myristate-13-acetate (PMA) and monitored for their maturation-related properties. We found that Vav1 was 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. Our data indicate that, in tumoral promyelocytes, Vav1 is a component of lineage-specific transduction machineries that can be recruited by various differentiating agents. Since Vav1 plays a central role in the completion of the differentiation program of leukemic promyelocytes along diverse hematopoietic lineages, it can be considered a common target for developing new therapeutic strategies for the various subtypes of myeloid leukemias.

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Abbreviations

ATRA:

All trans-retinoic acid

APL:

Acute promyelocytic leukemia

BSA:

Bovine serum albumin

DAPI:

4,6-Diamino-2-phenylindole

DABCO:

1,4-Diazabicyclo [2.2.2] octane

DMSO:

Dimethyl sulfoxide

FBS:

Fetal bovine serum

FITC:

Fluorescein isothiocyanate

GEF:

Guanine Nucleotide exchange factor

PBS:

Phosphate-buffered saline

PIC:

Piceatannol

PMA:

Phorbol-12-myristate-13-acetate

siRNA:

Small interfering RNA

TRITC:

Tetramethylrhodamine isothiocyanate

TBS:

TRIS-buffered saline

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Author information

Correspondence to Valeria Bertagnolo.

Additional information

This research was supported by grants from MIUR Cofin (2007) to S.C., MAE (Italy-Croatia bilateral project 2009–2010) to V.B., and local funds from the University of Ferrara (Italy) to S.C. and V.B.

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Bertagnolo, V., Nika, E., Brugnoli, F. et al. Vav1 is a crucial molecule in monocytic/macrophagic differentiation of myeloid leukemia-derived cells. Cell Tissue Res 345, 163–175 (2011). https://doi.org/10.1007/s00441-011-1195-5

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Keywords

  • Myeloid leukemia
  • Vav1
  • Monocytic differentiation
  • Cytoskeleton
  • Actin
  • Cell culture