Role of CREBBP missense mutations in lymphomagenesis

研究综述 在美国，非霍奇金淋巴瘤是第五大致癌原因。其中，弥漫较大 B细胞淋巴瘤(DLBCL)和滤泡性淋巴瘤(FL)是最常见的两种类型 占诊断的60%以上。尽管在治疗这些疾病方面取得了显著的进步， 高达40%的DLBCL患者的死亡率仍然很高，FL虽然被认为是一种惰性疾病， 在晚期是无法治愈的，通常会转化为高度侵袭性的恶性肿瘤。旧病复发和 转化与共同突变的祖细胞相关联，这些祖细胞维持着一组“创始人”突变 存在于诊断显性肿瘤克隆中。因此，提高了对普通动物生物学的理解 前兆和识别可能易受靶向治疗干预的机制是 因此，提高我们治愈这些疾病的能力是当务之急。 CREBBP乙酰转移酶失活的体细胞突变，包括截断和HAT结构域 错义突变是FL(70%的病例)和DLBCL中第二常见的基因改变 (40%的病例属于最近发现的EZB/C3基因亚集)，揭示了 GC来源淋巴瘤发病机制中的表观遗传异常(Pasquucci等人，《自然》，2011；Morin等人 等，《自然》杂志，2011)。CREBBP突变代表了肿瘤系统进化的早期事件，这是 在获得额外致癌病变之前由普通突变前体获得的(帕斯夸鲁奇 等人，《细胞报告2014》；Okosun等人，《自然遗传学》2014年)。事实上，减少CREBBP的剂量可以起到协同作用 用bcl2去调控促进类人FL/DLBCL的发展。虽然截断突变具有 虽然已经进行了广泛的研究，但错义突变的作用在很大程度上仍未被探索。这是一个很大的差距 当考虑到错义突变占FL中CREBBP改变的绝大多数时， 与截断突变不同，这些等位基因是表达的，这表明它们可能会干扰 与其他乙酰转移酶的补偿机制或转录复合体的招募。在……里面 与这一假说一致，来自我们和其他人的初步数据表明，热点CREBBP是错误的 与CREBBP缺陷细胞中观察到的变化相比，HAT突变引起明显的变化。 在这些结果的基础上，该项目的总体目标是阐明CREBBP错义的影响 (VS截断)突变对体内前体GC-B细胞恶性转化的影响 目的：i)研究最常见的R1446H突变宿主点在GC反应中的体内作用 淋巴增生症；ii)识别错义调控的共享转录程序与独特转录程序 截断GC B细胞前体突变；iii)研究CREBBP突变在重编程中的作用 GC微环境。我们期待从这些研究中获得的结果将提供新的见解 关于启动肿瘤转化的机制及其特定的治疗靶点。

RESEARCH SUMMARY Non-Hodgkin lymphomas are the 5th leading cause of cancer in the United States. Among them, diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) represent the two most common forms, together accounting for over 60% of diagnoses. Despite remarkable advances in the treatment of these diseases, mortality remains high in as many as 40% of DLBCL patients, and FL, although regarded as an indolent disease, is incurable in advanced stages, often transforming into a highly aggressive malignancy. Relapse and transformation are linked to common mutated progenitor cells that maintain a subset of “founder” mutations present in the diagnostic dominant tumor clone. Therefore, improved understanding of the biology of the common precursor and the identification of mechanisms that could be vulnerable to targeted therapeutic intervention are therefore a priority in order to advance our ability to cure these diseases. Somatic mutations that inactivate the CREBBP acetyltransferase, including truncating and HAT domain missense mutations, emerged as the second most common genetic alteration in FL (70% of cases) and DLBCL (40% of cases belonging to the recently identified EZB/C3 genetic subset), revealing a prominent role for epigenetic aberrations in the pathogenesis of GC-derived lymphomas (Pasqualucci et al., Nature 2011; Morin et al., Nature 2011). CREBBP mutations represent early events during the tumor phylogenetic evolution, which are acquired by the common mutated precursor prior to the acquisition of additional oncogenic lesions (Pasqualucci et al, Cell Reports 2014; Okosun et al., Nature Genetics 2014). Indeed, reduced dosage of CREBBP synergizes with BCL2 deregulation to enhance the development of human-like FL/DLBCL. While truncating mutations have been extensively studied, the role of missense mutations remains largely unexplored. This is a significant gap when considering that missense mutations account for the overwhelming majority of CREBBP alterations in FL, and that different from truncating mutations, these alleles are expressed, suggesting that they could interfere with compensatory mechanisms by other acetyltransferases or the recruitment of transcription complexes. In line with this hypothesis, preliminary data from us and others have shown that the hotspot CREBBP missense HAT mutation induces distinct changes compared to those observed in CREBBP-deficient cells. Building on these results, the general goal of this project is to elucidate the impact of CREBBP missense (vs truncating) mutations on the malignant transformation of the precursor GC B cell in vivo, with three Specific Aims: i) investigate the in vivo role of the most common R1446H mutational hostspot in GC responses and lymphomagenesis; ii) identify the shared vs unique transcriptional programs dysregulated by missense vs truncating mutations in the GC B cell precursor; iii) investigate the role of CREBBP mutations in reprogramming the GC microenvironment. We anticipate that the results obtained from these studies will provide new insights on the mechanisms initiating neoplastic transformation and on their specific therapeutic targeting.