Guanine nucleotide biosynthesis blockade impairs MLL complex formation and sensitizes leukemias to menin inhibition
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.
Authors
- Alexandra McLean Stevens (ORCID: https://orcid.org/0000-0002-7292-2464)
- Yusuke Hara (ORCID: https://orcid.org/0000-0001-7271-3454)
- Swetha Mahesula
- Yuki Kageyama (ORCID: https://orcid.org/0000-0002-0564-2227)
- Michalis Agathocleous (ORCID: https://orcid.org/0000-0002-3427-1023)
- Zian Liu (ORCID: https://orcid.org/0000-0003-4803-0906)
- Koichi Takahashi (ORCID: https://orcid.org/0000-0002-8027-9659)
- Mengdie Feng (ORCID: https://orcid.org/0009-0006-4804-9761)
- Daisuke Nakada (ORCID: https://orcid.org/0000-0001-6010-7094)
- Ghayas C. Issa (ORCID: https://orcid.org/0000-0002-4339-8683)
- Philip L. Lorenzi (ORCID: https://orcid.org/0000-0003-0385-7774)
- Xuan Luo (ORCID: https://orcid.org/0000-0001-6313-4709)
- Md. Abul Hassan Samee (ORCID: https://orcid.org/0000-0002-7472-1156)
- Kathryn A. Patras (ORCID: https://orcid.org/0000-0003-2631-8810)
- Xiangguo Shi (ORCID: https://orcid.org/0000-0001-8334-5706)
- Jacob J. Tao (ORCID: https://orcid.org/0000-0003-2772-137X)
- Jonathan Tiessen (ORCID: https://orcid.org/0000-0002-3981-2220)
- Jing Zhou (ORCID: https://orcid.org/0000-0003-2177-4569)
- Ding Qing
- Suming Huang (ORCID: https://orcid.org/0000-0002-4788-2085)
- Lin Tan (ORCID: https://orcid.org/0000-0001-8440-5643)
- Yuan Li (ORCID: https://orcid.org/0000-0003-2979-0803)
- Yudan Zhu
- Minhua Li (ORCID: https://orcid.org/0009-0000-2077-110X)
Institutions
- Children's Medical Center (US)
- Pennsylvania State University (US)
- The University of Texas MD Anderson Cancer Center (US)
- Baylor College of Medicine (US)
- Children's Cancer Center (US)
- Baylor Genetics (US)
- Penn State Milton S. Hershey Medical Center (US)
- The University of Texas Southwestern Medical Center (US)
- The University of Texas Health Science Center at Houston (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-18
- DOI
- https://doi.org/10.1038/s41467-025-57544-9
- Citations
- 7
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 12.39
Funders
- Leukemia and Lymphoma Society
- National Heart and Lung Institute
- National Cancer Institute