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ACUTE MYELOID LEUKEMIA

SETBP1 is dispensable for normal and malignant hematopoiesis

Leukemia volume 37, pages 1802–1811 (2023)Cite this article

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Abstract

SETBP1 is a potential epigenetic regulator whose hotspot mutations preventing proteasomal degradation are recurrently detected in myeloid malignancies with poor prognosis. It is believed that the mutant SETBP1 exerts amplified effects of wild-type SETBP1 rather than neomorphic functions. This indicates that dysregulated quantitative control of SETBP1 would result in the transformation of hematopoietic cells. However, little is known about the roles of endogenous SETBP1 in malignant and normal hematopoiesis. Thus, we integrated the analyses of primary AML and healthy samples, cancer cell lines, and a newly generated murine model, Vav1-iCre;Setbp1fl/fl. Despite the expression in long-term hematopoietic stem cells, SETBP1 depletion in normal hematopoiesis minimally alters self-renewal, differentiation, or reconstitution in vivo. Indeed, its loss does not profoundly alter transcription or chromatin accessibilities. Furthermore, although AML with high SETBP1 mRNA is associated with genetic and clinical characteristics for dismal outcomes, SETBP1 is dispensable for the development or maintenance of AML. Contrary to the evidence that SETBP1 mutations are restricted to myeloid malignancies, dependency on SETBP1 mRNA expression is not observed in AML. These unexpected results shed light on the unrecognized idea that a physiologically nonessential gene can act as an oncogene when the machinery of protein degradation is damaged.

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Fig. 1: Characteristics of SETBP1 expression in malignant and normal hematopoiesis.
Fig. 2: Generation and phenotypic characterization of hematopoietic cell-specific Setbp1 KO mice.
Fig. 3: The Setbp1 depletion had limited effects on the repopulating capacity and the fitness of HSCs.
Fig. 4: Setbp1 KO induced minimal effects on gene expression or chromatin accessibility.
Fig. 5: AML cells are not dependent on SETBP1 for their survival.

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Data availability

RNA-seq data generated by Beat AML (dbGaP accession phs001657.v1.p1) were downloaded from the National Cancer Institute’s Genomic Data Commons. The RNA-seq data generated in this study were deposited in Sequence Read Archive under BioProject ID: PRJNA898600 and PRJNA974068, and the ATAC-seq data under BioProject ID: PRJNA898579 and PRJNA974069.

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Funding

DI is supported by American Society of Hematology, Japanese Society of Hematology, The Naito Foundation, The Uehara Memorial Foundation, KAKETSUKEN, The Princess Takamatsu Cancer Research Fund, SGH Foundation, The Mother and Child Health Foundation, Kato Memorial Bioscience Foundation, JSPS KAKENHI (23H00430, JP20H00537 and JP20H03717) and the Japan Agency for Medical Research and Development (AMED) (21ck0106697h0001). AT is supported by JSPS KAKENHI (JP21J15620). Other financial support includes Grant-in-Aid for Scientific Research (MEXT/JSPS KAKENHI JP19H05656 (SO), JP26221308 (SO), JP21K08394 (AK), JP18K16084 (AK)), AMED (JP21cm0106501h0006 (SO), JP22ama221508h0001 (AK)).

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Authors and Affiliations

  1. Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Hyogo, Japan

    Atsushi Tanaka, Koutarou Nishimura, Wataru Saika, Yui Koike, Masaki Nomura, Weijia Zang, Hiromi Yamazaki, Miki Fukumoto, Hiromi Ito, Yasutaka Hayashi, Toshio Kitamura & Daichi Inoue

  2. Laboratory of Immunology, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan

    Atsushi Tanaka & Hiroshi Kawamoto

  3. Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Atsushi Tanaka, Weijia Zang, Akifumi Takaori-Kondo & Daichi Inoue

  4. Department of Hematology, Shiga University of Medical Science, Shiga, Japan

    Wataru Saika

  5. Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Ayana Kon, June Takeda & Seishi Ogawa

  6. RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan

    Hiromi Tatsumi, Masashi Matsuda & Haruhiko Koseki

  7. Facility for iPS Cell Therapy, CiRA Foundation, Kyoto, Japan

    Masaki Nomura

  8. Laboratory of Medical Omics Research, Department of Frontier Research and Development, Kazusa DNA Research Institute, Kazusa-Kamatari, Kisarazu, Chiba, Japan

    Manabu Nakayama

  9. Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan

    Seishi Ogawa

  10. Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institute, Stockholm, Sweden

    Seishi Ogawa

Authors
  1. Atsushi Tanaka
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  2. Koutarou Nishimura
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  3. Wataru Saika
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Contributions

AT, KN, and DI designed the study; KA, JT, HT, MNakayama, MM, HK, and SO established Setbp1 conditional knock-out mice. MNomura and DI performed computational analyses of clinical information; WZ, MNomura, and DI performed computational analyses of RNA-seq and ATAC-seq data; AT, YK, WZ, HY, MF, WS, HI, YH, HK, TK, AT-K, and DI performed animal experiments; AT, MNomura, MNakayama, MM, WZ, and DI wrote the manuscript with approval from all co-authors.

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Correspondence to Daichi Inoue.

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Tanaka, A., Nishimura, K., Saika, W. et al. SETBP1 is dispensable for normal and malignant hematopoiesis. Leukemia 37, 1802–1811 (2023). https://doi.org/10.1038/s41375-023-01970-5

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