Targeting DLBCL by mutation-specific disruption of cancer-driving oncogenes.

IF 4.9 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Frontiers in genome editing Pub Date : 2024-10-14 eCollection Date: 2024-01-01 DOI:10.3389/fgeed.2024.1427322
Najmeh Heshmatpour, S Maryam Kazemi, Niklas D Schmidt, Sarita R Patnaik, Patrick Korus, Bodo G C Wilkens, Arturo Macarrón Palacios
{"title":"Targeting DLBCL by mutation-specific disruption of cancer-driving oncogenes.","authors":"Najmeh Heshmatpour, S Maryam Kazemi, Niklas D Schmidt, Sarita R Patnaik, Patrick Korus, Bodo G C Wilkens, Arturo Macarrón Palacios","doi":"10.3389/fgeed.2024.1427322","DOIUrl":null,"url":null,"abstract":"<p><p>Diffuse large B cell lymphomas (DLBCL) are highly aggressive tumors. Their genetic complexity and heterogeneity have hampered the development of novel approaches for precision medicine. Our study aimed to develop a personalized therapy for DLBCL by utilizing the CRISPR/Cas system to induce knockouts (KO) of driver genes, thereby causing cancer cell death while minimizing side effects. We focused on OCI-LY3 cells, modeling DLBCL, and compared them with BJAB cells as controls. Analysis of whole exome sequencing revealed significant mutations in genes like <i>PAX5</i>, <i>CD79B</i>, and <i>MYC</i> in OCI-LY3 cells. CRISPR/Cas9-mediated KO of these genes resulted in reduced cancer cell viability. Subsequent single and dual gRNA targeting of <i>PAX5</i> mutations inhibited proliferation specifically in OCI-LY3 cells. Moreover, dual gRNA targeting of <i>PAX5</i> and <i>MYC</i> induced chromosomal rearrangements, reducing cell proliferation substantially. However, targeting single intronic mutations did not affect cell viability, highlighting the importance of disrupting protein function. Targeting multiple mutations simultaneously addresses intra-tumoral heterogeneity, and the transient delivery of CRISPR/Cas9 allows for permanent gene disruption. While challenges such as incomplete editing efficiency and delivery limitations exist, further optimization may enhance therapeutic efficacy. Overall, our findings demonstrate the efficacy of CRISPR/Cas9 in targeting oncogenic mutations, opening avenues for precision medicine in DLBCL treatment.</p>","PeriodicalId":73086,"journal":{"name":"Frontiers in genome editing","volume":"6 ","pages":"1427322"},"PeriodicalIF":4.9000,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513324/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Frontiers in genome editing","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.3389/fgeed.2024.1427322","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Diffuse large B cell lymphomas (DLBCL) are highly aggressive tumors. Their genetic complexity and heterogeneity have hampered the development of novel approaches for precision medicine. Our study aimed to develop a personalized therapy for DLBCL by utilizing the CRISPR/Cas system to induce knockouts (KO) of driver genes, thereby causing cancer cell death while minimizing side effects. We focused on OCI-LY3 cells, modeling DLBCL, and compared them with BJAB cells as controls. Analysis of whole exome sequencing revealed significant mutations in genes like PAX5, CD79B, and MYC in OCI-LY3 cells. CRISPR/Cas9-mediated KO of these genes resulted in reduced cancer cell viability. Subsequent single and dual gRNA targeting of PAX5 mutations inhibited proliferation specifically in OCI-LY3 cells. Moreover, dual gRNA targeting of PAX5 and MYC induced chromosomal rearrangements, reducing cell proliferation substantially. However, targeting single intronic mutations did not affect cell viability, highlighting the importance of disrupting protein function. Targeting multiple mutations simultaneously addresses intra-tumoral heterogeneity, and the transient delivery of CRISPR/Cas9 allows for permanent gene disruption. While challenges such as incomplete editing efficiency and delivery limitations exist, further optimization may enhance therapeutic efficacy. Overall, our findings demonstrate the efficacy of CRISPR/Cas9 in targeting oncogenic mutations, opening avenues for precision medicine in DLBCL treatment.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
通过突变特异性地破坏致癌基因来靶向 DLBCL。
弥漫性大B细胞淋巴瘤(DLBCL)是一种侵袭性极强的肿瘤。它们的遗传复杂性和异质性阻碍了精准医疗新方法的开发。我们的研究旨在利用CRISPR/Cas系统诱导驱动基因敲除(KO),从而导致癌细胞死亡,同时将副作用降至最低,从而开发出针对DLBCL的个性化疗法。我们重点研究了模拟DLBCL的OCI-LY3细胞,并将其与作为对照的BJAB细胞进行了比较。全外显子组测序分析显示,OCI-LY3 细胞中的 PAX5、CD79B 和 MYC 等基因发生了显著突变。CRISPR/Cas9 介导的这些基因的 KO 可降低癌细胞的活力。随后,PAX5 突变的单gRNA靶向和双gRNA靶向可特异性抑制 OCI-LY3 细胞的增殖。此外,PAX5 和 MYC 的双 gRNA 靶向会诱导染色体重排,从而大幅降低细胞增殖。然而,靶向单个内含子突变并不会影响细胞活力,这突出了破坏蛋白质功能的重要性。同时靶向多个突变可解决瘤内异质性问题,CRISPR/Cas9的瞬时传递可实现永久性基因破坏。虽然存在编辑效率不完全和递送限制等挑战,但进一步优化可能会提高疗效。总之,我们的研究结果证明了 CRISPR/Cas9 在靶向致癌突变方面的功效,为 DLBCL 的精准医疗开辟了道路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
CiteScore
7.00
自引率
0.00%
发文量
0
审稿时长
13 weeks
期刊最新文献
Towards functional maps of non-coding variants in cancer. Beyond the traditional distinctions of genome editing: evaluating a vulnerability framework. Knockout mutation in TaD27 enhances number of productive tillers in hexaploid wheat. Targeting DLBCL by mutation-specific disruption of cancer-driving oncogenes. The potential of HBV cure: an overview of CRISPR-mediated HBV gene disruption.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1