Project 4. Targeting genomic instability and evolution in myeloma

项目概要（项目4） 基因组不稳定性，导致与癌症进展相关的遗传变化， 表型和最终耐药性的发展，是多重耐药的一个突出特征。 骨髓瘤（MM）。因此，了解基因组不稳定性及其潜在机制是非常重要的。 重要是开发抑制克隆进化及其对基因组的影响的治疗策略， 临床结果。在上一个资助期，我们在最初的研究中定义了MM的突变谱。 诊断和发现异质性的样本，很大程度上不同套染色体重排 和个体患者中存在的基因突变。重要的是，患者MM细胞的连续取样揭示了 不同的克隆进化模式，包括线性进化、差异克隆反应或分支 进化我们还确定了至少两种生物学上不同的突变特征， 观察到的突变，这表明了平行，发散，甚至趋同进化的模式。有趣的是， 突变的数量是唯一与总生存率和无复发生存率相关的因素， 强调了理解MM基因组不稳定性机制的重要性。 进化可能是由来自治疗、微环境和固有基因组的压力驱动的， 表观基因组机制，导致克隆选择和新克隆的形成。通过深度测序 单基因IgH，我们证明了在治疗后发生非常低频率克隆的选择， 由于持续的突变变化，可能会出现新的克隆。与我们之前的数据一致， 确定失调的同源重组（HR）作为基因组学的重要机制， 我们观察到HR活动增加的患者的无事件生存率较低， 剩下的我们假设，治疗影响克隆选择和克隆进化，推动最终的克隆选择。 最终在复发时出现的肿瘤基因型和表型，表明靶向潜在的 克隆进化机制是实现治疗结果所必需的。为此，我们将扩大 正在进行的研究，以调查治疗对基因组不稳定性和相关克隆的影响， MM的选择、克隆进化和潜在机制（Sp Aim 1）;确定基因组 MM的不稳定性（Sp Aim 2）;并评估基因组不稳定性抑制剂影响 MM的基因组变化（Sp Aim 3）。这些研究将进一步提高我们对基因组的理解。 MM的不稳定性和进展，识别新药，并可能促进治疗药物的开发， 抑制/减少进化的策略以及相关的令人沮丧的结果。

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.