RT Journal Article
T1 Critical Requirement of SOS1 for Development of BCR/ABL-Driven Chronic Myelogenous Leukemia.
A1 Gómez, Carmela
A1 Garcia-Navas, Rósula
A1 Baltanás, Fernando C
A1 Fuentes-Mateos, Rocío
A1 Fernández-Medarde, Alberto
A1 Calzada, Nuria
A1 Santos, Eugenio
K1 CML
K1 GEF
K1 RAC
K1 RAS
K1 SOS-KO phenotypes
K1 SOS1
K1 SOS2
K1 myeloproliferative disorders
AB 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 p210BCR/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, p210BCR/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 p210BCR/ABL transgenic mice. The specific blockade of CML development caused by SOS1 ablation in p210BCR/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.
SN 2072-6694
YR 2022
FD 2022-08-11
LK http://hdl.handle.net/10668/20912
UL http://hdl.handle.net/10668/20912
LA en
DS RISalud
RD Apr 11, 2025