EMBO Molecular Medicine (Jan 2023)
IMPDH inhibition activates TLR‐VCAM1 pathway and suppresses the development of MLL‐fusion leukemia
- Xiaoxiao Liu,
- Naru Sato,
- Tomohiro Yabushita,
- Jingmei Li,
- Yuhan Jia,
- Moe Tamura,
- Shuhei Asada,
- Takeshi Fujino,
- Tsuyoshi Fukushima,
- Taishi Yonezawa,
- Yosuke Tanaka,
- Tomofusa Fukuyama,
- Akiho Tsuchiya,
- Shiori Shikata,
- Hiroyuki Iwamura,
- Chieko Kinouchi,
- Kensuke Komatsu,
- Satoshi Yamasaki,
- Tatsuhiro Shibata,
- Atsuo T Sasaki,
- Janet Schibler,
- Mark Wunderlich,
- Eric O'Brien,
- Benjamin Mizukawa,
- James C Mulloy,
- Yuki Sugiura,
- Hitoshi Takizawa,
- Takuma Shibata,
- Kensuke Miyake,
- Toshio Kitamura,
- Susumu Goyama
Affiliations
- Xiaoxiao Liu
- Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences The University of Tokyo Tokyo Japan
- Naru Sato
- Division of Cellular Therapy, The Institute of Medical Science The University of Tokyo Tokyo Japan
- Tomohiro Yabushita
- Division of Cellular Therapy, The Institute of Medical Science The University of Tokyo Tokyo Japan
- Jingmei Li
- Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences The University of Tokyo Tokyo Japan
- Yuhan Jia
- Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences The University of Tokyo Tokyo Japan
- Moe Tamura
- Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences The University of Tokyo Tokyo Japan
- Shuhei Asada
- Division of Cellular Therapy, The Institute of Medical Science The University of Tokyo Tokyo Japan
- Takeshi Fujino
- Division of Cellular Therapy, The Institute of Medical Science The University of Tokyo Tokyo Japan
- Tsuyoshi Fukushima
- Division of Cellular Therapy, The Institute of Medical Science The University of Tokyo Tokyo Japan
- Taishi Yonezawa
- Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences The University of Tokyo Tokyo Japan
- Yosuke Tanaka
- Division of Cellular Therapy, The Institute of Medical Science The University of Tokyo Tokyo Japan
- Tomofusa Fukuyama
- Division of Cellular Therapy, The Institute of Medical Science The University of Tokyo Tokyo Japan
- Akiho Tsuchiya
- Division of Cellular Therapy, The Institute of Medical Science The University of Tokyo Tokyo Japan
- Shiori Shikata
- Division of Cellular Therapy, The Institute of Medical Science The University of Tokyo Tokyo Japan
- Hiroyuki Iwamura
- FUJIFILM Corporation: Pharmaceutical Products Division Tokyo Japan
- Chieko Kinouchi
- FUJIFILM Corporation: Bio Science & Engineering Laboratories Kanagawa Japan
- Kensuke Komatsu
- FUJIFILM Corporation: Bio Science & Engineering Laboratories Kanagawa Japan
- Satoshi Yamasaki
- Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science The University of Tokyo Tokyo Japan
- Tatsuhiro Shibata
- Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science The University of Tokyo Tokyo Japan
- Atsuo T Sasaki
- Division of Hematology and Oncology, Department of Internal Medicine University of Cincinnati Cincinnati OH USA
- Janet Schibler
- Division of Experimental Hematology and Cancer Biology Cincinnati Children's Hospital Medical Center Cincinnati OH USA
- Mark Wunderlich
- Division of Experimental Hematology and Cancer Biology Cincinnati Children's Hospital Medical Center Cincinnati OH USA
- Eric O'Brien
- Division of Oncology, Department of Pediatrics, University of Cincinnati Cincinnati OH USA
- Benjamin Mizukawa
- Division of Experimental Hematology and Cancer Biology Cincinnati Children's Hospital Medical Center Cincinnati OH USA
- James C Mulloy
- Division of Experimental Hematology and Cancer Biology Cincinnati Children's Hospital Medical Center Cincinnati OH USA
- Yuki Sugiura
- Department of Biochemistry Keio University School of Medicine Tokyo Japan
- Hitoshi Takizawa
- Laboratory of Stem Cell Stress, International Research Center for Medical Sciences Kumamoto University Kumamoto Japan
- Takuma Shibata
- Division of Innate Immunity, Department of Microbiology and Immunology The Institute of Medical Science, The University of Tokyo Tokyo Japan
- Kensuke Miyake
- Division of Innate Immunity, Department of Microbiology and Immunology The Institute of Medical Science, The University of Tokyo Tokyo Japan
- Toshio Kitamura
- Division of Cellular Therapy, The Institute of Medical Science The University of Tokyo Tokyo Japan
- Susumu Goyama
- Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences The University of Tokyo Tokyo Japan
- DOI
- https://doi.org/10.15252/emmm.202115631
- Journal volume & issue
-
Vol. 15,
no. 1
pp. n/a – n/a
Abstract
Abstract Inosine monophosphate dehydrogenase (IMPDH) is a rate‐limiting enzyme in de novo guanine nucleotide synthesis pathway. Although IMPDH inhibitors are widely used as effective immunosuppressants, their antitumor effects have not been proven in the clinical setting. Here, we found that acute myeloid leukemias (AMLs) with MLL‐fusions are susceptible to IMPDH inhibitors in vitro. We also showed that alternate‐day administration of IMPDH inhibitors suppressed the development of MLL‐AF9‐driven AML in vivo without having a devastating effect on immune function. Mechanistically, IMPDH inhibition induced overactivation of Toll‐like receptor (TLR)‐TRAF6‐NF‐κB signaling and upregulation of an adhesion molecule VCAM1, which contribute to the antileukemia effect of IMPDH inhibitors. Consequently, combined treatment with IMPDH inhibitors and the TLR1/2 agonist effectively inhibited the development of MLL‐fusion AML. These findings provide a rational basis for clinical testing of IMPDH inhibitors against MLL‐fusion AMLs and potentially other aggressive tumors with active TLR signaling.
Keywords
