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  2. Targeting FEN1 Suppresses the Proliferation of Chronic Myeloid Leukemia Cells Through Regulating Alternative End-Joining Pathways

Targeting FEN1 Suppresses the Proliferation of Chronic Myeloid Leukemia Cells Through Regulating Alternative End-Joining Pathways

  • DNA Cell Biol. 2021 Aug;40(8):1101-1111. doi: 10.1089/dna.2021.0239.
Yalin Zhu 1 Hongdan Dai 1 Yonghong Wang 1 Yang Liang 1 Wenli Feng 1 Ying Yuan 2
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing Medical University, Chongqing, China.
  • 2 Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Abstract

Chronic myeloid leukemia (CML) is characterized by the formation of the Bcr-Abl fusion gene. The Bcr-Abl protein leads to an increased level of Reactive Oxygen Species, which is a major cause of endogenous DNA double-strand breaks (DSBs). CML cells are prone to rely on a highly mutagenic alternative end-joining (Alt-EJ) pathway to cope with enhanced DSBs, which aggravates chromosomal instability. Hence, targeting dysregulated DNA repair proteins provides new insights into Cancer treatment. In this study, we discovered the abnormal upregulation of FLAP endonuclease 1 (FEN1) in CML, as well as FEN1's participation in the error-prone Alt-EJ repair pathway and its interplay with DNA Ligase1 and proliferating cell nuclear antigen in DSB repair. Knockdown of FEN1 by shRNA not only inhibited the proliferation and induced Apoptosis but also enhanced the efficacy of imatinib (IM) in drug-resistant CML cell K562/G01. Moreover, excessive DSB accumulation was detected after FEN1 inhibition. In summary, our results demonstrated that FEN1 is a promising therapeutic target in CML treatment. This work extends the understanding of regulating abnormal DSB repair for Cancer treatment.

Keywords

Alt-EJ; BCR-ABL; DNA double-strand breaks; FEN1; chronic myeloid leukemia.

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