The Ten-Eleven Translocation (TET) proteins (TET1-3) are iron and Î±-ketoglutarate-dependent (Fe2+/Î±-KGDDs) enzymes that oxidize methylated cytosines in the genome, a key intermediate step in the process of DNA demethylation and transcriptional regulation. TET2 loss-of-function mutations are a driving event in hematopoietic malignancies, occurring in up to 30% of patients with myeloid malignancies and clonal hematopoiesis, a pre-malignant state seen in approximately 10% of healthy elderly individuals that increases their risk of progression to acute myeloid leukemia (AML). The ability to restore and maintain the function of epigenetic regulators, such as the TET family of dioxygenases, and other Fe2+/Î±-KGDDs, by altering the micronutrient environment, represents a novel therapeutic strategy to prevent and treat diseases of the hematopoietic system.
Using genetic models of reversible TET2 deficiency she has shown that restoring TET2 function can block aberrant hematopoietic stem cell self-renewal and leukemia progression. Enhancing TET function to block disease progression provides an attractive strategy for pharmacologic intervention. Vitamin C is an essential dietary requirement for humans and acts as a cofactor of TET enzymes by maintaining iron in the ferrous state. High-dose vitamin C treatment can mimic Tet2 restoration by increasing the activity of residual TET proteins in Tet2-deficient mouse models and human AML cells (Cimmino et al., Cell 2017). Targeted activation of TET2 function using high-dose vitamin C treatment could, therefore, provide a safe and effective strategy to treat patients with TET2 mutations.
Ongoing studies in the lab include using reversible Tet2- knockdown transgenic mice and vitamin C treatment to monitor the molecular kinetics of clonal hematopoiesis and progression of hematopoietic malignancy. They are also performing screens for novel small molecules that can mimic vitamin C to activate TET function with potentially increased activity and bioavailability, discover compounds or druggable targets that can partner with vitamin C to enhance TET activity in hematopoietic stem cells (HSCs) and leukemia cells and probe for resistance mechanisms that may render cells able to bypass the effects of vitamin C treatment.
Genetic mouse models of iron deficiency and anemia can also be used to investigate the role of iron metabolism in HSC homeostasis. These studies will determine how cofactors modulate TET enzymatic activity to drive or maintain clonal hematopoiesis and to what extent prolonged or intermittent periods of micronutrient deficiency, over time, can lead to reversible or permanent epigenetic or genetic changes that contribute to disease initiation and progression. Given that TET2 mutation is an early driver of disease initiation and progression, our goal is to determine how a deficiency in TET2 and/or the micronutrient co-factors can affect epigenetic heterogeneity upon aging, and in pre-malignant and malignant HSCs.