RECQ1 helicase is involved in replication stress survival and drug resistance in multiple myeloma.
RECQ1 helicase is involved in replication stress survival and drug resistance in multiple myeloma.
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DOI：
10.1038/leu.2017.54
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发表时间：
2017-10
期刊：
影响因子：
11.4
通讯作者：
Moreaux J
中科院分区：
文献类型：
--
作者：
Viziteu E;Klein B;Basbous J;Lin YL;Hirtz C;Gourzones C;Tiers L;Bruyer A;Vincent L;Grandmougin C;Seckinger A;Goldschmidt H;Constantinou A;Pasero P;Hose D;Moreaux J
多发性骨髓瘤（MM）是一种生存率低的浆细胞癌，其特征在于骨髓中多发性骨髓瘤细胞（MMC）的扩增。使用基于微阵列的全基因组筛选对MM细胞中DNA甲基转移酶（DNMT）抑制反应的基因，我们在最下调的基因中鉴定了RECQ 1。RecQ解旋酶是参与维持染色体稳定性的DNA解旋酶。在这里，我们表明，RECQ 1是显着过表达的MMC相比，正常的浆细胞，增加RECQ 1的表达与不良预后在三个独立的队列的患者。有趣的是，RECQ 1敲低抑制细胞生长并诱导MMC凋亡。此外，RECQ 1缺失促进DNA双链断裂的发展，如通过53 BP 1灶的形成以及共济失调-毛细血管扩张突变（ATM）和组蛋白变体H2A.X（H2 AX）的磷酸化所证明的。相比之下，RECQ 1过表达可以保护MMC免受美法仑和硼替佐米的细胞毒性。RECQ 1与暴露于治疗的MMC中的PARP 1相互作用，RECQ 1缺失使MMC对聚（ADP-核糖）聚合酶（PARP）抑制剂敏感。DNMT抑制剂治疗通过MMC中的miR-203失调导致RECQ 1下调。总之，这些数据表明，DNA损伤剂和/或PARP抑制剂与DNMT抑制剂的联合可能代表了与预后不良相关的RECQ 1高表达患者的治疗方法。
Multiple myeloma (MM) is a plasma cell cancer with poor survival, characterized by the expansion of multiple myeloma cells (MMCs) in the bone marrow. Using a microarray-based genome-wide screen for genes responding to DNA methyltransferases (DNMT) inhibition in MM cells, we identified RECQ1 among the most downregulated genes. RecQ helicases are DNA unwinding enzymes involved in the maintenance of chromosome stability. Here we show that RECQ1 is significantly overexpressed in MMCs compared to normal plasma cells and that increased RECQ1 expression is associated with poor prognosis in three independent cohorts of patients. Interestingly, RECQ1 knockdown inhibits cells growth and induces apoptosis in MMCs. Moreover, RECQ1 depletion promotes the development of DNA double-strand breaks, as evidenced by the formation of 53BP1 foci and the phosphorylation of ataxia-telangiectasia mutated (ATM) and histone variant H2A.X (H2AX). In contrast, RECQ1 overexpression protects MMCs from melphalan and bortezomib cytotoxicity. RECQ1 interacts with PARP1 in MMCs exposed to treatment and RECQ1 depletion sensitizes MMCs to poly(ADP-ribose) polymerase (PARP) inhibitor. DNMT inhibitor treatment results in RECQ1 downregulation through miR-203 deregulation in MMC. Altogether, these data suggest that association of DNA damaging agents and/or PARP inhibitors with DNMT inhibitors may represent a therapeutic approach in patients with high RECQ1 expression associated with a poor prognosis.
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影响因子：
16.8
作者：
Berti, Matteo;Chaudhuri, Arnab Ray;Thangavel, Saravanabhavan;Gomathinayagam, Shivasankari;Kenig, Sasa;Vujanovic, Marko;Odreman, Federico;Glatter, Timo;Graziano, Simona;Mendoza-Maldonado, Ramiro;Marino, Francesca;Lucic, Bojana;Biasin, Valentina;Gstaiger, Matthias;Aebersold, Ruedi;Sidorova, Julia M.;Monnat, Raymond J., Jr.;Lopes, Massimo;Vindigni, Alessandro
通讯作者：
Vindigni, Alessandro
影响因子：
28.2
作者：
Cottini F;Hideshima T;Suzuki R;Tai YT;Bianchini G;Richardson PG;Anderson KC;Tonon G
通讯作者：
Tonon G
DOI：
10.1200/jco.2011.37.8919
发表时间：
2012-02-01
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
Anderson KC
通讯作者：
Anderson KC
影响因子：
16.6
作者：
Croteau DL;Popuri V;Opresko PL;Bohr VA
通讯作者：
Bohr VA
影响因子：
20.3
作者：
Keats, Jonathan J.;Chesi, Marta;Bergsagel, P. Leif
通讯作者：
Bergsagel, P. Leif