Molecular Diagnosis, Prognosis, and Therapeutic Targets in Mantle Cell Lymphoma

套细胞淋巴瘤的分子诊断、预后和治疗靶点

• 批准号: 10237157
• 负责人: Elias Campo
• 金额: $ 21.23万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-19 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10237157
• 关键词: Automobile Driving; B cell differentiation; B-Lymphocytes; Behavior; Biological; Biological Markers; Biology; CCND1 gene; Cell Cycle; Cell Cycle Regulation; Cell Differentiation process; Cell model; Cell physiology; Cells; Chromosomal Instability; Classification; Clinical; Cyclin D1; DNA Damage; DNA Replication Induction; DNA Sequence Alteration; DNA biosynthesis; DNA copy number; Data; Development; Diagnosis; Disease; Epigenetic Process; Evaluation; Event; Evolution; Generations; Genetic; Genetic Transcription; Genome; Genomic Instability; Genomics; Goals; Guidelines; Indolent; Lymphoma; Mantle Cell Lymphoma; Memory; Methylation; Molecular; Molecular Diagnosis; Mutation; Oncogenic; Pathway interactions; Patients; Phenotype; Play; Prognosis; Relapse; Role; Running; SOX11 gene; Sampling; Solid; Somatic Mutation; Specimen; TP53 gene; Testing; Therapeutic; Therapeutic Intervention; Transcriptional Regulation; Travel; Update; Work; base; clinical heterogeneity; clinical practice; cohort; driver mutation; epigenomics; improved; leukemia; lymphoid neoplasm; neoplastic cell; novel marker; novel therapeutic intervention; overexpression; patient stratification; predicting response; pressure; prognostic model; programs; replication stress; response; risk stratification; standard care; stem; targeted treatment; therapeutic target; tumor; tumor behavior; tumor microenvironment; tumor progression; whole genome

Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasm considered incurable with current therapies. However, recent studies have recognized a subtype of leukemic non-nodal MCL (nnMCL) with indolent course that may be amendable to conservative management for long periods. The mechanisms leading to this disparate behavior are not well known. Furthermore, biological criteria to justify conservative management or determine the most appropriate treatment are not well defined. Previous studies have shown the relevance of CCND1 and SOX11 oncogenic events in MCL deregulating cell cycle, B-cell differentiation program and tumor/microenvironment interactions combined with alterations in the DNA damage response (DDR) and survival pathways. However, these events do not capture the full clinical heterogeneity. We hypothesize that this diversity may stem from the different cell-of-origin of the tumors combined with genomic instability that seems to run in parallel with increasing changes in their epigenetic profile. The long term goal of our project is to understand the genomic, epigenomic and molecular mechanisms driving the biological and clinical diversity of MCL, to define targets that may open new therapeutic strategies and to identify biomarkers that can provide strong biological support for management decisions. Our specific aims are: 1) To investigate the role of CCND1 in the generation of MCL diversity, beyond its cell cycle regulation, promoting chromosomal instability or dysregulating other cellular processes and possible interactions with SOX11. We will use different cell models overexpressing and silencing CCND1 in different cell contexts of SOX11 expression in order to study DNA replication stress, interactions of CCND1 with the replication and transcription machineries, activation of DDR, and strategies to interfere with these mechanisms; 2) To identify secondary genomic and epigenetic alterations that may drive the different clinical and biological behavior of conventional and non-nodal MCL. We will exploit the recent whole genome/epigenomic data generated by our group and will complete the landscape of alterations in metachronic paired samples at diagnosis and progression or relapse. We will also characterize the progressive epigenomic changes in relationship to the genomic complexity of MCL and define their role in the clinical evolution of the patients; and 3) To identify novel biomarkers for therapeutic intervention and risk stratification of the patients beyond the proliferation activity and validate their clinical impact in large cohorts of patients with both MCL subtypes. This integrated genomic/epigenomic perspective of MCL together with a better understanding of the mechanisms leading to its genomic instability should provide solid biological bases for new management strategies and targets for therapeutic intervention.

地幔细胞淋巴瘤（MCL）是一种侵袭性淋巴肿瘤肿瘤，被认为是当前疗法无法治愈的。 但是，最近的研究已经认识到具有顽固性的白血病非鼻MCL（NNMCL）亚型 长期以来，这可能是对保守管理的修正案。导致此的机制 不同的行为不是众所周知的。此外，为保守管理或 确定最合适的治疗方法没有很好地定义。先前的研究表明了 MCL过度调节细胞周期，B细胞分化程序和 肿瘤/微环境相互作用结合了DNA损伤反应（DDR）的改变和 生存途径。但是，这些事件并不能捕获完整的临床异质性。我们假设这一点 这种多样性可能源于肿瘤的不同原始细胞，以及基因组不稳定性， 似乎与增加其表观遗传谱的变化并行运行。我们项目的长期目标是 了解驱动生物学和临床多样性的基因组，表观基因组和分子机制 MCL的定义可能开放新的治疗策略的目标并确定可以提供的生物标志物 对管理决策的强烈生物学支持。我们的具体目的是：1）调查 CCND1在MCL多样性的产生中，超出其细胞周期调节，促进染色体 不稳定性或与Sox11的其他细胞过程和可能的相互作用失调。我们将使用不同的 在SOX11表达的不同细胞环境中过表达和沉默CCND1的细胞模型，以便 研究DNA复制应力，CCND1与复制和转录机械的相互作用， DDR的激活以及干扰这些机制的策略； 2）确定次级基因组和 表观遗传学改变可能会推动常规和 非节日MCL。我们将利用我们小组生成的最新整个基因组/表观基因组数据，并将 在诊断和进展或复发时完成元配对样品改变的景观。 我们还将表征与基因组复杂性的渐进表观基因组变化 MCL并定义其在患者临床演变中的作用； 3）确定新颖的生物标志物 在增殖活动之外的患者的治疗干预和风险分层并验证其 MCL亚型的大量患者队列的临床影响。这种综合的基因组/表观基因组 MCL的观点以及更好地理解导致其基因组不稳定性的机制 应为新的管理策略和治疗干预措施提供可靠的生物基础。