TET2 is one of the most frequently mutated genes in adult myeloid malignancies and normal individuals over 70 years of age. The TET2 protein is an enzyme catalyzing both DNA 5-methylcytosine (5mC) and RNA 5-methylcytosine (m5C) oxidation. So far, more than 700 TET2 mutations have been identified in myeloid malignancy patients, and the majority of mutations impair the enzymatic activity of TET2. Despite extensive studies establishing TET2 as a tumor suppressor of hematopoietic stem/progenitor cells and the requirement of its catalytic activity in the process, the underlying molecular mechanisms remain poorly defined. Our preliminary studies showed that TET2 oxidizes m5C on chromatin-associate...

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TET2 is one of the most frequently mutated genes in adult myeloid malignancies and normal individuals over 70 years of age. The TET2 protein is an enzyme catalyzing both DNA 5-methylcytosine (5mC) and RNA 5-methylcytosine (m5C) oxidation. So far, more than 700 TET2 mutations have been identified in myeloid malignancy patients, and the majority of mutations impair the enzymatic activity of TET2. Despite extensive studies establishing TET2 as a tumor suppressor of hematopoietic stem/progenitor cells and the requirement of its catalytic activity in the process, the underlying molecular mechanisms remain poorly defined. Our preliminary studies showed that TET2 oxidizes m5C on chromatin-associated RNAs to regulate gene expression via the chromatin-modifying protein complex recruitment by m5C specific reader protein MBD6. In this project, we will investigate whether and how the TET2-mediated m5C oxidation of chromatin-associated RNA plays a critical role in TET2's tumor suppressive function and in TET2 mutation caused pathogenesis of myeloid malignancies. Along our investigation, we will identify potential specific therapeutic targets for the eradication of TET2-mutated cells. Success of the proposed studies will fill a critical knowledge gap on how TET2 mutation leads to adult myeloid malignancies and clonal hematopoiesis and lay a solid foundation for future precision therapy developments targeting TET2-mutated myeloid malignancies and normal aged individuals.

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