HDAC11调控p53通路抑制MPN细胞凋亡的机制研究

骨髓增殖性肿瘤（MPN）是起源于造血干细胞的恶性克隆性疾病。MPN现有治疗方法有限，现有治疗不能降低突变基因负荷或逆转骨髓纤维化，对新型治疗药物的需求迫切。申请人近年来主要从事MPN治疗药物研究，已发表的成果（Yue et al, Blood, 2020）证实：HDAC11在MPN发病中发挥重要作用。HDAC11抑制剂能够抑制MPN细胞增殖、诱导凋亡，HDAC11基因缺失可延缓MPN小鼠疾病进展、延长生存期，但HDAC11的具体作用机制尚不清楚。初步研究显示，HDAC11可影响多种与细胞周期及凋亡相关的基因表达，HDAC11对多种通路的调控可能通过p53实现。因此，本项目将利用MPN患者骨髓、细胞系及免疫缺陷小鼠，研究HDAC11通过MDM2调控p53通路抑制细胞凋亡的机制，并探索HDAC11抑制剂在降低JAK2V617F突变负荷中的作用。本研究将为HDAC11抑制剂治疗MPN提供依据。

Myeloproliferative neoplasms (MPN) are hematopoietic stem cell malignancies with somatic driver mutations in JAK2, MPL or CALR genes. Current treatment strategies mainly ameliorate symptoms but fail to reduce mutant allele burden or reverse bone marrow fibrosis, thus novel disease-modifiable drugs are in need. The applicant has found in previous studies (Yue et al, Blood, 2020) that histone deacetylase 11 (HDAC11) participated in the pathogenesis of MPN. HDAC11 selective inhibitors markedly suppressed proliferation and induced apoptosis of MPN cells. Genetic HDAC11 deficiency significantly compromised the disease phenotype of MPN mouse model and prolonged survival. Currently, limited functions are known about HDAC11, while our studies suggested that HDAC11 regulated the expression of a series of apoptosis- and cell cycle-associated genes. Moreover, the modulation of HDAC11 on multiple pathways might be related with p53 pathway. Therefore, this study aimed to demonstrate how HDAC11 reduces p53 expression via MDM2 and suppresses apoptosis of MPN cells, and investigate the effect of HDAC11 inhibition on reducing JAK2V617F allele burden. The experiments will be performed using MPN cell lines, primary bone marrow cells from MPN patients, as well as immune-deficient mice. The results of the study are supposed to provide further support for HDAC11 inhibitors as potential therapy for MPN.