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

• Published in: Nature communications Vol. 16; no. 1; pp. 2641 - 20
• Main Authors: Shi, Xiangguo, Li, Minhua, Liu, Zian, Tiessen, Jonathan, Li, Yuan, Zhou, Jing, Zhu, Yudan, Mahesula, Swetha, Ding, Qing, Tan, Lin, Feng, Mengdie, Kageyama, Yuki, Hara, Yusuke, Tao, Jacob J., Luo, Xuan, Patras, Kathryn A., Lorenzi, Philip L., Huang, Suming, Stevens, Alexandra M., Takahashi, Koichi, Issa, Ghayas C., Samee, Md. Abul Hassan, Agathocleous, Michalis, Nakada, Daisuke
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.03.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 13/100; 13/31; 13/44; 631/67/1990/283/1897; 631/67/2327; 631/67/71; 64/60; Acute myeloid leukemia; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Biosynthesis; Cell Line, Tumor; Chromatin; Complex formation; Differentiation; Guanine; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Humanities and Social Sciences; Humans; IMP Dehydrogenase - antagonists & inhibitors; IMP Dehydrogenase - genetics; IMP Dehydrogenase - metabolism; Inhibitors; Inosine monophosphate; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Mice; multidisciplinary; Myeloid-Lymphoid Leukemia Protein - genetics; Myeloid-Lymphoid Leukemia Protein - metabolism; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Nucleotides; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; rRNA; Science; Science (multidisciplinary); Stem cells; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-025-57544-9

Targeting the dependency of MLL -rearranged ( MLL r) 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 MLL r 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 MLL r 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 MLL r leukemias to menin inhibitors. Resistance to menin inhibitors often occurs in the initially sensitive MLL-rearranged (MLLr) leukemias. Here authors discover that inhibition of guanine nucleotide biosynthesis leads to myeloid differentiation and sensitization to menin inhibitors in leukemia stem cells of MLLr leukemia.