多发性骨髓瘤 (MM) 是一种遗传异质性疾病，复发的治疗是最大的临床挑战之一。 TP53 改变已被确定为高风险标记，并包含在当前的疾病分期标准中。 KRAS 是最常见的突变基因，影响约 20% 的 MM 患者。通过共培养颜色标记的转基因细胞模型，应用克隆竞争测定 (CCA)，我们最近表明 TP53 中的单等位基因和双等位基因的改变向细胞传递了适应性优势。在这里，我们报告了 KRAS 中的两个突变（G12A 和 A146T）的类似动态，为 MM 复发时 KRAS 和 TP53 改变的高频率提供了生物学原理。另一方面，抗性突变并没有赋予MM细胞一般的适应性优势，而是与野生型相比呈现出劣势。 CUL4B KO 和 IKZF1 A152T 传递对免疫调节剂的抗性，PSMB5 A20T 对蛋白酶体抑制的抗性。然而，携带此类病变的 MM 细胞只有在相应药物存在的情况下才能在竞争中胜过培养物。为了更好地防止选择可能诱发复发的克隆，这些结果支持不治疗中断或更换作为维持治疗的药物类别。总之，TP53 和 KRAS 突变的健康益处与治疗无关，这与患者来源的耐药性改变不同，后者可能只会在治疗下产生优势。 CCA 是研究克隆进化和特定感兴趣的遗传病变所带来的竞争（不利）优势及其对治疗等外部因素的依赖性的合适模型。© 2024 作者。约翰·威利 (John Wiley) 出版的 HemaSphere

Multiple myeloma (MM) is a genetically heterogeneous disease and the management of relapses is one of the biggest clinical challenges. TP53 alterations are established high-risk markers and are included in the current disease staging criteria. KRAS is the most frequently mutated gene affecting around 20% of MM patients. Applying Clonal Competition Assays (CCA) by co-culturing color-labeled genetically modified cell models, we recently showed that mono- and biallelic alterations in TP53 transmit a fitness advantage to the cells. Here, we report a similar dynamic for two mutations in KRAS (G12A and A146T), providing a biological rationale for the high frequency of KRAS and TP53 alterations at MM relapse. Resistance mutations, on the other hand, did not endow MM cells with a general fitness advantage but rather presented a disadvantage compared to the wild-type. CUL4B KO and IKZF1 A152T transmit resistance against immunomodulatory agents, PSMB5 A20T to proteasome inhibition. However, MM cells harboring such lesions only outcompete the culture in the presence of the respective drug. To better prevent the selection of clones with the potential of inducing relapse, these results argue in favor of treatment-free breaks or a switch of the drug class given as maintenance therapy. In summary, the fitness benefit of TP53 and KRAS mutations was not treatment-related, unlike patient-derived drug resistance alterations that may only induce an advantage under treatment. CCAs are suitable models for the study of clonal evolution and competitive (dis)advantages conveyed by a specific genetic lesion of interest, and their dependence on external factors such as the treatment.© 2024 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.