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ACUTE MYELOID LEUKEMIA

Genetic deletion and pharmacologic inhibition of E3 ubiquitin ligase HOIP impairs the propagation of myeloid leukemia

Leukemia volume 37, pages 122–133 (2023)Cite this article

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Abstract

We investigated the role of Hoip, a catalytic subunit of linear ubiquitin chain assembly complex (LUBAC), in adult hematopoiesis and myeloid leukemia by using both conditional deletion of Hoip and small-molecule chemical inhibitors of Hoip. Conditional deletion of Hoip led to significantly longer survival and marked depletion of leukemia burden in murine myeloid leukemia models. Nevertheless, a competitive transplantation assay showed the reduction of donor-derived cells in the bone marrow of recipient mice was relatively mild after conditional deletion of Hoip. Although both Hoip-deficient hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs) impaired the maintenance of quiescence, conditional deletion of Hoipinduced apoptosis in LSCs but not HSCs in vivo. Structure-function analysis revealed that LUBAC ligase activity and the interaction of LUBAC subunits were critical for the propagation of leukemia. Hoip regulated oxidative phosphorylation pathway independently of nuclear factor kappa B pathway in leukemia, but not in normal hematopoietic cells. Finally, the administration of thiolutin, which inhibits the catalytic activity of Hoip, improved the survival of recipients in murine myeloid leukemia and suppressed propagation in the patient-derived xenograft model of myeloid leukemia. Collectively, these data indicate that inhibition of LUBAC activity may be a valid therapeutic target for myeloid leukemia.

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Fig. 1: Role of Hoip in adult hematopoiesis.
Fig. 2: Role of Hoip in murine myeloid leukemia.
Fig. 3: Role of HOIP in human myeloid leukemia.
Fig. 4: Hoip regulates the NF-κB pathway in myeloid leukemia.
Fig. 5: Hoip regulates apoptosis in myeloid leukemia.
Fig. 6: Hoip regulates oxidative phosphorylation in myeloid leukemia.
Fig. 7: Thiolutin, a Hoip inhibitor, suppresses the propagation of myeloid leukemia in vitro.
Fig. 8: Thiolutin, a Hoip inhibitor, suppresses the propagation of murine and human myeloid leukemia in vivo.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request. RNA sequencing data have been deposited in the DDBJ database under the accession number DRA013876.

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Acknowledgements

We would like to thank the lab members in Division of Molecular Therapy, Division of Hematopoietic Disease Control, and FACS Core Laboratory (The Institute of Medical Science, The University of Tokyo) for helpful support and comments. We would like to thank Toshio Kitamura (The Institute of Medical Science, The University of Tokyo) for kindly providing the pMYs-IRES-GFP vector, and Hisashi Kato (Osaka University) for kindly providing the FG12-UbiC-tdTomato vector. Hoipflox/flox mice (strain: B6.B6CB-Rnf31<tm1.1Kiwa>; RBRC09483) were provided by the RIKEN BRC through the National BioResource Project of the MEXT/AMED, Japan. This work was supported by the SGH foundation, the Japanese Society of Hematology Research Grant, the Princess Takamatsu Cancer Research Fund, and the Cooperative Research Program (Joint Usage/Research Center program) of Institute for Life and Medical Sciences, Kyoto University. This work was also supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant-in-Aid for Scientific Research (20K08748 to TK; 20J10521 to KJ; 19H05746 to AI).

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Authors and Affiliations

  1. Division of Hematopoietic Disease Control, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Koji Jimbo, Yasuhito Nannya & Takaaki Konuma

  2. Division of Stem Cell and Molecular Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Koji Jimbo, Shuhei Koide & Atsushi Iwama

  3. Division of Molecular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Koji Jimbo & Arinobu Tojo

  4. Laboratory of Cell Fate Dynamics and Therapeutics, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan

    Ayuna Hattori & Takahiro Ito

  5. Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Katsuhiro Sasaki & Kazuhiro Iwai

  6. Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Yasuhito Nannya, Arinobu Tojo & Takaaki Konuma

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Contributions

KJ performed the experiments, analyzed the data and contributed to the writing the manuscript. AH performed the establishment of PDX of AML model. SK performed the RNA sequencing analysis. AH, TI, and YN edited the manuscript. TK planned and guided the research, and wrote the manuscript. All authors approved the final version.

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Correspondence to Takaaki Konuma.

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Jimbo, K., Hattori, A., Koide, S. et al. Genetic deletion and pharmacologic inhibition of E3 ubiquitin ligase HOIP impairs the propagation of myeloid leukemia. Leukemia 37, 122–133 (2023). https://doi.org/10.1038/s41375-022-01750-7

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