Dr. Bernard’s group has long been involved in the structural and functional analyses of oncogenic events in human malignancies. They have recently identified the Ten-Eleven-Translocation (TET)2 as inactivated in myeloid malignancies. TET2 is able to hydroxylate methylated cytosine (mC) into hydroxymethyl cytosine (hmC), which is a step toward DNA demethylation. Together with DNMT3A and IDH mutations, these observations called attention to the importance of DNA methylation in the control of hematopoiesis and its deregulation in malignant processes.
Further analyses showed that TET2 inactivation is also observed in mature lymphoid malignancies, including B-cell and T-cell lymphomas. Up to 25% of angio-immunoblastic T-cell lymphoma (AITL) carry TET2 mutations. DNMT3A mutations are strongly associated with TET2 mutation in these diseases. In addition, mutations of both genes may be observed either in non-T-lymphoid cells and/or before diagnosis, indicating that they are present in multipotent progenitors before the clinical onset of the disease. This indicate that, similar to both chronic and acute human adult myeloid malignancies, mature lymphoid neoplasm may develop from clinical silent mutated hematopoietic progenitors.
Through its catalytic activity, TET2 participates in the transcriptional regulation of hematopoiesis. Indeed mouse models of Tet2 inactivation showed that the loss of Tet2 activity endows the cells with competitive advantage with respect to wild type cells and induce widespread abnormalities of hematopoietic differentiation. At advanced ages, mice develop either myeloid or lymphoid malignancies. Analyses are still on going to understand how Tet-deficiency perturbs hematopoiesis and cooperates with other oncogenic hits for full-blown malignancies.