Histone Methyltransferase SETD2 in Lymphoid Malignancy
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ABSTRACT
SETD2 (SET Domain Containing 2, Histone Lysine Methyltransferase) is the only human gene encoding the histone methyltransferase responsible for trimethylation of lysine 36 of histone H3. SETD2 protein is involved in multiple important cellular processes that include transcriptional regulation, DNA damage repair, alternative RNA splicing, genomic stability, apoptotic response, and interferon response. As a tumor suppressor, SETD2 loses its activities by loss-of-function mutations in a wide spectrum of tumors. The alterations of SETD2 are the most common genetic changes detected in monomorphic epitheliotropic intestinal T-cell lymphoma, seen in over 90% of the cases. SETD2 is the commonest silenced gene detected in hepatosplenic T-cell lymphoma, seen in 25% of the cases. SETD2 alterations have been detected in approximately 10% of precursor B-cell lymphoblastic leukemia/lymphoma cases, and commonly gained in the relapse of this disease. SETD2 alterations have also been found in about 10% of early-T-precursor lymphoblastic leukemia, up to 10% of diffuse large B cell lymphoma, up to 7% of chronic lymphoblastic leukemia/small lymphocytic lymphoma, and in a small portion of other lymphoid malignancies. Experimental loss of SETD2 can promote tumor cell proliferation and result in chemotherapy resistance. Targeting SETD2 may offer a potential therapeutic strategy for these lymphoid malignancies.
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