Elucidation of cellular and molecular mechanisms of lymphoma induction and evolution to identify therapeutic targets

阐明淋巴瘤诱导和进化的细胞和分子机制以确定治疗靶点

• 批准号: MR/R009708/1
• 负责人: Brian Huntly
• 金额: $ 96.32万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR009708%2F1
• 关键词: Elucidation; cellular; molecular; mechanisms; lymphoma

Malignant lymphomas are the 5th most common cancers in the world, accounting for ~5% of all tumours. They may be derived from the B-Cell or T-cell lineage and are generally mature in nature. The prognosis of lymphomas greatly varies and is dependent on the stage and histology of the disease. Although up to 60% of young patients (<60y) with aggressive Diffuse Large B-Cell Lymphoma (DLBCL) are cured by combination immune-chemotherapy, older patients have a fairly dismal outlook. In addition, although monoclonal antibodies and small molecule inhibitors have improved survival in patients with low-grade indolent disease such as Follicular lymphoma (FL), these diseases are commonly incurable. In addition, all of the aforementioned therapies are toxic and may lead to significant morbidities and occasional mortalities in lymphoma patients. Worryingly, the incidence of malignant lymphomas continues to rise, and at 3-4% per year4 appears far in excess of what would be expected simply from the ageing of the population. The identification of critical mediators of lymphomagenesis and novel therapies that target them is therefore a priority for this increasingly common malignancy and unmet medical need.Despite their clinical importance, we actually know very little about the molecular and cellular biology of lymphomas. Next generation sequencing (NGS) efforts are beginning to uncover mutations that occur in lymphomas, however the order of these mutations and how they collaborate to generate lymphomas remains mysterious. Likewise gene expression studies have identified critical genes that are drive lymphoma but for other pathways we do not know if these are cause or consequence of malignant transformation. In addition, we know that normal B-cell survival is dependent upon t singling events at the cell surface. Furthermore mutations that alter cell singling often occur in lymphomas suggesting that lymphomas are also dependent upon abnormal singling events. However, exactly how and where this occurs during the development of the lymphoma and the role that it plays in this evolution is unknown. Moreover, the cell biology of lymphoma is poorly characterized. Our knowledge of the cells from which lymphomas derive initially and the role that this cell typemight play in the eventual phenotype of the lymphoma are poorly understood, although initial transforming steps in haematopoietic stem and progenitor cells have been shown for the similar B-cell malignancies chronic lymphocytic leukaemia (CLL), hairy cell leukaemia (HCL) and for some T-cell lymphomas. We will address all of these questions within this application using a combination of mouse models, human cell lines and powerful genome-wide analysis.We will use unique mouse models that we have developed that generate loss of Crebbp at defined times within B-cell development, and will engineer within these models the ability to generate and identify further progression events by engineering a mutation inducing system that jumps around DNA sequences specifically in B cells. This system will allow us to robustly answer the question of the contribution of the initial cell-type to outcome and phenotype of lymphoma. Using the presence of a unique but easily identifiable premalignant phase within the model, we will also characterize alterations gene expression and signaling that occur during lymphoma evolution, through a combination of stat-of-the-art genomic techniques. Finally we will test a priori hypotheses about the requirement for specific DNA repair pathways and residual CREBBP/P300 function in these Crebbp-/- lymphomas, as well as performing a genomewide screen to identify further vulnerabilities in CREBBP mutated lymphoma cells, a subset of which will be further tested in our in vivo model

恶性淋巴瘤是世界上第五大常见癌症，占所有肿瘤的约5%。它们可以来源于B细胞或T细胞谱系，并且通常在性质上是成熟的。淋巴瘤的预后差异很大，取决于疾病的分期和组织学。虽然高达60%的年轻患者（<60岁）患有侵袭性弥漫性大B细胞淋巴瘤（DLBCL）通过联合免疫化疗治愈，但老年患者的前景相当暗淡。此外，尽管单克隆抗体和小分子抑制剂改善了低级别惰性疾病（如滤泡性淋巴瘤（FL））患者的生存率，但这些疾病通常无法治愈。此外，所有上述疗法都是有毒的，可能导致淋巴瘤患者的显著发病率和偶尔死亡。令人担忧的是，恶性淋巴瘤的发病率继续上升，每年3-4% 4，远远超过人口老龄化的预期。因此，识别淋巴瘤发生的关键介质和针对它们的新疗法是这种日益常见的恶性肿瘤和未满足的医疗需求的优先事项。尽管它们具有临床重要性，但我们实际上对淋巴瘤的分子和细胞生物学知之甚少。下一代测序（NGS）的努力开始发现淋巴瘤中发生的突变，然而这些突变的顺序以及它们如何合作产生淋巴瘤仍然是个谜。同样，基因表达研究已经确定了驱动淋巴瘤的关键基因，但对于其他途径，我们不知道这些是恶性转化的原因还是结果。此外，我们知道正常的B细胞存活依赖于细胞表面的单一事件。此外，改变细胞单一化的突变经常发生在淋巴瘤中，表明淋巴瘤也依赖于异常单一化事件。然而，究竟是如何和在哪里发生在淋巴瘤的发展和它在这一演变中发挥的作用是未知的。此外，淋巴瘤的细胞生物学特征很差。我们对淋巴瘤最初起源的细胞以及这种细胞类型可能在淋巴瘤的最终表型中发挥的作用的了解很少，尽管造血干细胞和祖细胞的初始转化步骤已被证明用于类似的B细胞恶性肿瘤慢性淋巴细胞白血病（CLL），毛细胞白血病（HCL）和一些T细胞淋巴瘤。我们将使用小鼠模型、人类细胞系和强大的全基因组分析的组合来解决本申请中的所有这些问题。我们将使用我们开发的独特小鼠模型，该模型在B细胞发育的规定时间内产生Crebbp的缺失，并将在这些模型中通过设计一个围绕DNA序列跳跃的突变诱导系统来产生和识别进一步进展事件的能力特别是在B细胞中。该系统将使我们能够有力地回答初始细胞类型对淋巴瘤的结果和表型的贡献的问题。利用模型中存在的独特但易于识别的癌前阶段，我们还将通过结合最先进的基因组技术来表征淋巴瘤演变过程中发生的基因表达和信号传导的改变。最后，我们将测试关于这些Crebbp-/-淋巴瘤中特定DNA修复途径和残留CREBBP/P300功能的需要的先验假设，以及进行全基因组筛选以鉴定CREBBP突变淋巴瘤细胞中的进一步脆弱性，其中一个子集将在我们的体内模型中进一步测试

项目成果

KAT2A complexes ATAC and SAGA play unique roles in cell maintenance and identity in hematopoiesis and leukemia.

• DOI: 10.1182/bloodadvances.2020002842
• 发表时间: 2022-01-11
• 期刊: Blood advances
• 影响因子: 7.5
• 作者: Arede L;Foerner E;Wind S;Kulkarni R;Domingues AF;Giotopoulos G;Kleinwaechter S;Mollenhauer-Starkl M;Davison H;Chandru A;Asby R;Samarista R;Gupta S;Forte D;Curti A;Scheer E;Huntly BJP;Tora L;Pina C
• 通讯作者: Pina C

Loss of Kat2a enhances transcriptional noise and depletes acute myeloid leukemia stem-like cells.

Kat2a 的缺失会增强转录噪音并消耗急性髓性白血病干细胞样细胞。

• DOI: 10.17863/cam.50784
• 发表时间: 2020
• 作者: Domingues A

Contrasting requirements during disease evolution identify EZH2 as a therapeutic target in AML

疾病演变过程中的对比要求将 EZH2 确定为 AML 的治疗靶点

• DOI: 10.17863/cam.37804
• 发表时间: 2019
• 作者: Basheer F