Role of TET dioxygenases in the regulation of both normal and pathological hematopoiesis

The family of ten-eleven translocation dioxygenases (TETs) consists of TET1, TET2, and TET3. Although all TETs are expressed in hematopoietic tissues, only TET2 is commonly found to be mutated in age-related clonal hematopoiesis and hematopoietic malignancies. TET2 mutation causes abnormal epigenetic landscape changes and results in multiple stages of lineage commitment/differentiation defects as well as genetic instability in hematopoietic stem/progenitor cells (HSPCs). TET2 mutations are founder mutations (first hits) in approximately 40-50% of cases of TET2-mutant (TET2(MT)) hematopoietic malignancies and are later hits in the remaining cases. In both situations, TET2(MT) collaborates with co-occurring mutations to promote malignant transformation. In TET2(MT) tumor cells, TET1 and TET3 partially compensate for TET2 activity and contribute to the pathogenesis of TET2(MT) hematopoietic malignancies. Here we summarize the most recent research on TETs in regulating of both normal and pathogenic hematopoiesis. We review the concomitant mutations and aberrant signals in TET2(MT) malignancies. We also discuss the molecular mechanisms by which concomitant mutations and aberrant signals determine lineage commitment in HSPCs and the identity of hematopoietic malignancies. Finally, we discuss potential strategies to treat TET2(MT) hematopoietic malignancies, including reverting the methylation state of TET2 target genes and targeting the concomitant mutations and aberrant signals.