Mutant IDH1 cooperates with NPM1c or FLT3^ITD to drive distinct myeloid diseases and molecular outcomes

Takashi Sakamoto^#^{1

2}, Julie Leca^#^{1

3}, Xin Zhang^#¹, Cem Meydan^#^{4

5

6

7}, Jonathan Foox^#^{4

5}, Parameswaran Ramachandran¹, Liam D Hendrikse¹, Wenjing Zhou¹, Thorsten Berger¹, Jerome Fortin^{1

8}, Steven M Chan¹, Ming-Feng Chiang¹, Satoshi Inoue^{1

9}, Wanda Y Li^{1

10}, Mandy F Chu¹, Gordon S Duncan¹, Andrew Wakeham¹, François Lemonnier^{1

11}, Chantal Tobin¹, Ryan Mcwilliam¹, Isabelle Colonna¹, Christophe Bontoux^{1

12}, Soode Moghadas Jafari¹, Robert L Bowman¹³, Brandon Nicolay¹⁴, Sebastien Ronseaux¹⁴, Rohini Narayanaswamy¹⁴, Ross L Levine^{13

15

16}, Ari M Melnick⁷, Christopher E Mason^{4

5

6}, Mark D Minden¹, Tak W Mak^{1

10

17}

Affiliations

¹ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada.
² Department of Hematology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
³ BMP, Ecosystem, stemness and dynamic in cancer Laboratory, Centre de Recherche en Cancerologie de Lyon, UMR INSERM 1052 CNRS 5286, Centre Léon Bérard, Université Claude Bernard Lyon 1, Lyon 69008, France.
⁴ Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065.
⁵ The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065.
⁶ WorldQuant Initiative for Quantitative Prediction, Weill Cornell Medicine, New York, NY 10065.
⁷ Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY 10021.
⁸ Department of Neurology and Neurosurgery, McGill University, Montréal, QC H3A 1A1, Canada.
⁹ Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
¹⁰ Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China.
¹¹ Institut Mondor de Recherche Biomédicale, INSERM U955, Université Paris Est Créteil, Créteil 94010, France.
¹² Department of Pathology, Cancer University Institute of Toulouse-Oncopole, University Hospital of Toulouse, INSERM U1037, Cancer Research Center in Toulouse, Toulouse 31059, France.
¹³ Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
¹⁴ Agios Pharmaceuticals, Cambridge, MA 02139.
¹⁵ Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
¹⁶ Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
¹⁷ Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.

^# Contributed equally.

PMID: 40377995
PMCID: PMC12107087 (available on 2025-11-16)
DOI: 10.1073/pnas.2415779122

Mutant IDH1 cooperates with NPM1c or FLT3^ITD to drive distinct myeloid diseases and molecular outcomes

Takashi Sakamoto et al. Proc Natl Acad Sci U S A. 2025.

. 2025 May 20;122(20):e2415779122.

doi: 10.1073/pnas.2415779122. Epub 2025 May 16.

Authors

Affiliations

¹ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada.
² Department of Hematology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
³ BMP, Ecosystem, stemness and dynamic in cancer Laboratory, Centre de Recherche en Cancerologie de Lyon, UMR INSERM 1052 CNRS 5286, Centre Léon Bérard, Université Claude Bernard Lyon 1, Lyon 69008, France.
⁴ Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065.
⁵ The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065.
⁶ WorldQuant Initiative for Quantitative Prediction, Weill Cornell Medicine, New York, NY 10065.
⁷ Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY 10021.
⁸ Department of Neurology and Neurosurgery, McGill University, Montréal, QC H3A 1A1, Canada.
⁹ Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
¹⁰ Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China.
¹¹ Institut Mondor de Recherche Biomédicale, INSERM U955, Université Paris Est Créteil, Créteil 94010, France.
¹² Department of Pathology, Cancer University Institute of Toulouse-Oncopole, University Hospital of Toulouse, INSERM U1037, Cancer Research Center in Toulouse, Toulouse 31059, France.
¹³ Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
¹⁴ Agios Pharmaceuticals, Cambridge, MA 02139.
¹⁵ Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
¹⁶ Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
¹⁷ Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.

^# Contributed equally.

PMID: 40377995
PMCID: PMC12107087 (available on 2025-11-16)
DOI: 10.1073/pnas.2415779122

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. Idh1^R132H combined with Npm1c induced overt AML, whereas Idh1^R132H plus Flt3^ITD resulted in Flt3^ITD-driven myelo- or lymphoproliferation that was minimally affected by Idh1^R132H and rarely generated AML. Gene expression profiling revealed differences between Idh1^R132H;Npm1c cells and Idh1^R132H;Flt3^ITD cells and suggested altered heme metabolism and immune responses in the former. The profile of Idh1^R132H;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 Idh1^R132H;Npm1c AML-bearing mice was less efficacious in improving cell differentiation and extending survival. The differential cooperation of Idh1^R132H with Npm1c vs. Flt3^ITD may have implications for the devising of subtype-specific treatments for human AML.

Keywords: FLT3; IDH1; NPM1; acute myeloid leukemia; preclinical mouse model.

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Conflict of interest statement

Competing interests statement:R.L.L. is on the supervisory board of Qiagen and is a scientific advisor to Imago, Mission Bio, Syndax, Zentalis, Ajax, Bakx, Auron, Prelude, C4 Therapeutics and Isoplexis, for which he receives equity support. R.L.L. has consulted for Incyte, Janssen, Morphosys and Novartis. C.E.M. is a consultant at Tempus Labs and Co-Founder of Onegevity Health. T.W.M. is a consultant for AstraZeneca and Tessa Therapeutics. R.L.L. is on the supervisory board of Qiagen and is a scientific advisor to Imago, Mission Bio, Syndax, Zentalis, Ajax, Bakx, Auron, Prelude, C4 Therapeutics and Isoplexis, for which he receives equity support. T.W.M. owns equity in Treadwell Therapeutics Inc. and Agios Pharmaceuticals. R.L.L. has received honoraria from Astra Zeneca and Kura for invited lectures and from Gilead for grant reviews.

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Mutant IDH1 cooperates with NPM1c or FLT3^ITD to drive distinct myeloid diseases and molecular outcomes

Affiliations

Mutant IDH1 cooperates with NPM1c or FLT3^ITD to drive distinct myeloid diseases and molecular outcomes

Authors

Affiliations

Abstract

Conflict of interest statement

References

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Grants and funding

LinkOut - more resources

Full Text Sources

Medical

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