Critical Requirement of SOS1 for Development of BCR/ABL-Driven Chronic Myelogenous Leukemia
| Autor: | Carmela Gómez, Rósula Garcia-Navas, Fernando C. Baltanás, Rocío Fuentes-Mateos, Alberto Fernández-Medarde, Nuria Calzada, Eugenio Santos |
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| Přispěvatelé: | Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica, Instituto de Salud Carlos III, FIS PI19/00934, Junta de Castilla-León, SA264P18-UIC 076, Fundación Ramón Areces, CIVP19A5942, Fundación a la memora de d. Samuel Solorzano Barruso, FS/32-2020, Centro de Investigación Biomédica en Red. Instituto de Salud Carlos III, CB16/12/00352, Fondos FEDER, Programa de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia de la Junta de Castilla y León, CLC-2017-01, Asociación Española Contra el Cáncer, Consejería de Educación de la Junta de Castilla y León (Orden), EDU/529/217, Instituto de Salud Carlos III, Junta de Castilla y León, Fundación Ramón Areces, Fundación Memoria de D. Samuel Solorzano Barruso, European Commission |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Cancers; Volume 14; Issue 16; Pages: 3893 |
| Popis: | 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. The E.S. group was supported by grants from ISCIII-MCUI (FIS PI19/00934), JCyL (SA264P18-UIC 076), the Areces Foundation (CIVP19A5942), the Solorzano-Barruso Foundation (FS/32-2020), and by ISCIII-CIBERONC (group CB16/12/00352). This research was cofinanced by FEDER funds. The CIC is supported by the Programa de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia of Castilla y León autonomous government (CLC-2017-01). C.G. was supported by the Spanish Association Against Cancer (AECC) postdoctoral fellowship; R.G.-N. was supported by ISCIII-CIBERONC (group CB16/12/00352); F.C.B. was supported by ISCIII-CIBERONC (group CB16/12/00352); and R.F.M. was supported by a predoc fellowship from Consejería Educación, JCyL (ORDEN EDU/529/217). |
| Databáze: | OpenAIRE |
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