TET2 is one of the most frequently mutated genes identified in patients with myelodysplastic syndromes (MDS). This study will help explore new avenues for the cure TET2 mutations, and Dr. Mukherji says he and his colleagues “will use our expertise to develop strategies to restore TET2 activity for the treatment of MDS.”
MDS develops due to genomic and epigenetic changes involving oncogenes and tumor suppressor genes. Unlike irreversible genomic damage, epigenetic changes are reversible with targeted therapy. Dr. Mukherji’s research is focusing on TET2, which is one of the most frequently mutated genes identified in patients with myelodysplastic syndromes (MDS). Results from recent studies have established that mutation in the TET2 tumor suppressor gene is one of the fundamental causes of MDS, as well as related myeloid malignancies (MDS-MPN and sAML). The protein product of the normal TET2 genes initiates the demethylation of 5-methylcytosine residues in the DNA, predominantly present in the regulatory regions of genes. In patients with TET2 mutations, progressive cytosine methylations in these regulatory regions cause epigenetic silencing of genes. This ultimately leads to the development of MDS, as well as related myeloid malignancies.
During the first year of the grant, he and his colleagues have made significant progress in developing a library of clinical samples which can be used to observe and rescue the activity of some TET2 clinical mutations. The second year of the study will focus on the potential of this research for targeting therapies for MDS based on these mutations.