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

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 glutamine in cells derived from these tumors and found that cells bearing the Idh1 mutation have an increased dependence on both glucose and glutamine. These data suggest that mutant IDH1 contributes to malignancy in the T-cell lineage and may alter the metabolic profile of malignant T cells.

SUBMITTER: Hao Z

PROVIDER: S-EPMC4747700 | biostudies-other | 2016 Feb

REPOSITORIES: biostudies-other

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

Hao Zhenyue Z Cairns Rob A RA Inoue Satoshi S Li Wanda Y WY Sheng Yi Y Lemonnier François F Wakeham Andrew A Snow Bryan E BE Dominguez-Brauer Carmen C Ye Jing J Larsen Dana M DM Straley Kimberly S KS Tobin Erica R ER Narayanaswamy Rohini R Gaulard Philippe P Mak Tak W TW

Proceedings of the National Academy of Sciences of the United States of America 20160119 5

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 acu ...[more]

PMID: 26787889

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Project description:Background Maffucci’s syndrome is characterized by the coexistence of multiple enchondromas and soft-tissue hemangiomas. It has been clear that somatic mosaic isocitrate dehydrogenase type 1 (IDH1) or isocitrate dehydrogenase type 2 (IDH2) mutations are associated with Maffucci’s syndrome and Ollier disease, but the mechanisms underlying hemangiomas of the Maffucci’s syndrome is still obscure. This study aimed to determine the mechanism of hemangiomas in Maffucci’s syndrome. Methods We received a 26-year-old female patient with typical Maffucci’s syndrome, and exome sequencing was conducted using DNA from her peripheral blood and enchondroma tissues. Somatic mutations were characterized by a comparative analysis of exome sequences and further confirmed by the sequencing of PCR products derived from original blood and tissue samples. The mutations of an additional 69 patients with Ollier disease were further tested. The functional impacts of these somatic mutations on Maffucci’s syndrome, especially the development of hemangiomas, were evaluated. Results We reported a typical case of Maffucci’s syndrome, which was confirmed by both imaging findings and pathology. Through exome sequencing of this patient’s DNA samples, we identified an R132C mutation in the isocitrate dehydrogenase type 1 (IDH1) gene and an L309I mutation in the ELKS/RAB6-interacting/CAST family member 2 (ERC2) gene in this patient. Approximately 33.3% of the clones were positive for the IDH1 R132C mutation, and 19.0% of the clones were positive for the ECR2 L309I mutation. The IDH1 R132C mutation was detected in most of the patients with Ollier disease (51/69 patients), and the mean frequency of this mutation was 63.3% in total sequence readouts, but the ECR2 L309I mutation was absent in all of the patients with Ollier disease. In vitro experiments confirmed that the IDH1 R132C mutation promotes chondrocyte proliferation, and the ERC2 L309I mutation enhances angiogenesis. Conclusions Our results suggest that while IDH1 is a known pathogenic gene in enchondromatosis, ERC2 is a novel gene identified in Maffucci’s syndrome. The somatic L309I mutation of ERC2 contributes to the pathogenesis of hypervascularization to facilitate the development of hemangiomas in Maffucci’s syndrome. The combination of the IDH1 R132C and ERC2 L309I mutations contributes to the development of Maffucci’s syndrome, and these results may enable further research on the pathogenesis of Maffucci’s syndrome.

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

Publications

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

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