Unique dependence on Sos1 in KrasG12D-induced leukemogenesis

Abstract

We and others have previously shown that <i>Kras</i> ^<i>G12D</i> is a much more potent oncogene than oncogenic Nras in hematological malignancies. We attributed the strong leukemogenic activity of Kras^G12D at least partially to its unique capability to hyperactivate wild-type (WT) Nras and Hras. Here, we report that Sos1, a guanine nucleotide exchange factor, is required to mediate this process. Sos1 is overexpressed in <i>Kras</i> ^{<i>G12D/+</i>} cells, but not in <i>Nras</i> ^{<i>Q61R/+</i>} and <i>Nras</i> ^{<i>G12D</i>/+} cells. Kras^G12D proteins form a complex with Sos1 in vivo. <i>Sos1</i> deficiency attenuates hyperactivation of WT Nras, Hras, and the downstream ERK signaling in <i>Kras</i> ^{<i>G12D</i>/+} cells. Thus, <i>Sos1</i> deletion ameliorates oncogenic <i>Kras</i>-induced myeloproliferative neoplasm (MPN) phenotypes and prolongs the survival of <i>Kras</i> ^{<i>G12D</i>/+} mice. In contrast, <i>Sos1</i> is dispensable for hyperactivated granulocyte-macrophage colony-stimulating factor signaling in <i>Nras</i> ^{<i>Q61R/+</i>} cells, and <i>Sos1</i> ^<i>-/-</i> does not affect MPN phenotypes in <i>Nras</i> ^{<i>Q61R/+</i>} mice. Moreover, the survival of <i>Kras</i> ^{<i>G12D/+</i>} <i>; Sos1</i> ^<i>-/-</i> recipients is comparable to that of <i>Kras</i> ^{<i>G12D/+</i>} recipients treated with combined MEK and JAK inhibitors. Our study suggests that targeting Sos1-oncogenic Kras interaction may improve the survival of cancer patients with <i>KRAS</i> mutations.