骨髓增生异常综合征表观遗传学与靶向治疗:第56届美国血液学会年会报道

骨髓增生异常综合征(MDS)为克隆性疾病,其特征为无效性造血,骨髓中造血细胞发育异常,不能产生足够的分化正常的成熟细胞,以致外周血血细胞减少.MDS发病随年龄的增长而增加,提示遗传性或表观遗传性改变的积累使造血干细胞发生DNA突变,癌基因活化或抑癌基因受抑,增加无限性自我增殖能力,进而导致克隆性造血而发病.约30％的MDS转化为急性髓系白血病(AML),常对细胞毒药物不敏感,而靶向药物有望改善其预后.     

Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers

Epigenetic therapy is emerging as a potential therapy for solid tumors. To investigate its mechanism of action, we performed integrative expression and methylation analysis of 63 cancer cell lines (breast, colorectal, and ovarian) after treatment with the DNA methyltransferase inhibitor 5-azacitidine (AZA). Gene Set Enrichment Analysis demonstrated significant enrichment for immunomodulatory pathways in all three cancers (14.4-31.3%) including interferon signaling, antigen processing and presentation, and cytokines/chemokines. Strong upregulation of cancer testis antigens was also observed. An AZA IMmune gene set (AIMs) derived from the union of these immunomodulatory pathway genes classified primary tumors from all three types into “high” and “low” AIM gene expression subsets in tumor expression data from both TCGA and GEO. Samples from selected patient biopsies showed upregulation of AIM genes after treatment with epigenetic therapy. These results point to a broad immune stimulatory role for DNA demethylating drugs in multiple cancers.     

弥漫大B细胞淋巴瘤的DNA甲基化改变及治疗进展

弥漫大B细胞淋巴瘤(DLBCL)异质性较高,具有不同的临床和病理特征,是成人淋巴瘤的一种常见类型。尽管一部分DLBCL已经可以治愈,但难治和复发患者的治疗仍然具有挑战性。近年来,DNA甲基化等表观遗传修饰成为DLBCL的研究热点。调控甲基化修饰的基因突变及抑癌基因甲基化修饰在DLBCL发病及预后中起到关键作用。本文对DLBCL的DNA甲基化研究进展进行综述。     

基于脑源性神经营养因子信号通路探讨针刺干预抑郁症的作用机制

通过检索相关数据库,对近年来针刺通过调控脑源性神经营养因子（BDNF）介导的信号通路及作用机制来干预抑郁的基础研究进行总结,发现针刺主要通过调节BDNF/酪氨酸激酶受体B(TrKB)、组织纤溶酶激活因子(tPA)/BDNF信号通路,调控突触可塑性、BDNF表观遗传等发挥抗抑郁作用。但当前大部分研究缺乏对BDNF通路进行反向验证,并且对通路或作用机制的研究仅限于经典的上下游靶点,同时局部的穴位与BDNF通路和疾病靶器官之间的特异性机制有待进一步阐明。     

组蛋白密码与胶质母细胞瘤关系的研究进展

组蛋白密码由组蛋白中被修饰氨基酸的种类、位置和修饰类型构成。目前研究发现组蛋白密码与胶质母细胞瘤（glioblastoma ,GBM）密切相关。GBM细胞中各种效应蛋白与组蛋白修饰后相应靶位点的结合效应控制着染色质的状态,进一步影响GBM细胞DNA 复制及基因表达调控等表观遗传现象。GBM组蛋白密码信息存在于包括组蛋白乙酰化、甲基化、磷酸化、泛素化等翻译修饰过程中。组蛋白密码与GBM关系的研究为GBM的发生发展、临床诊断和治疗研究提供了更多分子靶点。     

DNA甲基化与男性不育关系的研究进展

在严重的精子缺乏患者中普遍存在异常的表观遗传变化,已经发现亚甲基四氢叶酸还原酶(MTHFR)、PAX8、NTF3、SFN、HRAS、JHM2DA等基因DNA甲基化改变与不育患者中异常的精液参数有关,这些基因通常是高甲基化的.甲基化和去甲基化的正确调控对个体正常发育至关重要,微小的DNA甲基化异常与许多疾病有关,包括男性不育.阐述男性生殖细胞中正常的DNA甲基化,并对已经发现的异常DNA甲基化和男性不育的关系进行综述,从中探究男性不育的某些遗传学病因.     

A report on the Fetal Alcohol Spectrum Disorders Study Group meeting of 2012, theme title, “Biomarkers for FASD”

The 2012 meeting of the Fetal Alcohol Spectrum Disorders Study Group (FASDSG) focused on the development and ethics of biomarkers for fetal alcohol exposure. This one-day international conference brought students and trainees together with clinicians and researchers to discuss the latest research on FASD. One keynote speaker discussed the value of profiling epigenetic modifications in readily available fetal tissues to diagnose fetal exposure to environmental agents, while the second speaker discussed the ethics of biomarker development within the context of core principles of justice, autonomy, beneficence and non-maleficence. Three sessions of short data talks informed the audience of research advances with particular emphasis on the diagnosis of FASD. Other activities included updates on FASD-related activities by representatives of government agencies, a report on the implementation FASD-related diagnostic criteria in the fifth edition of the Diagnostic and Statistical Manual (DSM-5) of the American Psychiatric Association and a networking lunch, and the presentation of the “Merit Award” to Dr. Nathan Muraski for his work on behavioral outcomes of fetal alcohol exposure. The capstone of the meeting was the presentation of the “Henri Rosett” award to Dr. Denis Viljoen, in recognition of his role in raising awareness about the incidence of FASD in South Africa and in promoting FASD prevention and treatment programs as chairperson and chief executive officer of the Foundation for Alcohol Related Research (FARR).