Role of Specific Histone Deacetylases in Lymphoma Immunobiology and Therapy

特异性组蛋白脱乙酰酶在淋巴瘤免疫生物学和治疗中的作用

• 批准号: 8901549
• 负责人: EDUARDO M. SOTOMAYOR
• 金额: $ 38.54万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-07 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8901549
• 关键词: Adhesions; Agammaglobulinaemia tyrosine kinase; Antitumor Response; Apoptosis; B lymphoid malignancy; B-Cell NonHodgkins Lymphoma; Biology; Cell Cycle Arrest; Cell Line; Cell Proliferation; Cells; Characteristics; Complex; Cytokine Signaling; Development; Diagnosis; Disease; Drug resistance; EZH2 gene; Epigenetic Process; FDA approved; Family; Foundations; Genes; Genetic; Goals; HDAC3 gene; HDAC6 gene; Histones; Immune; Immunity; Immunobiology; Immunologics; Immunosuppression; Immunosuppressive Agents; Innovative Therapy; Knowledge; Lead; Lymphoma; Lymphomagenesis; Maintenance; Mantle Cell Lymphoma; Mediating; MicroRNAs; Modality; Molecular; Outcome; Pathogenesis; Patients; Phenotype; Play; Receptor Signaling; Receptors, Antigen, B-Cell; Refractory; Regulation; Relapse; Repression; Resistance; Role; STAT3 gene; Sampling; Signal Pathway; Signal Transduction; Speed; Stromal Cells; T cell response; Therapeutic; Tumor Suppressor Proteins; Tumorigenicity; Tyrosine Kinase Inhibitor; Untranslated RNA; autocrine; base; c-myc Genes; cell stroma; cytotoxicity; design; effective therapy; immunogenic; immunogenicity; improved; in vivo; inhibitor/antagonist; lenalidomide; member; new therapeutic target; novel; overexpression; public health relevance; response; sobriety; standard of care; targeted treatment; therapeutic target

 DESCRIPTION (provided by applicant): 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.

 描述（由申请人提供）：套细胞淋巴瘤（MCL）是一种侵袭性和不可治愈的B细胞非霍奇金淋巴瘤。更好地理解MCL中发生的分子改变对于合理设计针对这种疾病的新型靶向治疗是至关重要的。最近，我们发现HDAC家族的两个成员HDAC 3和HDAC 6在MCL中异常表达。这种表达在MCL细胞粘附到基质细胞后进一步上调，其作用与淋巴瘤存活率增加、获得耐药表型和免疫逃避相关。值得注意的是，HDAC 6的遗传或药理学抑制诱导细胞周期停滞、凋亡并克服基质介导的耐药性。此外，缺乏HDAC 6的MCL细胞更具免疫原性，并诱导更强的抗肿瘤T细胞应答。关于HDAC 3，我们迄今为止的研究表明，它是一组特定的小的非编码microRNA（miR-15 a/16-1）的重要调节因子，参与细胞增殖，凋亡，致瘤性和MCL的耐药表型。因此，本提案的目标是从机制上了解HDAC 6（Aim 1）和HDAC 3（Aim 2）在MCL中的表达和功能，并确定其药理学抑制是否导致对该疾病的更有效治疗（Aim 3）。这个团队的努力所产生的新知识，汇集了MCL的微环境和耐药性（Tao的实验室）和MCL的免疫生物学（Sotomayor的实验室）的专业知识，将加速MCL基于机制的表观遗传疗法的合理设计。