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TEN-ELEVEN-TRANSLOCATION-2(TET2) and DNA-METHYLTRANSFERASE-3A(DNMT3A), both encoding proteins involved in regulating DNA methylation, are mutated in hematological malignancies affecting both myeloid and lymphoid lineages. We previously reported an association of TET2and DNMT3Amutations in progenitors of patients with angioimmunoblastic T-cell lymphomas (AITL). Here, we report on the cooperative effect of Tet2inactivation and DNMT3Amutation affecting arginine 882 (DNMT3AR882H) using a murine bone marrow transplantation assay. Five out of eighteen primary recipients developed hematological malignancies with one mouse developing an AITL-like disease, two mice presenting acute myeloid leukemia (AML)-like and two others T-cell acute lymphoblastic leukemia (T-ALL)-like diseases within 6 months following transplantation. Serial transplantations of DNMT3AR882HTet2-/-progenitors led to a differentiation bias toward the T-cell compartment, eventually leading to AITL-like disease in 9/12 serially transplanted recipients. Expression profiling suggested that DNMT3AR882HTet2-/-T-ALLs resemble those of NOTCH1mutant. Methylation analysis of DNMT3AR882HTet2-/-T-ALLs showed a global increase in DNA methylation affecting tumor suppressor genes and local hypomethylation affecting genes involved in the Notch pathway. Our data confirm the transformation potential of DNMT3AR882HTet2-/-progenitors and represent the first cooperative model in mice involving Tet2inactivation driving lymphoid malignancies.