Oncogenic N-Ras and Tet2 haploinsufficiency collaborate to dysregulate hematopoietic stem and progenitor cells

Xi Jin, Tingting Qin, Meiling Zhao, Nathanael Bailey, Lu Liu, Kevin Yang, Victor Ng, Tomoyasu Higashimoto, Rosemary Coolon, Gina Ney, Maria E. Figueroa, Qing Li

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

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 NrasG12D 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-RasG12D and Tet2 haploinsufficiency together induced balanced hematopoietic stem cell (HSC) proliferation and enhanced competitiveness. NrasG12D/1/Tet21/2 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 NrasG12D/1/Tet21/2 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.

Original languageEnglish (US)
Pages (from-to)1259-1271
Number of pages13
JournalBlood Advances
Volume2
Issue number11
DOIs
StatePublished - Jun 12 2018

ASJC Scopus subject areas

  • Hematology

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    Jin, X., Qin, T., Zhao, M., Bailey, N., Liu, L., Yang, K., Ng, V., Higashimoto, T., Coolon, R., Ney, G., Figueroa, M. E., & Li, Q. (2018). Oncogenic N-Ras and Tet2 haploinsufficiency collaborate to dysregulate hematopoietic stem and progenitor cells. Blood Advances, 2(11), 1259-1271. https://doi.org/10.1182/bloodadvances.2018017400