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在新诊断的多发性骨髓瘤中与CELF2结合,导致对标准治疗的无进展生存期缩短。

binds to CELF2 in newly diagnosed multiple myeloma promoting short progression-free survival to standard therapy.

作者信息

Mishra Richa, Thunuguntla Prasanth, Perkin Alani, Duraiyan Dhanusha, Bagwill Katelyn, Gonzales Savannah, Brizuela Vanessa, Daly Steve, Chang Yoon Jae, Abebe Mahdote, Rajana Yash, Wichmann Kelly, Bolick Catheryn, King Jaiyana, Fiala Mark, Fortier Julie, Jayasinghe Reyka, Schroeder Mark, Ding Li, Vij Ravi, Silva-Fisher Jessica

机构信息

Department of Internal Medicine, Division of Oncology, School of Medicine, Washington University in St. Louis, MO, 631101.

Siteman Cancer Center, Washington University in St. Louis, MO, 631102.

出版信息

Res Sq. 2024 Oct 15:rs.3.rs-4888379. doi: 10.21203/rs.3.rs-4888379/v1.

Abstract

Multiple Myeloma (MM) is an incurable form of cancer that arises from malignant plasma cells, with over 35,000 new cases diagnosed annually in the United States. While there are a growing number of approved therapies, MM remains incurable and nearly all patients will relapse and exhaust available treatments. Mechanisms for disease progression are unclear and little is known regarding the role of long non-coding RNAs (lncRNA) in mediating disease progression and response to treatment. Here, we used transcriptome sequencing to compare newly diagnosed MM (NDMM) patients who had short progression-free survival (PFS) to standard first-line treatment (PFS < 24 months) to patients who had prolonged PFS (PFS > 24 months). We identified 157 differentially upregulated lncRNAs with short PFS and focused our efforts on characterizing the most upregulated lncRNA, . We investigated to show that its overexpression significantly increases cell viability and reduces apoptosis, while knockdown significantly reduces viability and increases apoptosis. Next, we show that directly interacts with the RNA binding protein, CELF2. Lastly, we showed that -targeted locked nucleic acid antisense oligonucleotides reduce viability and increases apoptosis. In summary, this fundamental study identified lncRNAs associated with short PFS to standard NDMM treatment and further characterized .

摘要

多发性骨髓瘤(MM)是一种无法治愈的癌症,起源于恶性浆细胞,在美国每年有超过35000例新发病例。虽然获批的治疗方法越来越多,但MM仍然无法治愈,几乎所有患者都会复发并耗尽可用的治疗手段。疾病进展的机制尚不清楚,关于长链非编码RNA(lncRNA)在介导疾病进展和对治疗反应中的作用知之甚少。在此,我们使用转录组测序,将无进展生存期短(PFS)的新诊断MM(NDMM)患者(PFS<24个月)与接受标准一线治疗且无进展生存期延长(PFS>24个月)的患者进行比较。我们鉴定出157种在PFS短的患者中差异上调的lncRNA,并集中精力对上调程度最高的lncRNA进行表征。我们对其进行研究,结果表明其过表达显著增加细胞活力并减少细胞凋亡,而敲低则显著降低活力并增加细胞凋亡。接下来,我们表明它直接与RNA结合蛋白CELF2相互作用。最后,我们表明靶向的锁核酸反义寡核苷酸降低活力并增加细胞凋亡。总之,这项基础研究鉴定出了与标准NDMM治疗的短PFS相关的lncRNA,并对其进行了进一步表征。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7450/11527149/98af8e4b8c30/nihpp-rs4888379v1-f0001.jpg

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