Phylogenetic Analysis of TET2 Gene Variants in Pakistani Acute Myeloid Leukemia Patients

Abstract Background Acute myeloid leukemia (AML) is a heterogeneous malignancy caused by the proliferation of neoplastic myeloid progenitor cells. Mutations in ten-eleven translocation methylcytosine dioxygenase 2 (TET2), a key regulator of DNA demethylation, are common in AML and play a role in its progression and response to treatment. Methods We performed a phylogenetic analysis of 25 TET2 gene sequences (12 AML and 13 normal) from Pakistani individuals using multiple sequence alignment, phylogenetic tree construction, and distance matrix evaluation. We also identified population-specific expression patterns and mutational hotspots. Results AML samples showed significant deletions in the catalytic domain (positions 693– 876) and lower sequence conservation compared to controls. These deletions may impair TET2 enzymatic activity and disrupt the epigenetic regulation. The Phylogenetic tree also showed two significant clades supported by high bootstrap values, differentiating AML from control individuals in the evolutionary direction. Conclusion Our findings reveal distinct TET2 mutational hotspots associated with acute myeloid leukemia (AML) in the Pakistani population. These results have implications for targeted epigenetic therapy and motivate large-scale, cross-population research to unravel the global effects of TET2 variations.