Mutant IDH1 cooperates with NPM1c or FLT3ITD to drive distinct myeloid diseases and molecular outcomes

• 成果类型: Article
• 署名作者: 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, Francois; 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.
• 署名单位: University of Toronto; University Health Network Toronto; Princess Margaret Cancer Centre; Kyoto University; Universite Claude Bernard Lyon 1; UNICANCER; Centre Leon Berard; Institut National de la Sante et de la Recherche Medicale (Inserm); Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; McGill University; National Cancer Center - Japan; Universite Paris-Est-Creteil-Val-de-Marne (UPEC); Institut National de la Sante et de la Recherche Medicale (Inserm); Universite de Toulouse; Universite Toulouse III - Paul Sabatier; CHU de Toulouse; Institut National de la Sante et de la Recherche Medicale (Inserm); Memorial Sloan Kettering Cancer Center; Agios Pharmaceuticals; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; University of Hong Kong
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15024
• DOI: 10.1073/pnas.2415779122
• 发表日期: 2025-05-20
• 关键词: isocitrate dehydrogenase mutations; prognostic relevance; mouse model; stem-cell; leukemia; idh2; nucleophosmin; CLASSIFICATION; progenitors; progression

摘要

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;Npm1cAML-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.