Mutant IDH1 cooperates with NPM1c or FLT3(ITD) to drive distinct myeloid diseases and molecular outcomes Journal Article
| Authors: | Sakamoto, T.; Leca, J.; Zhang, X.; Meydan, C.; Foox, J.; Ramachandran, P.; Hendrikse, L. D.; Zhou, W.; Berger, T.; Fortin, J.; Chan, S. M.; Chiang, M. F.; Inoue, S.; Li, W. Y.; Chu, M. F.; Duncan, G. S.; Wakeham, A.; Lemonnier, F.; Tobin, C.; Mcwilliam, R.; Colonna, I.; Bontoux, C.; Jafari, S. M.; Bowman, R. L.; Nicolay, B.; Ronseaux, S.; Narayanaswamy, R.; Levine, R. L.; Melnick, A. M.; Mason, C. E.; Minden, M. D.; Mak, T. W. |
| Article Title: | Mutant IDH1 cooperates with NPM1c or FLT3(ITD) to drive distinct myeloid diseases and molecular outcomes |
| Abstract: | In human acute myeloid leukemia (AML), mutations of isocitrate dehydrogenase-1 (IDH1) often co-occur with NPM1 mutations, and less frequently with FLT3 mutations. To investigate whether the effects of IDH1 mutation differ according to the specific co-occurring mutation, we generated two strains of double knock-in mutant mice. Idh1R132H combined with Npm1c induced overt AML, whereas Idh1R132H plus Flt3ITD resulted in Flt3ITD-driven myelo- or lymphoproliferation that was minimally affected by Idh1R132H and rarely generated AML. Gene expression profiling revealed differences between Idh1R132H;Npm1c cells and Idh1R132H;Flt3ITD cells and suggested altered heme metabolism and immune responses in the former. The profile of Idh1R132H;Npm1c cells corresponded to that of human IDH-mutated AML cells, particularly those resistant to inhibitors of mutant IDH. Compared to treatment with a menin inhibitor, IDH1-targeted therapy of Idh1R132H;Npm1c AML-bearing mice was less efficacious in improving cell differentiation and extending survival. The differential cooperation of Idh1R132H with Npm1c vs. Flt3ITD may have implications for the devising of subtype-specific treatments for human AML. © 2025 the Author(s). |
| Keywords: | genetics; mutation; leukemia, myeloid, acute; mouse; animal; metabolism; animals; mice; nuclear protein; pathology; nuclear proteins; gene knock-in techniques; isocitrate dehydrogenase; idh1; cd135 antigen; nucleophosmin; acute myeloid leukemia; fms-like tyrosine kinase 3; flt3; idh1 protein, human; humans; human; flt3 protein, human; gene knock-in; npm1; npm1 protein, human; flt3 protein, mouse; npm1 protein, mouse; preclinical mouse model; idh1 protein, mouse |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 122 |
| Issue: | 20 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2025-05-20 |
| Start Page: | e2415779122 |
| Language: | English |
| DOI: | 10.1073/pnas.2415779122 |
| PUBMED: | 40377995 |
| PROVIDER: | scopus |
| PMCID: | PMC12107087 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- Source: Scopus |
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