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Role of Specific Histone Deacetylases in Lymphoma Immunobiology and Therapy

Eduardo M. Sotomayor

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National Institutes of Health (NIH)
Mantle cell lymphoma (MCL) is an aggressive and incurable B-cell Non-Hodgkin's lymphoma. A better understanding of the molecular alterations that occurs in MCL is critical for the rational design of novel targeted therapies for this disease Recently, we have found an aberrant expression of two members of the HDAC family, HDAC3 and HDAC6 in MCL. This expression is further up-regulated following adhesion of MCL cells to stromal cells, effect associated with increased lymphoma survival, acquisition of a drug-resistance phenotype and immune evasion. Of note, genetic or pharmacologic inhibition of HDAC6 induced cell cycle arrest, apoptosis and overcomes stroma-mediated drug resistance. In addition, MCL cells lacking HDAC6 are more immunogenic and induce stronger antitumor T-cell responses. Regarding HDAC3, our studies to date have shown that it is an important regulator of a particular group of small non-coding microRNAs (miR-15a/16-1) involved in cell proliferation, apoptosis, tumorigenicity and the drug-resistance phenotype of MCL. Therefore, the goal of this proposal is to mechanistically understand the expression and function of HDAC6 (Aim 1) and HDAC3 (Aim2) in MCL and determine whether their pharmacologic inhibition lead to more effective therapies for this disease (Aim 3). The new knowledge to be generated by this team effort that brings together the expertise in MCL's microenvironment and drug resistance (Tao's lab) and MCL's immunobiology (Sotomayor's lab) would speed up the rational design of a mechanism-based epigenetic therapy for MCL.

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