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

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