Mitotic perturbation is a key mechanism of action of decitabine in myeloid tumor treatment

Tomohiro Yabushita; Takumi Chinen; Atsuya Nishiyama; Shuhei Asada; Ruka Shimura; Tomoya Isobe; Keita Yamamoto; Naru Sato; Yutaka Enomoto; Yosuke Tanaka; Tomofusa Fukuyama; Hitoshi Satoh; Keiko Kato; Kaori Saitoh; Takamasa Ishikawa; Tomoyoshi Soga; Yasuhito Nannya; Tatsuo Fukagawa; Makoto Nakanishi; Daiju Kitagawa; Toshio Kitamura; Susumu Goyama

doi:10.1016/j.celrep.2023.113098

Mitotic perturbation is a key mechanism of action of decitabine in myeloid tumor treatment

Cell Rep. 2023 Sep 26;42(9):113098. doi: 10.1016/j.celrep.2023.113098. Epub 2023 Sep 14.

Authors

Tomohiro Yabushita¹, Takumi Chinen², Atsuya Nishiyama³, Shuhei Asada⁴, Ruka Shimura⁵, Tomoya Isobe⁶, Keita Yamamoto⁵, Naru Sato¹, Yutaka Enomoto¹, Yosuke Tanaka¹, Tomofusa Fukuyama⁷, Hitoshi Satoh⁸, Keiko Kato⁹, Kaori Saitoh⁹, Takamasa Ishikawa⁹, Tomoyoshi Soga¹⁰, Yasuhito Nannya¹¹, Tatsuo Fukagawa¹², Makoto Nakanishi³, Daiju Kitagawa², Toshio Kitamura¹³, Susumu Goyama¹⁴

Affiliations

¹ Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
² Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
³ Division of Cancer Cell Biology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁴ Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; The Institute of Laboratory Animals, Tokyo Women's Medical University, Tokyo, Japan.
⁵ Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
⁶ Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan; Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁷ Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Department of Hematology, International University of Health and Welfare Hospital, Tochigi, Japan.
⁸ Division of Medical Genome Sciences, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
⁹ Infinity Lab, INC, Yamagata, Japan; Institute for Advanced Biosciences, Keio University, Yamagata, Japan.
¹⁰ Institute for Advanced Biosciences, Keio University, Yamagata, Japan.
¹¹ Division of Hematopoietic Disease Control, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
¹² Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
¹³ Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Hyogo, Japan.
¹⁴ Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan. Electronic address: goyama@edu.k.u-tokyo.ac.jp.

PMID: 37714156
DOI: 10.1016/j.celrep.2023.113098

Abstract

Decitabine (DAC) is clinically used to treat myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Our genome-wide CRISPR-dCas9 activation screen using MDS-derived AML cells indicates that mitotic regulation is critical for DAC resistance. DAC strongly induces abnormal mitosis (abscission failure or tripolar mitosis) in human myeloid tumors at clinical concentrations, especially in those with TP53 mutations or antecedent hematological disorders. This DAC-induced mitotic disruption and apoptosis are significantly attenuated in DNMT1-depleted cells. In contrast, overexpression of Dnmt1, but not the catalytically inactive mutant, enhances DAC-induced mitotic defects in myeloid tumors. We also demonstrate that DAC-induced mitotic disruption is enhanced by pharmacological inhibition of the ATR-CLSPN-CHK1 pathway. These data challenge the current assumption that DAC inhibits leukemogenesis through DNMT1 inhibition and subsequent DNA hypomethylation and highlight the potent activity of DAC to disrupt mitosis through aberrant DNMT1-DNA covalent bonds.

Keywords: ATR; CHK1; CP: Cancer; DNA hypomethylating agent; DNA methylation; DNMT1; HMA; cholesterol; decitabine; mitosis; mitotic catastrophe.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Antimetabolites, Antineoplastic / pharmacology
Azacitidine* / pharmacology
Azacitidine* / therapeutic use
DNA
DNA Methylation / genetics
Decitabine / pharmacology
Decitabine / therapeutic use
Humans
Leukemia, Myeloid, Acute* / pathology

Substances

Decitabine
Azacitidine
Antimetabolites, Antineoplastic
DNA
CLSPN protein, human
Adaptor Proteins, Signal Transducing