Abstract
BACKGROUND: Acute myeloid leukemia with erythroid and megakaryocytic differentiation (AML-EMD) is a rare and aggressive presentation of AML characterized by overlapping morphologic, immunophenotypic, and genetic features of erythroid and megakaryocytic lineages. The classification, pathogenesis, and clinical behavior of this entity remain poorly defined. METHODS: We report a series of three patients in conjunction with a systematic review of reported cases in published literature with AML-EMD. RESULTS: Cytogenetic and molecular studies revealed frequent abnormalities including complex karyotypes, TP53 mutations, and JAK1/2 mutations. Clinically, patients demonstrated a poor-risk profile. CONCLUSIONS: Collective phenotypic and genetic features suggest that AML-EMD represents a high-risk subgroup of either TP53-mutated AML or AML with myelodysplasia-related genetics, likely reflecting leukemic transformation from multipotent progenitors retaining erythro-megakaryocytic potential. Despite shared biologic features, current classification systems for AML-EMD are diagnostically incongruent. Recognition of this entity will allow for consistent subclassification, prognostication, and future studies aimed at defining its molecular underpinnings and therapeutic vulnerabilities.