ArticleNature communications2025
Guanine nucleotide biosynthesis blockade impairs MLL complex formation and sensitizes leukemias to menin inhibition.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Current perspectives on KMT2A fusion proteins and menin inhibition in paediatric acute myeloid leukaemia.The FEBS journal · 2026Review
- Resistance to Targeted Therapy in AML: Current Challenges and Emerging Treatment Strategies.Journal of clinical medicine · 2026Review
- Article
- Targeting nucleotide metabolism and epigenetic regulation to overcome the differentiation blockade in AML.Leukemia research reports · 2026Review
- KMT2A-rearranged leukemia: from mechanism to drug development.Experimental hematology · 2025Review
- Metabolic Signature ofJournal of personalized medicine · 2025Review
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Authors and funding
24 authors.
Funding
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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Registered trials
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