Diamond Benjamin, Chahar Dhanvantri, Jain Michael D, Poos Alexandra M, Durante Michael, Ziccheddu Bachisio, Kaddoura Marcella, Papadimitriou Marios, Maclachlan Kylee, Jelinek Tomas, Davies Faith, Figura Nicholas B, Morgan Gareth, Mai Elias, Weisel Katja C, Fenk Roland, Raab Marc S, Usmani Saad, Landgren Ola, Locke Frederick L, Goldschmidt Hartmut, Schatz Jonathan H, Weinhold Niels, Maura Francesco
Myeloma Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
Lymphoma Service, Sylvester Comprehensive Cancer Center, Miami, FL, USA.
bioRxiv. 2024 Nov 18:2024.11.15.623836. doi: 10.1101/2024.11.15.623836.
Ionizing radiotherapy (RT) is a widely used palliative and curative treatment strategy for malignancies. In solid tumors, RT-induced double strand breaks lead to the accumulation of indels, and their repair by non-homologous end-joining has been linked to the ID8 mutational signature in resistant cells. However, the extent of RT-induced DNA damage in hematologic malignancies and its impact on their evolution and interplay with commonly used chemotherapies has not yet been explored. Here, we interrogated 580 whole genome sequencing (WGS) from patients with large B-cell lymphoma, multiple myeloma, and myeloid neoplasms and identified ID8 only in relapsed disease. Yet, it was detected after exposure to both RT and mutagenic chemotherapy (i.e., platinum). Using WGS of single-cell colonies derived from treated lymphoma cells, we revealed a dose-response relationship between RT and platinum and ID8. Finally, using ID8 as a genomic barcode we demonstrate that a single RT-resistant cell may seed systemic relapse.
电离放射疗法（RT）是一种广泛应用于恶性肿瘤的姑息性和治愈性治疗策略。在实体瘤中，RT诱导的双链断裂会导致插入缺失的积累，并且通过非同源末端连接对其进行修复与耐药细胞中的ID8突变特征有关。然而，血液系统恶性肿瘤中RT诱导的DNA损伤程度及其对肿瘤进展的影响以及与常用化疗的相互作用尚未得到探索。在此，我们对580例大B细胞淋巴瘤、多发性骨髓瘤和髓系肿瘤患者的全基因组测序（WGS）进行了分析，仅在复发疾病中鉴定出ID8。然而，在接受RT和诱变化疗（即铂类）后均检测到了ID8。通过对经治疗的淋巴瘤细胞衍生的单细胞集落进行WGS，我们揭示了RT与铂类和ID8之间的剂量反应关系。最后，使用ID8作为基因组条形码，我们证明单个RT耐药细胞可能引发全身复发。
