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Oncogenic NRAS rapidly and efficiently induces CMML- and AML-like diseases in mice
Chaitali Parikh1, Ramesh Subrahmanyam, Ruibao Ren
1Rosenstiel Basic Medical Sciences Research Center, MS029, Brandeis University, Waltham, MA 02454-9110, USA.
Abstract:
Activating mutations in RAS, predominantly NRAS, are common in myeloid malignancies. Previous studies in animal models have shown that oncogenic NRAS is unable to induce myeloid malignancies effectively, and it was suggested that oncogenic NRAS might only act as a secondary mutation in leukemogenesis. In this study, we examined the leukemogenicity of NRAS using an improved mouse bone marrow transduction and transplantation model. We found that oncogenic NRAS rapidly and efficiently induced chronic myelomonocytic leukemia (CMML)- or acute myeloid leukemia (AML)- like disease in mice, indicating that mutated NRAS can function as an initiating oncogene in the induction of myeloid malignancies. In addition to CMML and AML, we found that NRAS induced mastocytosis in mice. This result indicates that activation of the RAS pathway also plays an important role in the pathogenesis of mastocytosis. The mouse model for NRAS leukemogenesis established here provides a system for further studying the molecular mechanisms in the pathogenesis of myeloid malignancies and for testing relevant therapies.
Insights
Activating NRAS mutations initiate myeloid malignancies like CMML and AML in mice, challenging previous theories. This study establishes NRAS as a primary oncogene in leukemogenesis and mastocytosis development.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Activating RAS mutations, particularly NRAS, are prevalent in myeloid malignancies.
- Prior research suggested oncogenic NRAS acts as a secondary mutation in leukemogenesis.
Purpose of the Study:
- To investigate the leukemogenic potential of NRAS using an advanced mouse model.
- To determine if NRAS can function as an initiating oncogene in myeloid cancer development.
Main Methods:
- Utilized an improved mouse bone marrow transduction and transplantation model.
- Assessed the effects of oncogenic NRAS expression on hematopoietic stem cells and disease induction.
Main Results:
- Oncogenic NRAS rapidly induced chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML)-like diseases in mice.
- NRAS activation was also found to induce mastocytosis, highlighting its role in RAS pathway-driven pathogenesis.
- Demonstrated that mutated NRAS can act as an initiating oncogene.
Conclusions:
- Mutated NRAS is capable of initiating myeloid malignancies, including CMML, AML, and mastocytosis.
- The established mouse model offers a platform for studying NRAS leukemogenesis and evaluating new therapies.
- RAS pathway activation is crucial in the pathogenesis of various myeloid neoplasms.
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