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Suppression of super-enhancer-driven TAL1 expression by KLF4 in T-cell acute lymphoblastic leukemia

Oncogene volume 43, pages 447–456 (2024)Cite this article

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Abstract

TAL1 is one of the most frequently dysregulated genes in T-ALL and is overexpressed in about 50% of T-ALL cases. One of the molecular mechanisms of TAL1 overexpression is abnormal mutations in the upstream region of the TAL1 promoter that introduce binding motifs for the MYB transcription factor. MYB binding at this location creates a 5’ TAL1 super-enhancer (SE), which leads to aberrant expression of TAL1 and is associated with unfavorable clinical outcomes. Although targeting TAL1 is considered to be an attractive therapeutic strategy for patients with T-ALL, direct inhibition of transcription factors is challenging. Here, we show that KLF4, a known tumor suppressor in leukemic cells, suppresses SE-driven TAL1 expression in T-ALL cells. Mechanistically, KLF4 downregulates MYB expression by directly binding to its promoter and inhibits the formation of 5’ TAL1 SE. In addition, we found that APTO-253, a small molecule inducer of KLF4, exerts an anti-leukemic effect by targeting SE-driven TAL1 expression in T-ALL cells. Taken together, our results suggest that the induction of KLF4 is a promising strategy to control TAL1 expression and could be a novel treatment for T-ALL patients with a poor prognosis.

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Fig. 1: KLF4 inhibited the proliferation of TAL1-positive T-ALL cells.
Fig. 2: KLF4 suppressed TAL1 expression in 5’ TAL1 SE-positive T-ALL cell lines.
Fig. 3: KLF4 directly downregulated MYB expression in T-ALL cells.
Fig. 4: TAL1 and MYB were expressed in a mutually-dependent manner and co-operatively supported the growth of 5’ TAL1 SE-positive T-ALL cells.
Fig. 5: APTO-253 inhibited the growth of T-ALL cells via inhibition of the MYB-TAL1 regulatory circuit.
Fig. 6: Antitumor activity of APTO-253 in a Jurkat T-ALL xenograft model.

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Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Acknowledgements

This work was supported by JSPS KAKENHI Grant Numbers 21K19505 and 22H03102 (to FH) and 23K15298 (to MN); and Grants for Practical Research for Innovative Cancer Control Grant Numbers JP21ck0106607 (to FH) from the Japan Agency for Medical Research and Development (AMED). We sincerely thank all for their support.

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Authors and Affiliations

  1. Division of Cellular and Genetic Sciences, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Mina Noura & Fumihiko Hayakawa

  2. Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Hidemasa Matsuo

  3. Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan

    Takahiko Yasuda

  4. Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan

    Shinobu Tsuzuki

  5. Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Hitoshi Kiyoi

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  1. Mina Noura
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Contributions

MN initiated the study, designed and performed the experiments, analyzed the data, and wrote the manuscript. HM performed the in vivo experiments. All others supervised the research and approved the final manuscript for submission.

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Correspondence to Mina Noura.

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Competing interests

HK has received research funds from FUJIFILM, Kyowa Hakko Kirin, Otsuka, Perseus Proteomics, Daiichi Sankyo, AbbVie, CURED, Astellas Pharma, Bristol-Myers Squibb; and scholarship funds from Zenyaku Kogyo, Nippon Shinyaku, Chugai, Astellas Pharma, Kyowa Hakko Kirin, Takeda, Sumitomo Dainippon Pharma, Sanofi, Eisai, and Ono; and honoraria from AbbVie, Chugai, Astellas Pharma, and Novartis. All other authors have nothing to disclose.

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Noura, M., Matsuo, H., Yasuda, T. et al. Suppression of super-enhancer-driven TAL1 expression by KLF4 in T-cell acute lymphoblastic leukemia. Oncogene 43, 447–456 (2024). https://doi.org/10.1038/s41388-023-02913-1

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