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ACUTE MYELOID LEUKEMIA

Regulation of metabolic adaptation and leukemia progression by MUSASHI2-DEPTOR-KIF11 axis

Leukemia (2025)Cite this article

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Abstract

Amino acid homeostasis is critical for leukemic cell survival, with the mTOR pathway playing a central role in sensing and responding to nutrient availability. DEPTOR, a component and negative regulator of mTOR complexes, has been extensively studied in solid tumors and multiple myeloma, but its role in acute myeloid leukemia (AML) remains unclear. Here, we identify DEPTOR as a key regulator of leukemia progression through its interaction with KIF11. DEPTOR expression is transcriptionally induced by ATF4 and post-transcriptionally stabilized by MSI2, which binds to DEPTOR mRNA and prevents its degradation. DEPTOR is highly expressed in leukemia stem cells (LSCs) and is associated with poor clinical outcomes. Functionally, DEPTOR loss impairs leukemogenesis in both AML and blast phase chronic myeloid leukemia (bpCML) models, without affecting normal hematopoietic stem cells. Mechanistically, DEPTOR stabilizes KIF11 by preventing its ubiquitination and proteasomal degradation, thereby ensuring proper mTORC1 localization and metabolic adaptation during nutrient stress. Collectively, our findings establish the MSI2/DEPTOR/KIF11 axis as a critical driver of leukemogenesis and a promising therapeutic target for aggressive myeloid leukemias.

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Fig. 1: Upregulation of DEPTOR during amino acid starvation is associated with ATF4/MSI2 axis.
Fig. 2: DEPTOR depletion impairs adaptive responses and disrupts mTORC1 localization during amino acid starvation.
Fig. 3: Elevated DEPTOR expression associates with poor prognosis in AML patients.
Fig. 4: Deptor is essential for the progression of KMT2A::MLLT3/NRAS-induced AML and bpCML in vivo.
Fig. 5: Hematopoiesis remains unaffected by Deptor deletion.
Fig. 6: DEPTOR binds to KIF11 and regulates its stability.
Fig. 7: DEPTOR depletion is partially rescued by the ectopic expression of KIF11.

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Data availability

The data supporting the findings of this study are provided within the article. Additional information related to this research is available upon request from the corresponding author.

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Acknowledgements

This work was supported by the National Research Foundation of Korea(NRF) grant funded by the Korean Government (MSIT) (NRF-2023R1A2C1003952) and by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (RS-2024-00437643).

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Author notes

  1. These authors contributed equally: Tania Setiawan, Jabir Aliyu Muhammad.

Authors and Affiliations

  1. Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan-si, Republic of Korea

    Tania Setiawan, Jabir Aliyu Muhammad, Nadya Marcellina, Lawrence Mario Wirawan, Nayoung Jun, Ita Novita Sari & Hyog Young Kwon

  2. Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan-si, Republic of Korea

    Tania Setiawan, Jabir Aliyu Muhammad, Nadya Marcellina & Hyog Young Kwon

  3. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Vivian G. Oehler

  4. Department of Hematology, Hematology Center, Uijeongbu Eulji Medical Center, Eulji University, Uijeongbu, Republic of Korea; Leukemia Omics Research Institute, Eulji University Uijeongbu Campus, Uijeongbu, Republic of Korea

    Dong-Wook Kim

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Contributions

TS and JAM planned, designed, and performed the majority of experiments and helped write the manuscript. NM, LMW, NJ, and INS performed mechanism studies, and VGO and DK analyzed patient-derived data. HYK planned and guided the project and wrote the manuscript.

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Correspondence to Hyog Young Kwon.

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Declaration of Generative AI and AI-assisted technologies in the writing process: During the preparation of this work, the author(s) used ChatGPT in order to improve readability and language. After using this tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication.

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Setiawan, T., Muhammad, J.A., Marcellina, N. et al. Regulation of metabolic adaptation and leukemia progression by MUSASHI2-DEPTOR-KIF11 axis. Leukemia (2025). https://doi.org/10.1038/s41375-025-02768-3

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