Unique dependence on Sos1 in KrasG12D-induced leukemogenesis

Abstract

<jats:title>Abstract</jats:title> <jats:p>We and others have previously shown that KrasG12D is a much more potent oncogene than oncogenic Nras in hematological malignancies. We attributed the strong leukemogenic activity of KrasG12D 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 KrasG12D/+ cells, but not in NrasQ61R/+ and NrasG12D/+ cells. KrasG12D proteins form a complex with Sos1 in vivo. Sos1 deficiency attenuates hyperactivation of WT Nras, Hras, and the downstream ERK signaling in KrasG12D/+ cells. Thus, Sos1 deletion ameliorates oncogenic Kras-induced myeloproliferative neoplasm (MPN) phenotypes and prolongs the survival of KrasG12D/+ mice. In contrast, Sos1 is dispensable for hyperactivated granulocyte-macrophage colony-stimulating factor signaling in NrasQ61R/+ cells, and Sos1−/− does not affect MPN phenotypes in NrasQ61R/+ mice. Moreover, the survival of KrasG12D/+; Sos1−/− recipients is comparable to that of KrasG12D/+ 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.</jats:p>

Long non-coding RNA LINC01268 promotes cell growth and inhibits cell apoptosis by modulating miR-217/SOS1 axis in acute myeloid leukemia

“…SOS1 could act as an oncogene and play an important role in cancers (25,26). You et al (27) suggested that SOS1 was relevant to leukemogenesis. Moreover, SOS1 has been found to affect RAS/MAPK and PI3K/AKT pathways to regulate various cellular processes (28,29).…”

Recent insights regarding the molecular basis of myeloproliferative neoplasms

“…Oncogenic RAS mutations have been identified in a variety of hematologic malignances, such as juvenile myelomonocytic leukemia, chronic myelomonocytic leukemia, AML, and MPN [79]. A recent knock-in mouse study showed that the Kras G12D mutation drives the aggressive MPN phenotype through mediation of Sos1, a guanine nucleotide exchange factor [80,81]. The authors suggested that the survival of patients with KRAS mutations may increase with therapies that target the Sos1-oncogenic Kras interaction [81].…”

“…A recent knock-in mouse study showed that the Kras G12D mutation drives the aggressive MPN phenotype through mediation of Sos1, a guanine nucleotide exchange factor [80,81]. The authors suggested that the survival of patients with KRAS mutations may increase with therapies that target the Sos1-oncogenic Kras interaction [81].…”

RASmutations drive proliferative chronic myelomonocytic leukemia via activation of a novel KMT2A-PLK1 axis

“…All animal experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals and approved by an Animal Care and Use Committee. For lineage analysis of PB and BM, flow cytometric analyses were performed as described (You et al, 2018). Stained cells were analyzed on a LSR II flow cytometer (BD Biosciences).…”

“…Surface proteins were detected with FITCconjugated antibodies (eBioscience unless specified) against B220 (RA3-6B2), Gr-1 (RB6-8C5), CD3 (17A2, Biolegend), CD4 (GK1.5), CD8 (53-6.7), and TER119 (TER-119), and PEconjugated anti-CD117/c-Kit (2B8) antibody. To analyze phospho-ERK1/2, total BM cells were deprived of serum and cytokines and then stimulated with cytokines as previously described (You et al, 2018). Phosphorylated ERK1/2 (p-ERK1/2) was analyzed in defined Lin -/low c-Kit + cells as described.…”