Guanine Nucleotide Biosynthesis Blockade Impairs Mll Complex Formation and Sensitizes Leukemias to Menin Inhibition

Authors

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
Daisuke Nakada

Publication Date

3-18-2025

Journal

Nature Communications

DOI

10.1038/s41467-025-57544-9

PMID

40102405

PMCID

PMC11920272

PubMedCentral® Posted Date

3-18-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Proto-Oncogene Proteins, Humans, Myeloid-Lymphoid Leukemia Protein, Leukemia, Myeloid, Acute, Histone-Lysine N-Methyltransferase, Animals, Mice, Cell Line, Tumor, IMP Dehydrogenase, Neoplastic Stem Cells, Adaptor Proteins, Signal Transducing, Transcription Factors

Published Open-Access

yes

Recommended Citation

Shi, Xiangguo; Li, Minhua; Liu, Zian; et al., "Guanine Nucleotide Biosynthesis Blockade Impairs Mll Complex Formation and Sensitizes Leukemias to Menin Inhibition" (2025). Faculty, Staff and Student Publications. 3856.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/3856