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

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.

Engagement in Free Open Access Medical Education by US Nephrology Fellows.

BACKGROUND: As free open access medical education (FOAMed) use increases, it is important to characterize how and why learners are using this educational material in nephrology. We describe the frequency, purpose, and type of FOAMed usage across US nephrology fellows. METHODS: In this cross-sectional survey, items were emailed to all US adult and pediatric nephrology fellows via the American Society of Nephrology (ASN) Fellow Survey in May 2022. The eight-item survey, developed to measure FOAMed engagement, had previously undergone instrument validation. The results were analyzed by descriptive statistics. RESULTS: In total, 43% (359/842) adult nephrology fellows and 51% (45/88) pediatric nephrology fellows completed the survey. Seventy-four percent (300/404) of fellows reported using FOAMed, and 72% (215/300) started using FOAMed within the past 2 years. Of FOAMed users, 41% (122/300) reported viewing FOAMed and 33% (99/300) reported applying knowledge gained from these resources daily or weekly. Common purposes for FOAMed engagement included searching Twitter to learn about others' opinions in the field (43%; 130/300), reading blogs to answer clinical questions (35%; 105/300), and listening to podcasts for the most up-to-date information (39%; 116/300). Compared with traditional educational resources, fellows preferred using FOAMed for staying up to date on nephrology topics (75%) and answering clinical questions (37%). Among all fellows, the greatest barriers to FOAMed use were unfamiliarity with FOAMed (27%; 111/404), validity concerns (22%; 90/404), and a lack of a local community of FOAMed users (22%; 87/404). CONCLUSIONS: Seventy-four percent of nephrology fellows used FOAMed resources in a variety of ways, and of them, 33% of fellows clinically applied knowledge gained from these resources. Reasons for engaging with FOAMed varied across resources.

Mutant IDH1 Downregulates ATM and Alters DNA Repair and Sensitivity to DNA Damage Independent of TET2.

Mutations in the isocitrate dehydrogenase-1 gene (IDH1) are common drivers of acute myeloid leukemia (AML) but their mechanism is not fully understood. It is thought that IDH1 mutants act by inhibiting TET2 to alter DNA methylation, but there are significant unexplained clinical differences between IDH1- and TET2-mutant diseases. We have discovered that mice expressing endogenous mutant IDH1 have reduced numbers of hematopoietic stem cells (HSCs), in contrast to Tet2 knockout (TET2-KO) mice. Mutant IDH1 downregulates the DNA damage (DD) sensor ATM by altering histone methylation, leading to impaired DNA repair, increased sensitivity to DD, and reduced HSC self-renewal, independent of TET2. ATM expression is also decreased in human IDH1-mutated AML. These findings may have implications for treatment of IDH-mutant leukemia.