Key Points Dnmt3a ablation in HSCs predisposes mice to develop a spectrum of myeloid and lymphoid malignancies. Dnmt3a-KO-derived myeloid malignancies and T-cell acute lymphocytic leukemia/lymphoma show distinct methylation aberrations.

SUMMARY DNMT3A, the gene encoding the de novo DNA methyltransferase 3A, is among the most frequently mutated genes in hematologic malignancies. However, the mechanisms through which DNMT3A normally suppresses malignancy development are unknown. Here, we show that DNMT3A loss synergizes with the FLT3 internal tandem duplication (ITD) in a dose-influenced fashion to generate rapid lethal lymphoid or myeloid leukemias similar to their human counterparts. Loss of DNMT3A leads to reduced DNA methylation, predominantly at hematopoietic enhancer regions in both mouse and human samples. Myeloid and lymphoid diseases arise from transformed murine hematopoietic stem cells. Broadly, our findings support a role for DNMT3A as a guardian of the epigenetic state at enhancer regions, critical for inhibition of leukemic transformation.

Background Systemic forms of EBV‐associated T‐cell lymphoproliferative disorders of childhood (S‐EBV‐T‐LPD) comprise three major forms: EBV‐positive hemophagocytic lymphohistiocytosis (EBV‐HLH), systemic EBV‐positive T‐cell lymphoma (S‐EBV‐TCL), and systemic chronic active EBV infection (S‐CAEBV). These disorders occur rarely in children in Western countries. Here, we described eight children of such entities. Design Eight cases (six clinical and two autopsy) with S‐EBV‐T‐LPD of childhood were retrospectively identified from 1990 to 2015. Clinicopathologic parameters including histomorphology, immunophenotype, EBV studies, and T‐cell receptor gene rearrangement studies were recorded. Results Patients include five females and three males of Hispanic, Asian, and Caucasian origins with an age range of 14 months to 9 years. Fever, hepatosplenomegaly, cytopenias, abnormal EBV serologies, and very high EBV viral loads were common findings. Histologic findings showed EBV+ T‐cell infiltrates with variable degrees of architectural distortion and cytologic atypia ranging from no to mild cytologic atypia to overt lymphoma and tissue hemophagocytosis. All showed aberrant CD4+ or CD8+ T cells with dim to absent CD5, CD7, and CD3, and bright CD2 and CD45 by flow cytometry or loss of CD5 by immunohistochemistry. TCR gene rearrangement studies showed monoclonal rearrangements in all clinical cases (6/6). Outcomes were poor with treatment consisting of chemotherapy per the HLH‐94 or HLH‐2004 protocols with or without bone marrow transplant. Conclusion In this large pediatric clinicopathologic study of S‐EBV‐T‐LPD of childhood in the United States, EBV‐HLH, S‐EBV‐TCL, and S‐CAEBV show many overlapping features. Diagnosis is challenging, and overall outcome is poor using current HLH‐directed therapies.