Idh1 mutations contribute to the development of T-cell malignancies in genetically engineered mice

Proceedings of the National Academy of Sciences of the United States of America
Zhenyue HaoTak W Mak

Abstract

Gain-of-function mutations in isocitrate dehydrogenase 1 (IDH1) are key drivers of hematopoietic malignancies. Although these mutations are most commonly associated with myeloid diseases, they also occur in malignancies of the T-cell lineage. To investigate their role in these diseases and provide tractable disease models for further investigation, we analyzed the T-cell compartment in a conditional knock-in (KI) mouse model of mutant Idh1. We observed the development of a spontaneous T-cell acute lymphoblastic leukemia (T-ALL) in these animals. The disease was transplantable and maintained expression of mutant IDH1. Whole-exome sequencing revealed the presence of a spontaneous activating mutation in Notch1, one of the most common mutations in human T-ALL, suggesting Idh1 mutations may have the capacity to cooperate with Notch1 to drive T-ALL. To further investigate the Idh1 mutation as an oncogenic driver in the T-cell lineage, we crossed Idh1-KI mice with conditional Trp53 null mice, a well-characterized model of T-cell malignancy, and found that T-cell lymphomagenesis was accelerated in mice bearing both mutations. Because both IDH1 and p53 are known to affect cellular metabolism, we compared the requirements for glucose and...Continue Reading

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Citations

Apr 20, 2017·The EMBO Journal·Ji ZhangCraig B Thompson
Jan 7, 2017·Cold Spring Harbor Symposia on Quantitative Biology·Thorsten BergerTak W Mak
Dec 14, 2016·Proceedings of the National Academy of Sciences of the United States of America·François LemonnierTak W Mak
May 5, 2021·Journal of Hematology & Oncology·Mathieu SimoninVahid Asnafi

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