Abstract
N-Ras
G12D
and haploinsufficient Tet2 collaborate to induce lethal and highly penetrant CMML in mice with shortened overall survival.
N-Ras
G12D
and haploinsufficient Tet2 together promote balanced proliferation and enhanced competitiveness and self-renewal in HSPCs.
Concurrent genetic lesions exist in a majority of patients with hematologic malignancies. Among these, somatic mutations that activate
RAS
oncogenes and inactivate the epigenetic modifier ten-eleven translocation 2 (
TET2
) frequently co-occur in human chronic myelomonocytic leukemias (CMMLs) and acute myeloid leukemias, suggesting a cooperativity in malignant transformation. To test this, we applied a conditional murine model that endogenously expressed oncogenic
Nras
G12D
and monoallelic loss of
Tet2
and explored the collaborative role specifically within hematopoietic stem and progenitor cells (HSPCs) at disease initiation. We demonstrate that the 2 mutations collaborated to accelerate a transplantable CMML-like disease in vivo, with an overall shortened survival and increased disease penetrance compared with single mutants. At preleukemic stage, N-Ras
G12D
and Tet2 haploinsufficiency together induced balanced hematopoietic stem cell (HSC) proliferation and enhanced competitiveness.
Nras
G12D/+
/
Tet2
+/−
HSCs displayed increased self-renewal in primary and secondary transplantations, with significantly higher reconstitution than single mutants. Strikingly, the 2 mutations together conferred long-term reconstitution and self-renewal potential to multipotent progenitors, a pool of cells that usually have limited self-renewal compared with HSCs. Moreover, HSPCs from
Nras
G12D/+
/
Tet2
+/−
mice displayed increased cytokine sensitivity in response to thrombopoietin. Therefore, our studies establish a novel tractable CMML model and provide insights into how dysregulated signaling pathways and epigenetic modifiers collaborate to modulate HSPC function and promote leukemogenesis.
