Mixed phenotype acute leukemia (MPAL) is a heterogeneous group of poor-prognosis leukemias with immunophenotypic features of at least two cell lineages. The full spectrum of genetic mutations in this rare disease has not been elucidated, limiting our understanding of disease pathogenesis and our ability to devise targeted therapeutic strategies. We sought to define the mutational landscape of MPAL by performing whole exome sequencing on samples from 23 adult and pediatric MPAL patients. We identified frequent mutations of epigenetic modifiers, most notably mutations of DNMT3A in 33% of adult MPAL patients. Mutations of activated signaling pathways, tumor suppressors and transcription factors were also frequent. Importantly, many of the identified mutations are potentially therapeutically targetable with agents currently available or in various stages of clinical development. Therefore, the mutational spectrum we identified provides potential biological insights and is likely to have clinical relevance for patients with this poor-prognosis disease.

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.

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