Mutational cooperativity in TET2-associated hematological malignancies.

项目摘要/摘要 外周T细胞淋巴瘤(PTCL)是一组来源于成熟T细胞的侵袭性血癌 细胞，仍然是一个高度未得到满足的临床需求，预后差，缺乏标准的护理和 有效的治疗。最近PTCL患者的外显子组测序揭示了一种频繁的共同发生的 表观遗传修饰物(TET2)和小GTP酶(RHOA)的突变。这一发现预示着 剖析T细胞淋巴瘤新致病机制的分子时代。少年派有 研究表明，仅小鼠血细胞中TET2的基因缺失就会导致造血细胞的偏向分化 干细胞和祖细胞(HSPC)朝向髓系，但不足以引起淋巴肿瘤。 第二次打击，如在PTCL中经常发现的RHOA-G17V，需要促进全面的恶性肿瘤。 为了满足对PTCL动物模型的迫切需要，PI培育了一种转基因啮齿动物 在TET2和RHOA中都有遗传损害的模仿PTCL相关基因的模型。这是转基因的 小鼠模型非常适合研究PTCL，因为它发生在外周淋巴中的T细胞淋巴瘤 在PTCL患者中所见的器官和概括的标志表型。这些令人兴奋的发现奠定了强有力的基础 科学基础假设：CD4T细胞中共存的TET2和RHOA突变有助于 PTCLS发病机制的研究进展 (I) 破坏DNA羟甲基化和基因转录使T细胞易感 癌前状态的细胞(目标1；机制上强调R环堆积和异常RNA 聚合酶II暂停参与肌醇磷脂代谢的关键基因)，以及 (Ii) 扰乱RHO GTPase信号异常激活致癌途径以促进恶性转化(目标2；与 优先关注PI3K/AKT信令)。该团队在试点研究中提出了令人信服的证据 有力地支持了中心假设和我们方法的可行性。技术创新 包括一个独特的小鼠模型，它反映了PTCL相关的基因和疾病特征，以及 一套新的分子工具，用于精确的表观基因组作图/编辑和小分子的光遗传控制 GTP酶信号转导。这些工具使团队克服了表型研究的一个主要障碍-- 癌前和恶性T细胞的表型因果关系。这项研究在概念上也是 创新性，因为它引入了一个以前被低估的维度来研究表观遗传调控 驱动淋巴肿大的机制，以及异常的GTPase信号。拟议的研究将 可能阐明表观遗传和GTPase信号通路中的体细胞突变是如何协同作用的 与淋巴瘤的发生、转化和发展有关。从翻译的角度来看，这些发现 可能为淋巴瘤的治疗提供新的分子靶点和途径。

Project Summary/ Abstract Peripheral T cell lymphoma (PTCL) represents a group of aggressive blood cancers derived from mature T cells, and remains as a high unmet clinical need with poor prognosis and lack of standards of care and effective treatment. Recent exome sequencing in PTCL patients has unveiled a frequent co-occurrence of mutations in an epigenetic modifier (TET2) and a small GTPase (RHOA). This discovery heralds the advent of a molecular era in the dissection of novel pathogenic mechanisms underlying T cell lymphoma. The PI has shown that genetic depletion of murine Tet2 alone in blood cells causes biased differentiation of hematopoietic stem and progenitor cells (HSPCs) toward the myeloid lineage, but is insufficient to cause lymphoid neoplasms. A second hit, such as RHOA-G17V frequently found in PTCL, is required to promote full-blown malignancies. To meet the immediate need for animal models of PTCL, The PI has generated a genetically modified rodent model mimicking the PTCL-associated genotype with genetic lesions in both TET2 and RHOA. This transgenic mouse model is well suited to study PTCL because it developed T cell lymphoma in peripheral lymphoid organs and recapitulated hallmark phenotypes as seen in PTCL patients. These exciting findings laid a strong scientific foundation to hypothesize that: co-existing TET2 and RHOA mutations in CD4 T cells contribute to the pathogenesis of PTCLs by (i) impairing DNA hydroxymethylation and gene transcription to predispose T cells for pre-malignant status (Aim 1; with a mechanistic emphasis on R-loop accumulation and aberrant RNA polymerase II pausing in key genes involved in phosphoinositide metabolism), and (ii) disrupting the Rho GTPase signaling to abnormally activate pro-oncogenic pathways for malignant transformation (Aim 2; with a prioritized focus on the PI3K/Akt signaling). The team has presented compelling evidence in pilot studies that lends strong support to the central hypotheses and the feasibility of our approach. Technical innovations include a unique mouse model that reflects the PTCL-associated genotype and disease hallmarks, as well as a set of novel molecular tools tailored for precise epigenome mapping/editing and optogenetic control of small GTPase signaling. These tools allow the team to overcome a major impediment to studies of epigenotype- phenotype causal relations in pre-malignant and malignant T cells. This research is also conceptually innovative as it introduces a previously underappreciated dimension for studying the epigenetic regulatory mechanisms, as well as aberrant GTPase signaling, that drive lymphomagenesis. The proposed studies will likely illuminate how somatic mutations in epigenetic and GTPase signaling pathways cooperatively contribute to the initiation, transformation and progression of lymphoma. From a translational perspective, the findings may reveal novel molecular targets and pathways for therapies against lymphoma.