Tet2 is a tumor suppressor in the pre-leukemic phase of T-cell acute lymphoblastic leukemia

• the tumor suppressor role of Tet2 is context dependent in the development of T-ALL

• Tet2 loss of expression is observed during the malignant transformation towards T-ALL

TET2-mediated DNA demethylation plays a pivotal role in regulating pre-leukemic clonal expansion in acute myeloid leukemia (AML), where TET2 mutations are also linked to AML progression. However, its function in other types of leukemias, including T-cell acute lymphoblastic leukemia (T-ALL), remains unclear. Here, we used two different T-ALL mouse models to study the possible tumor suppressor role of Tet2 in pre-leukemic T-ALL. Overexpression of Tet2 resulted in a mild but significant increase in T-ALL latency in the immature CD2-Lmo2tg T-ALL mouse model, but no effect on survival was observed in the mature Lck-Cretg/+ Ptenfl/lf T-ALL mouse model. In contrast to the pre-leukemic thymocytes from CD2-Lmo2tg mice, Lck-Cretg/+ Ptenfl/fl thymi do not display self-renewal suggesting that the anti-leukemic effect of Tet2 occurs mainly in the pre-leukemic phase of T-ALL. In conclusion, we demonstrated that the Tet2 tumor suppressor function is dependent on the differentiation stage of T-ALL and limited to the pre-leukemic phase.