NrasG12D/+ promotes leukemogenesis by aberrantly regulating hematopoietic stem cell functions

Abstract

Key Points NrasG12D/+ induces proliferation and increases self-renewal and myeloid differentiation bias in HSCs. ERK1/2 is constitutively hyperactivated in NrasG12D/+ HSCs and downregulation of the MEK/ERK signaling attenuates NrasG12D/+ HSC phenotypes.

Molecular synergy underlies the co-occurrence patterns and phenotype of NPM1-mutant acute myeloid leukemia

“…Nras G12D/1 mice have been shown to have increased hematopoietic stem (HSC) and progenitor cell numbers, due to increased proliferation and self-renewal of the HSC and MPP compartments. 14,15 Our results confirm these data, demonstrating significant increases in total myeloid progenitors, that is, granulocyte-macrophage (GMP) and common-myeloid progenitors (CMP). Total numbers Figure 1C; supplemental Figure 2A).…”

Preclinical efficacy of MEK inhibition in Nras-mutant AML

“…Inactivating WT Nras did not enhance the in vivo competitive advantage previously reported for heterozygous Nras G12D -mutant BM cells ( Figure 2E). 31 These data are consistent with a recent study that failed Given the lack of mechanistic-based therapies for cancers with NRAS mutations, we asked if Nras G12D murine AMLs are dependent on canonical Ras effector pathways in vivo. We transplanted 5 independent myeloid malignancies into cohorts of sublethally irradiated recipients and assigned these mice to treatment with control vehicle, a potent allosteric MEK inhibitor (PD901), a pan-PI3K inhibitor (GDC-0941), or a combination of both compounds.…”

Molecular determinants of pathogenesis and clinical phenotype in myeloproliferative neoplasms

“…These mutations appear to result in a gain-of-function, resulting in myeloid differentiation and increased HSC self-renewal, and can induce a chronic myelomonocytic leukemia (CMML)-like disease in a mouse model. 61 Similarly, negative regulators of RAS, such as NF1 62 and PTPN11, 63 have also been found to be mutated in some MPN or MPN/MDS-overlap cases.…”