Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
Oncogene. 2022 Apr;41(14):2106-2121. doi: 10.1038/s41388-022-02227-8. Epub 2022 Feb 21.
Recurrent cytogenetic abnormalities are the main hallmark of multiple myeloma (MM) and patients having 2 or more high-risk prognostic events are associated with extremely poor outcome. 17p13(del) and 1q21(gain) are critical and independent high-risk cytogenetic markers, however, the biological significance underlying the poor outcome in MM patients having co-occurrence of both these chromosomal aberrations has never been interrogated. Herein, we identified that patients harbouring concomitant 17p13(del) with 1q21(gain) demonstrated the worst prognosis as compared to patients with single- (either 17p13(del) or 1q21(gain)) and with no chromosomal events (WT for both chromosomal loci); and they are highly enriched for genomic instability (GI) signature. We discovered that the GI feature in the patients with concomitant 17p13(del)-1q21(gain) was recapitulating the biological properties of myeloma cells with co-existing p53-deficiency and NEIL1 mRNA-hyper-editing (associated with chromosome 17p and 1q, respectively) that have inherent DNA damage response (DDR) and persistent activation of Chk1 pathway. Importantly, this became a vulnerable point for therapeutic targeting whereby the cells with this co-abnormalities demonstrated hyper-sensitivity to siRNA- and pharmacological-mediated-Chk1 inhibition, as observed at both the in vitro and in vivo levels. Mechanistically, this was attributable to the synthetic lethal relationship between p53-NEIL1-Chk1 abnormalities. The Chk1 inhibitor (AZD7762) tested showed good synergism with standard-of-care myeloma drugs, velcade and melphalan, thus further reinforcing the translational potential of this therapeutic approach. In summary, combination of NEIL1-p53 abnormalities with an ensuing Chk1 activation could serve as an Achilles heel and predispose MM cells with co-existing 1q21(gain) and 17p13(del) to therapeutic vulnerability for Chk1 inhibition.
复发性细胞遗传学异常是多发性骨髓瘤（MM）的主要标志，有 2 个或更多高危预后事件的患者预后极差。17p13(del)和 1q21(gain)是关键且独立的高危细胞遗传学标志物，然而，同时存在这两种染色体异常的 MM 患者预后不良的生物学意义从未被研究过。在此，我们发现与单一异常（17p13(del)或 1q21(gain)）和无染色体事件（两个染色体位点均为 WT）相比，同时存在 17p13(del)和 1q21(gain)的患者预后最差；并且他们具有高度的基因组不稳定性（GI）特征。我们发现，同时存在 17p13(del)-1q21(gain)的患者的 GI 特征再现了同时存在 p53 缺陷和 NEIL1 mRNA 超编辑（分别与染色体 17p 和 1q 相关）的骨髓瘤细胞的生物学特性，这些细胞具有内在的 DNA 损伤反应（DDR）和持续激活 Chk1 通路。重要的是，这成为了治疗靶向的一个弱点，因为具有这种共异常的细胞对 siRNA 和药理学介导的 Chk1 抑制表现出超敏感性，这在体外和体内水平都得到了观察。从机制上讲，这归因于 p53-NEIL1-Chk1 异常之间的合成致死关系。测试的 Chk1 抑制剂（AZD7762）与标准骨髓瘤药物硼替佐米和马法兰表现出良好的协同作用，从而进一步加强了这种治疗方法的转化潜力。总之，NEIL1-p53 异常的联合以及随之而来的 Chk1 激活可能成为阿喀琉斯之踵，并使同时存在 1q21(gain)和 17p13(del)的 MM 细胞对 Chk1 抑制产生治疗易感性。
