Department of Oncology, Livestrong Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, TX.
College of Natural Sciences, The University of Texas at Austin, Austin, TX.
Blood Adv. 2023 Jul 25;7(14):3551-3560. doi: 10.1182/bloodadvances.2022009387.
Tumor relapse and drug resistance are major factors that limit the curability of multiple myeloma (MM). New regimens have improved overall MM survival rates, but patients with high-risk features continue to have inferior outcomes. Chromosome 17p13 deletion (del17p) that includes the loss of the TP53 gene is a high-risk cytogenetic abnormality and is associated with poor clinical outcomes owing to relatively short remissions and the development of pan-drug resistant disease. Increased relapse rates suggest that del17p enhances clonogenic growth, and we found that the loss of p53 increased both the frequency and drug resistance of tumor-initiating MM cells (TICs). Subsequent RNA sequencing (RNA-seq) studies demonstrated significant activation of the Notch signaling pathway and upregulation of inhibitor of DNA binding (ID1/ID2) genes in p53-knock out (p53-KO) cells. We found that the loss of ID1 or HES-1 expression or treatment with a gamma-secretase inhibitor (GSI) significantly decreased the clonogenic growth of p53-KO but not p53 wild-type cells. GSI treatment in a small set of MM specimens also reduced the clonogenic growth in del17p samples but not in non-del17p samples. This effect was specific as overexpression of the Notch intracellular domain (NICD) rescued the effects of GSI treatment. Our study demonstrates that the Notch signaling and ID1 expression are required for TIC expansion in p53-KO MM cells. These findings also suggest that GSI may be specifically active in patients with p53 mutant MM.
肿瘤复发和耐药性是限制多发性骨髓瘤（MM）治愈率的主要因素。新方案提高了总体 MM 生存率，但具有高危特征的患者仍有较差的预后。包括 TP53 基因缺失的 17 号染色体短臂缺失（del17p）是一种高危细胞遗传学异常，由于缓解时间相对较短和出现泛耐药疾病，其临床结局较差。复发率增加表明 del17p 增强了集落形成生长，我们发现 p53 缺失增加了肿瘤起始 MM 细胞（TIC）的频率和耐药性。随后的 RNA 测序（RNA-seq）研究表明，p53 敲除（p53-KO）细胞中 Notch 信号通路显著激活，DNA 结合抑制剂（ID1/ID2）基因上调。我们发现 ID1 或 HES-1 表达缺失或用 γ-分泌酶抑制剂（GSI）治疗显著降低了 p53-KO 但不降低 p53 野生型细胞的集落形成生长。在一小部分 MM 标本中，GSI 治疗也降低了 del17p 标本的集落形成生长，但不降低非 del17p 标本的集落形成生长。这种作用是特异性的，因为 Notch 细胞内结构域（NICD）的过表达挽救了 GSI 治疗的作用。我们的研究表明，Notch 信号和 ID1 表达是 p53-KO MM 细胞中 TIC 扩增所必需的。这些发现还表明，GSI 可能在 p53 突变 MM 患者中具有特异性活性。
