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

TitleIdh1 mutations contribute to the development of T-cell malignancies in genetically engineered mice
Authors
KeywordsT-ALL
Isocitrate dehydrogenase
P53
Lymphoma
Issue Date2016
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2016, v. 113, n. 5, p. 1387-1392 How to Cite?
AbstractGain-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.
Persistent Identifierhttp://hdl.handle.net/10722/292932
ISSN
2020 Impact Factor: 11.205
2020 SCImago Journal Rankings: 5.011
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorHao, Zhenyue-
dc.contributor.authorCairns, Rob A.-
dc.contributor.authorInoue, Satoshi-
dc.contributor.authorLi, Wanda Y.-
dc.contributor.authorSheng, Yi-
dc.contributor.authorLemonnier, François-
dc.contributor.authorWakeham, Andrew-
dc.contributor.authorSnow, Bryan E.-
dc.contributor.authorDominguez-Brauer, Carmen-
dc.contributor.authorYe, Jing-
dc.contributor.authorLarsen, Dana M.-
dc.contributor.authorStraley, Kimberly S.-
dc.contributor.authorTobin, Erica R.-
dc.contributor.authorNarayanaswamy, Rohini-
dc.contributor.authorGaulard, Philippe-
dc.contributor.authorMak, Tak W.-
dc.date.accessioned2020-11-17T14:57:31Z-
dc.date.available2020-11-17T14:57:31Z-
dc.date.issued2016-
dc.identifier.citationProceedings of the National Academy of Sciences of the United States of America, 2016, v. 113, n. 5, p. 1387-1392-
dc.identifier.issn0027-8424-
dc.identifier.urihttp://hdl.handle.net/10722/292932-
dc.description.abstractGain-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.-
dc.languageeng-
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of America-
dc.subjectT-ALL-
dc.subjectIsocitrate dehydrogenase-
dc.subjectP53-
dc.subjectLymphoma-
dc.titleIdh1 mutations contribute to the development of T-cell malignancies in genetically engineered mice-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1073/pnas.1525354113-
dc.identifier.pmid26787889-
dc.identifier.pmcidPMC4747700-
dc.identifier.scopuseid_2-s2.0-84956617340-
dc.identifier.volume113-
dc.identifier.issue5-
dc.identifier.spage1387-
dc.identifier.epage1392-
dc.identifier.eissn1091-6490-
dc.identifier.isiWOS:000369085100078-
dc.identifier.issnl0027-8424-

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