多发性骨髓瘤（MM）靶向治疗的发展受到可行性遗传异常的低频率的限制。chr1q 的获得或扩增（Amp1q）是患者MM中最常见的染色体级别拷贝数增益，尽管近期治疗手段取得了进展，但它与较高的进展和死亡风险相关。因此，为患有MM和Amp1q的患者开发靶向治疗有望受益于大部分需要更有效管理的患者。在这里，我们采用大规模依赖筛选和药物筛选系统地表征了MM具有Amp1q的治疗易感性，并显示出对MCL1和PI3K抑制剂联合使用的敏感性增加。使用单细胞RNA测序，我们比较了同一患者肿瘤中具有和不具有Amp1q的亚克隆，并显示Amp1q与更高水平的MCL1和PI3K途径相关。此外，通过隔离拷贝数不同的chr1q染色体臂的同源克隆体，我们显示出对有染色体级别增益的MCL1和PI3K抑制剂敏感性增加的情况。最后，我们证明了MCL1和PI3K抑制剂的协同作用，并剖析了它们在具有Amp1q的MM中的作用机制。

The development of targeted therapy for patients with Multiple Myeloma (MM) is hampered by the low frequency of actionable genetic abnormalities. Gain or amplification of chr1q (Amp1q) is the most frequent arm-level copy number gain in patients with MM, and it is associated with higher risk of progression and death despite recent advances in therapeutics. Thus, developing targeted therapy for patients with MM and Amp1q stands to benefit a large portion of patients in need of more effective management. Here, we employed large-scale dependency screens and drug screens to systematically characterize the therapeutic vulnerabilities of MM with Amp1q and showed increased sensitivity to the combination of MCL1 and PI3K inhibitors. Using single-cell RNA sequencing, we compared subclones with and without Amp1q within the same patient tumors and showed that Amp1q is associated with higher levels of MCL1 and the PI3K pathway. Furthermore, by isolating isogenic clones with different copy number for part of the chr1q arm, we showed increased sensitivity to MCL1 and PI3K inhibitors with arm-level gain. Lastly, we demonstrated synergy between MCL1 and PI3K inhibitors and dissected their mechanism of action in MM with Amp1q.