The Intlekofer lab investigates how the L- and D- enantiomers of the metabolite 2-hydroxyglutarate (2HG) regulate the differentiation and function of normal stem cells, immune cells, and cancer cells. Our prior work demonstrated that controlled physiologic production of L-2HG plays a key role in maintaining the ‘stemness’ of cells residing in hypoxic niches. In contrast, uncontrolled production of D-2HG by isocitrate dehydrogenase (IDH) mutations excessively drives the ‘stemness’ program and leads to development of cancer. We employ cutting-edge metabolic assays, novel genetically engineered mouse models, and patient biospecimens to investigate the mechanisms by which 2HG enantiomers influence chromatin marks, gene expression, and cell differentiation. We seek to manipulate the metabolism of L- and D-2HG as a strategy to improve stem cell function, boost immune responses, or inhibit cancer cell growth. Major areas of investigation in the lab include:
Define how L-2HG couples microenvironmental cues to a chromatin landscape that maintains the undifferentiated state of normal stem cells, immune cells, and cancer cells.
Elucidate the mechanisms through which IDH mutations and D-2HG drive hematopoietic oncogenesis and determine whether mutant IDH represents a viable therapeutic target in these diseases.