Proceedings of the National Academy of Sciences of the United States of America · 2025
Mutant IDH1 cooperates with NPM1c or FLT3ITD to drive distinct myeloid diseases and molecular outcomes.
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Sakamoto Takashi, Leca Julie, Zhang Xin, Meydan Cem, Foox Jonathan, Ramachandran Parameswaran, Hendrikse Liam D, Zhou Wenjing, Berger Thorsten, Fortin Jerome, Chan Steven M, Chiang Ming-Feng, Inoue Satoshi, Li Wanda Y, Chu Mandy F, Duncan Gordon S, Wakeham Andrew, Lemonnier François, Tobin Chantal, Mcwilliam Ryan, Colonna Isabelle, Bontoux Christophe, Jafari Soode Moghadas, Bowman Robert L, Nicolay Brandon, Ronseaux Sebastien, Narayanaswamy Rohini, Levine Ross L, Melnick Ari M, Mason Christopher E, Minden Mark D, Mak Tak W
Аннотация
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.