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.

套细胞淋巴瘤（MCL）是一种侵袭性淋巴样肿瘤，被认为是目前治疗无法治愈的。 然而，最近的研究已经认识到一个亚型的白血病非淋巴结MCL（nnMCL）与惰性过程 这可能是长期保守管理的结果。导致这种情况的机制 不同行为并不为人所知。此外，生物学标准，以证明保守管理或 确定最合适的治疗方法并没有很好的定义。以前的研究表明， MCL中CCND 1和SOX 11致癌事件对细胞周期、B细胞分化程序和 肿瘤/微环境相互作用结合DNA损伤反应（DDR）的改变， 生存之路。然而，这些事件并未涵盖全部临床异质性。我们假设 这种多样性可能源于肿瘤的不同起源细胞以及基因组不稳定性， 似乎与其表观遗传特征的变化平行。我们项目的长期目标是 了解驱动生物和临床多样性的基因组，表观基因组和分子机制 的MCL，以确定可能开辟新的治疗策略的目标，并确定生物标志物， 为管理决策提供强有力的生物学支持。我们的具体目标是：1）调查的作用 CCND 1在MCL多样性的产生中，超越了其细胞周期调控，促进染色体 不稳定或失调的其他细胞过程和可能的相互作用与SOX 11。我们将使用不同的 在SOX 11表达的不同细胞环境中过表达和沉默CCND 1的细胞模型， 研究DNA复制应激，CCND 1与复制和转录机制的相互作用， DDR激活，以及干预这些机制的策略; 2）鉴定次级基因组和 表观遗传改变，可能会驱动不同的临床和生物学行为的传统和 非结MCL。我们将利用我们小组最近产生的全基因组/表观基因组数据， 在诊断和进展或复发时完成元时配对样本中的改变的景观。 我们还将描述与基因组复杂性相关的渐进性表观基因组变化， MCL，并确定其在患者的临床演变中的作用;和3）鉴定新的生物标志物， 治疗干预和患者的风险分层超出增殖活性，并验证其 在两种MCL亚型患者的大型队列中的临床影响。这种整合的基因组/表观基因组 MCL的观点，以及更好地了解导致其基因组不稳定性的机制 应该为新的管理策略和治疗干预的目标提供坚实的生物学基础。