2. Academic Validation
  3. Guanine nucleotide biosynthesis blockade impairs MLL complex formation and sensitizes leukemias to menin inhibition

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

  • Nat Commun. 2025 Mar 18;16(1):2641. doi: 10.1038/s41467-025-57544-9.
Xiangguo Shi 1 2 3 4,  Minhua Li 5,  Zian Liu 6,  Jonathan Tiessen 7,  Yuan Li 8,  Jing Zhou 5,  Yudan Zhu 9,  Swetha Mahesula 10,  Qing Ding 10,  Lin Tan 11,  Mengdie Feng 9,  Yuki Kageyama 9,  Yusuke Hara 9,  Jacob J Tao 5,  Xuan Luo 12,  Kathryn A Patras 13,  Philip L Lorenzi 11,  Suming Huang 12 14,  Alexandra M Stevens 15,  Koichi Takahashi 16 17,  Ghayas C Issa 16,  Md Abul Hassan Samee 6,  Michalis Agathocleous 10,  Daisuke Nakada 18 19 20
Affiliations

Affiliations

  • 1 Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA. xshi@pennstatehealth.psu.edu.
  • 2 Department of Molecular and Precision Medicine, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA. xshi@pennstatehealth.psu.edu.
  • 3 Penn State Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA. xshi@pennstatehealth.psu.edu.
  • 4 Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA. xshi@pennstatehealth.psu.edu.
  • 5 Development, Disease Models & Therapeutics Graduate Program, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 6 Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 7 Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 8 Department of Biostatistics and Data Science, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
  • 9 Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 10 Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75235, USA.
  • 11 Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 12 Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.
  • 13 Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 14 Penn State Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.
  • 15 Section of Hematology/Oncology, Department of Pediatrics, Texas Children's Cancer and Hematology Center, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 16 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 17 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 18 Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA. nakada@bcm.edu.
  • 19 Development, Disease Models & Therapeutics Graduate Program, Baylor College of Medicine, Houston, TX, 77030, USA. nakada@bcm.edu.
  • 20 Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA. nakada@bcm.edu.
PMID: 40102405 DOI: 10.1038/s41467-025-57544-9
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.

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