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

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.