Work

Sos1 deficiency ameliorates oncogenic KRAS-mediated hematopoietic stem cell exhaustion and myeloid progenitor expansion

Year: 2024

Type: article

Abstract: Constitutive KRAS activating mutations are prevalent in hematopoietic malignancies. Our previous study showed that the deficiency of Sos1 prolongs the survival of Kras G12D/+ mice. However, whether Sos1 deletion ameliorates oncogenic Kras -mediated hematopoietic defects remains unknown. Here, we found that Sos1 deletion restored Kras G12D -mediated hematopoietic stem cell (HSC) and multipotent progenitor (MPP) exhaustion by maintaining quiescent HSC and MPP pools. Sos1 knockout attenuates hyperactivation of ERK signaling in Kras G12D/+ HSCs and MPPs. Additionally, the loss of Sos1 reduced the frequency and colony-forming capability of myeloid progenitors in Kras G12D/+ mice, resulting in a less severe myeloproliferative neoplasm phenotype. Moreover, Sos1 knockout prolonged the survival of Kras G12D/+ mice in a cell-autonomous manner. In general, cells with Sos1 deletion remained sensitive to MEK and JAK inhibition, suggesting that combined Sos1 inhibition and other therapies could be a promising strategy for the treatment of oncogenic KRAS -driven leukemia.

Source: Pharmaceutical Science Advances

DOI: 10.1016/j.pscia.2024.100053