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

套细胞淋巴瘤(MCL)是一种侵袭性淋巴样肿瘤，目前的治疗方法被认为是无法治愈的。 然而，最近的研究发现了一种亚型白血病非结节性MCL(NnMCL)，其病程迟缓。 对于长期保守的管理层来说，这可能是可以修改的。导致这一现象的机制 不同的行为并不为人所知。此外，证明保守管理的生物学标准或 确定最合适的治疗方法是没有很好定义的。之前的研究已经表明， CCND1和Sox11致癌事件在MCL对细胞周期、B细胞分化程序和 肿瘤/微环境相互作用与DNA损伤反应(DDR)和 生存之路。然而，这些事件并不能完全反映临床的异质性。我们假设 这种多样性可能源于肿瘤起源细胞的不同，以及基因组的不稳定性 似乎与它们表观遗传学特征的日益变化同步进行。我们项目的长期目标是 了解推动生物和临床多样性的基因组、表观基因组和分子机制 以定义可能开启新的治疗策略的靶点，并识别能够提供 为管理决策提供强大的生物支持。我们的具体目标是：1)调查 CCND1在MCL生成中的多样性，超出其对细胞周期的调控，促进染色体 不稳定或失调的其他细胞过程以及可能与sox11的相互作用。我们将使用不同的 细胞模型在不同细胞环境中过度表达和沉默CCND1的sox11表达，以便 研究DNA复制应激，CCND1与复制和转录机制的相互作用， DDR的激活，以及干扰这些机制的策略；2)识别次级基因组和 表观遗传学改变可能导致传统的和不同的临床和生物学行为 非结节MCL。我们将利用我们团队最近产生的全基因组/表观基因组数据，并将 完成后时间配对样本在诊断和进展或复发时的改变情况。 我们也将描述进行性表观基因组变化与基因组复杂性的关系。 MCL并确定它们在患者临床演变中的作用；以及3)寻找新的生物标志物 超出增殖活动的患者的治疗干预和危险分层，并验证其有效性 对两种MCL亚型患者的大量队列的临床影响。这个整合的基因组/表观基因组 MCL的前景以及对其基因组不稳定性机制的更好理解 应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。

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.