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Guanine nucleotide biosynthesis blockade impairs MLL complex formation and sensitizes leukemias to menin inhibition

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  • Xiangguo Shi

    (Pennsylvania State University College of Medicine
    Pennsylvania State University College of Medicine
    Pennsylvania State University College of Medicine
    Baylor College of Medicine)

  • Minhua Li

    (Baylor College of Medicine)

  • Zian Liu

    (Baylor College of Medicine)

  • Jonathan Tiessen

    (Baylor College of Medicine)

  • Yuan Li

    (The University of Texas Health Science Center at Houston)

  • Jing Zhou

    (Baylor College of Medicine)

  • Yudan Zhu

    (Baylor College of Medicine)

  • Swetha Mahesula

    (University of Texas Southwestern Medical Center)

  • Qing Ding

    (University of Texas Southwestern Medical Center)

  • Lin Tan

    (The University of Texas MD Anderson Cancer Center)

  • Mengdie Feng

    (Baylor College of Medicine)

  • Yuki Kageyama

    (Baylor College of Medicine)

  • Yusuke Hara

    (Baylor College of Medicine)

  • Jacob J. Tao

    (Baylor College of Medicine)

  • Xuan Luo

    (Pennsylvania State University College of Medicine)

  • Kathryn A. Patras

    (Baylor College of Medicine)

  • Philip L. Lorenzi

    (The University of Texas MD Anderson Cancer Center)

  • Suming Huang

    (Pennsylvania State University College of Medicine
    Pennsylvania State University College of Medicine)

  • Alexandra M. Stevens

    (Baylor College of Medicine)

  • Koichi Takahashi

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Ghayas C. Issa

    (The University of Texas MD Anderson Cancer Center)

  • Md. Abul Hassan Samee

    (Baylor College of Medicine)

  • Michalis Agathocleous

    (University of Texas Southwestern Medical Center)

  • Daisuke Nakada

    (Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine)

Abstract

Targeting the dependency of MLL-rearranged (MLLr) leukemias on menin with small molecule inhibitors has opened new therapeutic strategies for these poor-prognosis diseases. However, the rapid development of menin inhibitor resistance calls for combinatory strategies to improve responses and prevent resistance. Here we show that leukemia stem cells (LSCs) of MLLr acute myeloid leukemia (AML) exhibit enhanced guanine nucleotide biosynthesis, the inhibition of which leads to myeloid differentiation and sensitization to menin inhibitors. Mechanistically, targeting inosine monophosphate dehydrogenase 2 (IMPDH2) reduces guanine nucleotides and rRNA transcription, leading to reduced protein expression of LEDGF and menin. Consequently, the formation and chromatin binding of the MLL-fusion complex is impaired, reducing the expression of MLL target genes. Inhibition of guanine nucleotide biosynthesis or rRNA transcription further suppresses MLLr AML when combined with a menin inhibitor. Our findings underscore the requirement of guanine nucleotide biosynthesis in maintaining the function of the LEDGF/menin/MLL-fusion complex and provide a rationale to target guanine nucleotide biosynthesis to sensitize MLLr leukemias to menin inhibitors.

Suggested Citation

  • Xiangguo Shi & Minhua Li & Zian Liu & Jonathan Tiessen & Yuan Li & Jing Zhou & Yudan Zhu & Swetha Mahesula & Qing Ding & Lin Tan & Mengdie Feng & Yuki Kageyama & Yusuke Hara & Jacob J. Tao & Xuan Luo , 2025. "Guanine nucleotide biosynthesis blockade impairs MLL complex formation and sensitizes leukemias to menin inhibition," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57544-9
    DOI: 10.1038/s41467-025-57544-9
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