Significance of TET2 mutations in myeloid and lymphoid neoplasms

The TET2 gene is an epigenetic regulator. Loss-of-function mutations of TET2 are found in a variety of blood cancers in both myeloid and lymphoid lineages. Meanwhile, clonal blood cells carrying leukemia-driver mutations have been detected in significant proportions of different cohorts without blood cancers. Amongst these driver mutations, those in the TET2 gene are second/third most frequent. The presence of such clonal blood cells predicts elevated risk for developing various blood cancers. These results indicate that acquisition of TET2 mutations in blood cells does not per se cause cancers; however, TET2 mutations are likely to be acquired at the common myeloid/lymphoid progenitor levels. Such hematopoietic stem/progenitor cells may wait for second hit mutations for the development of multiple blood cancers, and play a role as pre-leukemia/pre-lymphoma cells. Combinations of TET2 and disease-specific gene mutations have been demonstrated in individual blood cancers. Correspondingly, mice into which such combinatorial gene abnormalities have been introduced will recapitulate the respective blood cancers.