Critical Requirement of SOS1 for Development of BCR/ABL-Driven Chronic Myelogenous Leukemia

Simple Summary The p210(BCR/ABL) oncoprotein is necessary and sufficient to trigger chronic myelogenous leukemia (CML) in mice. Our prior in vitro studies showing that the ABL-mediated phosphorylation of SOS1 promotes RAC activation and contributes to BCR-ABL leukemogenesis suggested the significant role of SOS1 in the development of CML. To provide direct in vivo experimental evidence of the specific contribution of SOS1 to the development of CML, here, we analyzed the effect of the direct genetic ablation of SOS1 or SOS2 on the genesis of p210(BCR/ABL) -driven CML in mice. Our data showed that direct SOS1 genetic ablation causes the significant suppression of all the pathological hallmarks typical of CML, demonstrating that SOS1 deficiency is protective against CML development and identifying this cellular GEF as a relevant, novel therapeutic target for the clinical treatment of this hematological malignancy. We showed previously that the ABL-mediated phosphorylation of SOS1 promotes RAC activation and contributes to BCR-ABL leukemogenesis, suggesting the relevant role of SOS1 in the pathogenesis of CML. To try and obtain direct experimental evidence of the specific mechanistic implication of SOS1 in CML development, here, we combined a murine model of CML driven by a p210(BCR/ABL) transgene with our tamoxifen-inducible SOS1/2-KO system in order to investigate the phenotypic impact of the direct genetic ablation of SOS1 or SOS2 on the pathogenesis of CML. Our observations showed that, in contrast to control animals expressing normal levels of SOS1 and SOS2 or to single SOS2-KO mice, p210(BCR/ABL) transgenic mice devoid of SOS1 presented significantly extended survival curves and also displayed an almost complete disappearance of the typical hematological alterations and splenomegaly constituting the hallmarks of CML. SOS1 ablation also resulted in a specific reduction in the proliferation and the total number of colony-forming units arising from the population of bone marrow stem/progenitor cells from p210(BCR/ABL) transgenic mice. The specific blockade of CML development caused by SOS1 ablation in p210(BCR/ABL) mice indicates that SOS1 is critically required for CML pathogenesis and supports the consideration of this cellular GEF as a novel, alternative bona fide therapeutic target for CML treatment in the clinic.

Automated summary

This study demonstrates the protective role of SOS1 deficiency in the development of CML and identifies it as a novel therapeutic target.