Project 4. Targeting genomic instability and evolution in myeloma

项目总结(项目4) 基因组不稳定，导致与癌症进展相关的基因变化，使其更具侵袭性 表型并最终发展为耐药治疗，是多发性疾病的一个显著特征 骨髓瘤(MM)。因此，理解基因组不稳定性及其潜在机制是极其重要的 重要的是制定治疗策略，抑制克隆进化及其对基因组的影响 和临床结果。在之前的资助阶段，我们在最初的时候定义了MM的突变谱 诊断和发现样本之间的异质性，具有很大程度上不同的染色体重排集 而基因突变存在于个别患者身上。重要的是，对患者多发性骨髓瘤细胞的连续采样显示 克隆进化的多种模式，包括线性进化、差异克隆反应或分支 进化论。我们还确定了至少两个生物学上不同的突变特征，导致了大多数 观察到的突变的，暗示着平行的、发散的、甚至收敛的进化模式。有趣的是， 突变的数量是与总生存率和无复发生存率相关的唯一因素，因此 强调了解MM基因组不稳定机制的重要性。克隆 进化可能是由来自治疗、微环境和固有基因组和 表观基因组学机制，导致克隆选择和新克隆的形成。通过对序列进行深度测序 单基因IgH，我们证明了极低频率克隆的选择发生在治疗后，并且 由于正在进行的突变变化，可能会出现新的克隆。与我们之前的数据一致 发现失调的同源重组(HR)是基因组的重要机制 进化，我们观察到HR活动增加的患者与以下患者相比无事件生存率较差 剩下的。我们假设，治疗同时影响克隆选择和克隆进化，从而推动最终的 最终在复发时出现的肿瘤基因型和表型，表明靶向潜在 克隆进化机制是取得疗效所必需的。为此，我们将延长我们的 正在进行的调查研究治疗对基因组不稳定性和相关克隆的影响 多发性骨髓瘤的选择、克隆进化和潜在机制(Sp目标1)；确定基因组的介体 MM中的不稳定性(Sp Aim 2)；并评估基因组不稳定性抑制物影响MM进化的能力 多发性骨髓瘤(Sp Aim 3)的基因组变化建议的研究将进一步提高我们对基因组的理解。 多发性骨髓瘤的不稳定性和进展，寻找新的药物，并可能促进治疗的发展 将抑制/减少进化和相关的悲惨结果的战略。

Project Summary (Project 4) Genomic instability, which leads to genetic changes associated with progression of cancer to more aggressive phenotypes and ultimately the development of resistance to therapy, is a prominent feature of multiple myeloma (MM). Understanding genomic instability and its underlying mechanisms is, therefore, extremely important to develop therapeutic strategies which would suppress clonal evolution and its impact on genomic and clinical outcome. In previous funding period, we defined the mutational spectrum in MM at the time of initial diagnosis and found heterogeneity across samples, with largely distinct sets of chromosomal rearrangements and gene mutations present in individual patients. Importantly, serial sampling of patient MM cells revealed diverse patterns of clonal evolution, including linear evolution, differential clonal response, or branching evolution. We also identified at least two biologically distinct mutational signatures responsible for the majority of observed mutations, suggesting a pattern of parallel, divergent, or even convergent evolution. Interestingly, the number of mutations was the only factor correlating with overall as well as relapse free survival, thus highlighting the importance of understanding the mechanisms of genomic instability in MM. The clonal evolution which is probably driven by pressures from therapy, microenvironment, and inherent genomic and epigenomic mechanisms, leads to both clonal selection and formation of new clones. By deep sequencing of single gene IgH, we demonstrated that selection of very low frequency clone occurs following therapy, and that new clones may come up due to ongoing mutational changes. Consistent with our previous data which identified dysregulated homologous recombination (HR) as an important mechanism underlying genomic evolution, we have observed that patients with increased HR activity had poor event-free survival compared to the rest. We hypothesize that therapy affects both clonal selection and clonal evolution, driving the ultimate tumor genotype and phenotype that eventually emerges at relapse, suggesting that targeting underlying mechanisms of clonal evolution is necessary to achieve curative outcomes. To this end we will extend our ongoing investigations to investigate the impact of therapy on genomic instability and associated clonal selection, clonal evolution, and underlying mechanisms in MM (Sp Aim 1); identify mediators of genomic instability in MM (Sp Aim 2); and assess the ability of inhibitors of genomic instability to impact evolution of genomic changes in MM (Sp Aim 3). The proposed studies will further improve our understanding of genomic instability and progression of MM, identify novel drugs, and may facilitate the development of therapeutic strategies which would inhibit/reduce evolution and associated dismal outcome.