| First Author | You X | Year | 2018 |
| Journal | Blood | Volume | 132 |
| Issue | 24 | Pages | 2575-2579 |
| PubMed ID | 30377195 | Mgi Jnum | J:269361 |
| Mgi Id | MGI:6273133 | Doi | 10.1182/blood-2018-09-874107 |
| Citation | You X, et al. (2018) Unique dependence on Sos1 in Kras (G12D) -induced leukemogenesis. Blood 132(24):2575-2579 |
| abstractText | We and others have previously shown that Kras (G12D) 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 Kras (G12D/+) cells, but not in Nras (Q61R/+) and Nras (G12D/+) cells. Kras(G12D) proteins form a complex with Sos1 in vivo. Sos1 deficiency attenuates hyperactivation of WT Nras, Hras, and the downstream ERK signaling in Kras (G12D/+) cells. Thus, Sos1 deletion ameliorates oncogenic Kras-induced myeloproliferative neoplasm (MPN) phenotypes and prolongs the survival of Kras (G12D/+) mice. In contrast, Sos1 is dispensable for hyperactivated granulocyte-macrophage colony-stimulating factor signaling in Nras (Q61R/+) cells, and Sos1 (-/-) does not affect MPN phenotypes in Nras (Q61R/+) mice. Moreover, the survival of Kras (G12D/+) ; Sos1 (-/-) recipients is comparable to that of Kras (G12D/+) 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 KRAS mutations. |
