Understanding the biological and clinical impact of copy number aberrations (CNAs) on the development of precision therapies in cancer remains an unmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNA conferring an adverse prognosis in several types of cancer, including in the blood cancer multiple myeloma (MM). Although several genes across chromosome 1 (chr1q) portend high-risk MM disease, the underpinning molecular etiology remains elusive. Here, with reference to the 3-dimensional (3D) chromatin structure, we integrate multi-omics data sets from patients with MM with genetic variables to obtain an associated clinical risk map across chr1q and to identify 103 adverse prognosis genes in chr1q-amp MM. Prominent among these genes, the transcription factor PBX1 is ectopically expressed by genetic amplification and epigenetic activation of its own preserved 3D regulatory domain. By binding to reprogrammed superenhancers, PBX1 directly regulates critical oncogenic pathways and a FOXM1-dependent transcriptional program. Together, PBX1 and FOXM1 activate a proliferative gene signature that predicts adverse prognosis across multiple types of cancer. Notably, pharmacological disruption of the PBX1-FOXM1 axis with existing agents (thiostrepton) and a novel PBX1 small molecule inhibitor (T417) is selectively toxic against chr1q-amp myeloma and solid tumor cells. Overall, our systems medicine approach successfully identifies CNA-driven oncogenic circuitries, links them to clinical phenotypes, and proposes novel CNA-targeted therapy strategies in MM and other types of cancer.

中文翻译：

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chr1q-amp 的系统医学解剖揭示了一种用于多发性骨髓瘤靶向治疗的新型 PBX1-FOXM1 轴。

了解拷贝数畸变 (CNA) 对癌症精准疗法开发的生物学和临床影响仍然是一个尚未解决的挑战。染色体 1q (chr1q-amp) 的基因扩增是一种主要的 CNA，可导致多种癌症的不良预后，包括血癌多发性骨髓瘤 (MM)。尽管 1 号染色体 (chr1q) 上的几个基因预示着高危 MM 疾病，但其基础分子病因仍然难以捉摸。在这里，参考 3 维 (3D) 染色质结构，我们将来自 MM 患者的多组学数据集与遗传变量相结合，以获得跨 chr1q 的相关临床风险图，并识别 chr1q-amp MM 中的 103 个不良预后基因. 在这些基因中突出，转录因子 PBX1 通过其自身保留的 3D 调节域的基因扩增和表观遗传激活而异位表达。通过与重编​​程的超增强子结合，PBX1 直接调节关键的致癌途径和 FOXM1 依赖性转录程序。PBX1 和 FOXM1 一起激活增殖基因特征，预测多种癌症的不良预后。值得注意的是，现有药物（硫链丝菌肽）和新型 PBX1 小分子抑制剂（T417）对 PBX1-FOXM1 轴的药理学破坏对 chr1q-amp 骨髓瘤和实体瘤细胞具有选择性毒性。总体而言，我们的系统医学方法成功地识别了 CNA 驱动的致癌电路，将它们与临床表型联系起来，并在 MM 和其他类型的癌症中提出了新的 CNA 靶向治疗策略。