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

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, Kathryn A. Patras, Philip L. Lorenzi, Suming Huang, Alexandra M. Stevens, Koichi Takahashi, Ghayas C. Issa, Md. Abul Hassan Samee, Michalis Agathocleous and Daisuke Nakada ()
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Xiangguo Shi: Pennsylvania State University 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
Alexandra M. Stevens: Baylor College of Medicine
Koichi Takahashi: 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

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57544-9

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