Concomitant inhibition of the thioredoxin system and nonhomologous DNA repair potently sensitizes Philadelphia‐positive lymphoid leukemia to tyrosine kinase inhibitors

Author:

Komorowski Lukasz12ORCID,Dabkowska Agnieszka13,Madzio Joanna4,Pastorczak Agata4,Szczygiel Kacper15,Janowska Martyna3,Fidyt Klaudyna1,Bielecki Maksymilian6,Hunia Jaromir1,Bajor Malgorzata3,Stoklosa Tomasz7,Winiarska Magdalena13,Patkowska Elzbieta8,Firczuk Malgorzata13

Affiliation:

1. Department of Immunology Medical University of Warsaw Warsaw Poland

2. Postgraduate School of Molecular Medicine Medical University of Warsaw Warsaw Poland

3. Laboratory of Immunology, Mossakowski Medical Research Institute Polish Academy of Sciences Warsaw Poland

4. Department of Pediatrics, Oncology and Hematology Medical University of Lodz Lodz Poland

5. Polpharma Biologics SA Gdańsk Poland

6. Department of Psychology SWPS University of Social Sciences and Humanities Warsaw Poland

7. Department of Tumor Biology and Genetics Medical University of Warsaw Warsaw Poland

8. Institute of Hematology and Transfusion Medicine Warsaw Poland

Abstract

AbstractBreakpoint cluster region‐Abelson (BCR::ABL1) gene fusion is an essential oncogene in both chronic myeloid leukemia (CML) and Philadelphia‐positive (Ph+) B‐cell acute lymphoblastic leukemia (B‐ALL). While tyrosine kinase inhibitors (TKIs) are effective in up to 95% of CML patients, 50% of Ph+ B‐ALL cases do not respond to treatment or relapse. This calls for new therapeutic approaches for Ph+ B‐ALL. Previous studies have shown that inhibitors of the thioredoxin (TXN) system exert antileukemic activity against B‐ALL cells, particularly in combination with other drugs. Here, we present that peroxiredoxin‐1 (PRDX1), one of the enzymes of the TXN system, is upregulated in Ph+ lymphoid as compared to Ph+ myeloid cells. PRDX1 knockout negatively affects the viability of Ph+ B‐ALL cells and sensitizes them to TKIs. Analysis of global gene expression changes in imatinib‐treated, PRDX1‐deficient cells revealed that the nonhomologous end‐joining (NHEJ) DNA repair is a novel vulnerability of Ph+ B‐ALL cells. Accordingly, PRDX1‐deficient Ph+ B‐ALL cells were susceptible to NHEJ inhibitors. Finally, we demonstrated the potent efficacy of a novel combination of TKIs, TXN inhibitors, and NHEJ inhibitors against Ph+ B‐ALL cell lines and primary cells, which can be further investigated as a potential therapeutic approach for the treatment of Ph+ B‐ALL.

Funder

Narodowe Centrum Nauki

Publisher

Wiley

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3