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
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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.

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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。
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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
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. Use of paired Cas9-NG nickase and truncated sgRNAs for single-nucleotide microbial genome editing. Making gene editing accessible in resource limited environments: recommendations to guide a first-time user.
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