Targeting Epigenetic Circuits in B-Cell Lymphomas

摘要 主要研究者是一位医生科学家，他对癌症有重大发现。 表观遗传学领域他发表了220多篇科学论文，其中130篇是在过去五年中发表的，其中许多是在 高知名度的期刊，其中30个被1000名教师引用。他一直受到NCI的资助 自1997年完成临床培训以来，他的提议将阐明B细胞淋巴瘤是如何通过 破坏调节和控制体液免疫的表观遗传机制的复杂网络， 反应在普遍接受的恶性转化模型中，体细胞突变导致正常细胞 表现出异常的表型特征，将其定义为恶性肿瘤细胞。然而，PI建议 恶性转化在生发中心（GC）B细胞中以一种根本不同的方式发生， 引起滤泡性淋巴瘤（FL）和弥漫性大B细胞淋巴瘤（DLBCL）。他特别指出， GC B细胞在其活化后，令人惊讶地表现出许多典型的癌症表型（例如，巨大的 增殖、耐受基因组不稳定性等），这使它们能够经历快速的克隆进化， 免疫球蛋白亲和力成熟。引人注目的是，GC反应是一个短暂的过程，之后B细胞 消灭这种“假恶性”表型并进行终末分化，这突出了PI 关键点是癌症表型不是固有的不可逆的。他提出了一个新的假设， 和DLBCL的产生是由于GC B细胞表型由于动力学的破坏而未能解决， 组蛋白读者和作者之间的平衡。更具体地说，他提出免疫突触 滤泡辅助性T细胞和GC B细胞之间通常向表观基因组发出信号以恢复B细胞 在B细胞经历GC反应时表观遗传学沉默的分化程序。他假设 免疫突触无法消除GC表观遗传标记，并在存在免疫缺陷的情况下恢复B细胞表观遗传标记。 组蛋白乙酰转移酶CREBBP和EP 300以及组蛋白甲基转移酶的体细胞突变 KMT2D和EZH2，在发病早期发生在约80%的FL和DLBCL患者中，表明 淋巴瘤本质上代表不受控制的GC反应。最后，他预测，具有这些特性的FL和DLBCL 可以使用表观遗传靶向药物来选择性地治疗这些突变， 在表观基因组上。后一种观点得到了支持，例如，他发现CREBBP突变型淋巴瘤 在生物学上特别依赖于HDAC3，HDAC3抑制剂逆转了表观遗传， CREBBP突变的转录和生物学效应。为了这项研究，他收集了独特而新颖的 技术，如GC类器官，允许精确，时间观察免疫突触信号， 必要的基因工程小鼠模型，以及初级免疫缺陷病毒中广泛的表观基因组图谱库。 人和鼠淋巴瘤。PI有将其发现转化为临床和本提案的跟踪记录 将为淋巴瘤患者带来新的合理设计的临床试验。

ABSTRACT The principal investigator is a physician scientist who has contributed significant discoveries to the cancer epigenetics field. He has published > 220 scientific papers, 130 of them in the past five years - many of them in high profile journals, and 30 of which were cited by the Faculty of 1000. He has been continuously NCI funded since completing his clinical training in 1997. His proposal will elucidate how B-cell lymphomas arise through disruption of an intricate network of epigenetic mechanisms that regulate and control the humoral immune response. In the generally accepted model for malignant transformation, somatic mutations cause normal cells to manifest aberrant phenotypic hallmarks that define them as malignant tumor cells. However, the PI proposes that malignant transformation occurs in a fundamentally different way in the germinal center (GC) B-cells that give rise to follicular lymphoma (FL) and diffuse large B-cell lymphomas (DLBCL). Specifically, he notes that upon their activation, GC B-cells surprisingly manifest many canonical cancer phenotypes (e.g. massive proliferation, tolerating genomic instability, etc.), which enables them to undergo rapid clonal evolution and immunoglobulin affinity maturation. Strikingly the GC reaction is a transient process after which B-cells extinguish this “pseudo-malignant” phenotype and undergo terminal differentiation, which highlights the PIs critical point that cancer phenotypes are not inherently irreversible. He proposes the novel hypothesis that FLs and DLBCLs arise from a failure of the GC B-cell phenotype to resolve due to disruption in the dynamic equilibrium between histone readers and writers. More specifically, he proposes that the immune synapse between T-follicular helper and GC B-cells normally signals to the epigenome to re-instate the B-cell differentiation program that is epigenetically silenced while B-cells undergo the GC reaction. He hypothesizes that the immune synapse fails to erase GC epigenetic marks and restore B-cell epigenetic marks in the presence of somatic mutations of the histone acetyltransferases CREBBP and EP300, and histone methyltransferases KMT2D and EZH2, which occur early during pathogenesis in ~80% of FL and DLBCL patients suggesting that lymphomas in essence represent uncontrolled GC reactions. Finally he predicts that FLs and DLBCLs with these mutations can be selectively treated using epigenetic-targeted drugs that counteract the effect of these mutations on the epigenome. This latter notion is supported for example by his finding that CREBBP mutant lymphomas are specifically biologically dependent on HDAC3, and that HDAC3 inhibitors reverse the epigenetic, transcriptional and biological effects of CREBBP mutation. For this research he has assembled unique and novel technologies such as GC organoids that allow precise, temporal observation of immune synapse signaling, the necessary genetically engineered mouse models, and extensive libraries of epigenomic profiles in primary human and murine lymphomas. The PI has a track record of translating his findings to the clinic and this proposal will lead to novel rationally designed clinical trials for lymphoma patients.