基因组不稳定性
生物
染色体不稳定性
癌症研究
合成致死
多发性骨髓瘤
DNA损伤
相伴的
DNA修复
染色体
内科学
遗传学
DNA
免疫学
基因
医学
作者
Phaik Ju Teoh,Ömer An,Tae-Hoon Chung,Thamil Vaiyapuri,Anandhkumar Raju,Michal Marek Hoppe,Sabrina Hui Min Toh,Wilson Wang,Ming Chun Chan,Melissa J. Fullwood,Anand D. Jeyasekharan,Vinay Tergaonkar,Leilei Chen,Henry Yang,Wee Joo Chng
出处
期刊:Oncogene
[Springer Nature]
日期:2022-02-21
卷期号:41 (14): 2106-2121
被引量:3
标识
DOI:10.1038/s41388-022-02227-8
摘要
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.
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