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.

Public Health Relevance

In 2014, MCL remains incurable and no standard of care exist for this B-cell malignancy. As such, innovative therapies based in a better mechanistic understanding of the molecular alterations that characterize MCL are greatly needed. Our findings that abnormal expression of histone deacetylases 3 and 6 influence the function of critical genes involved in the molecular pathogenesis of MCL, provides the basis for the development of more specific and less toxic epigenetic-based therapy for this challenging disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Immunopathology and Immunotherapy Study Section (CII)
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Howcroft, Thomas K
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H. Lee Moffitt Cancer Center & Research Institute
United States
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Jiang, Huijuan; Lwin, Tint; Zhao, Xiaohong et al. (2018) Venetoclax as a single agent and in combination with PI3K-MTOR1/2 kinase inhibitors against ibrutinib sensitive and resistant mantle cell lymphoma. Br J Haematol :
Woods, David M; Woan, Karrune V; Cheng, Fengdong et al. (2017) T cells lacking HDAC11 have increased effector functions and mediate enhanced alloreactivity in a murine model. Blood 130:146-155
Zhao, Xiaohong; Lwin, Tint; Silva, Ariosto et al. (2017) Unification of de novo and acquired ibrutinib resistance in mantle cell lymphoma. Nat Commun 8:14920