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P62dok and p56dok-2 oppose leukemogenesis by p210Bcr-Abl


, : P62dok and p56dok-2 oppose leukemogenesis by p210Bcr-Abl. Blood 102(11): 650a-651a, November 16

Chronic myelogenous leukemia (CML) is characterized by the presence of the chimeric p210Bcr-Abl oncoprotein which shows elevated and constitutive protein tyrosine kinase activity relative to the normal c-abl tyrosine kinase. Several target proteins of p210Bcr-Abl have been identified. However, the relevance of such substrates in leukemogenesis has not been determined in vivo. We have recently identified a family of proteins, termed DOK (for downstream of tyrosine kinase), coexpressed in hematopoietic progenitor cells. p62dok is known to associate with the p120 rasGTPase-activating protein(rasGAP) upon phosphorylation by p210Bcr-Abl as well as by receptor and non-receptor tyrosine kinases. This led to the hypothesis that p62dok mediate ras activation, thus transducing the p210Bcr-Abl oncogenic signal. p56dok-2 was also identified as rasGAP binding tyrosine phosphorylated proteins by p210Bcr-Abl. In order to assess in vivo the role of p62dok and p56dok-2 in CML pathogenesis, we inactivated both genes by homologous recombination. Both p62dok and p56dok-2-/- mice are born following mendelian frequencies and display no major developmental abnormalities. We intercrossed these DOK mutants with Tec-p210Bcr-Abl transgenic mice (TM) previously generated and characterized by Hirai et al. In these mutants, p210Bcr-Abl is driven by the promoter of the tec gene, a cytoplasmic tyrosine kinase preferentially expressed in the hematopoietic lineage. These TM exhibit a marked granulocyte hyperplasia with thrombocytosis and develop, after long latency period, a myeloproliferative disorders closely resembling human CML. Strikingly and surprisingly, leukemia onset was markedly accelerated in both Tec- p210Bcr-Abl(+)/p62dok-/- mice and Tec- p210Bcr-Abl(+)/p56dok-2-/- (Tec-p210Bcr-Abl(+)p62dok+/+ (n=19), Tec-p210Bcr-Abl(+)/p62dok-/-(n=15), Tec-p210Bcr-Abl(+)/p56dok-2+/+ (n=15), Tec-p210Bcr-Abl(+)/p56dok-2-/- (n=10); p=0.0003). Tec-p210Bcr-Abl(+)/p62dok+/- and Tec-p210Bcr-Abl(+)/p56dok-2+/- also displayed acceleration in leukemia onset when compared with TM in a DOK wild-type background. However, the difference between these DOK heterozygous cohorts did not reach statistical significance. Leukemia in all types was indistinguishable by morphological and flow-cytometric analysis utilizing c-Kit, CD34, Sca-1, Mac-1, Gr-1, F4/80, B220 and Thy1.2 markers. In agreement with these findings, cells of various histological origins from both p62dok and p56dok-2 mutants displayed a proliferative advantage both at the steady state and upon activating stimuli. Taken together our findings uncover the growth-tumor suppressive role of p62dok and p56dok-2 and demonstrate that these DOK proteins do not mediate, but rather oppose leukemogenesis by p210Bcr-Abl.

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