<![CDATA[Introduction: Non-Down syndrome acute megakaryocytic leukemia (Non-DS-AMKL) is a rare leukemia. Pediatric acute myeloid leukemia (AML) accounts for only 4—15% of all leukemia cases, while AMKL accounts for only 3-10% of pediatric AML. Most AMKLs are Down syndrome (DS) (> 75%). Diagnostic criteria require a minimum of 20 % blasts in the bone marrow, of the megakaryocytic lineage, in a person without Down syndrome. Flow cytometry in blast cells must reveal expressions of one or more platelet markers (CD41a, CD42b, or CD61). Genetic test differentiates treatment and prognosis. This is the first AMKL report in Indonesia that approaches comprehensive genetic testing. Case Presentation: The patient was a 26-month-old boy who had bruises over his tummy, arm, and legs. He was anemic, having splenomegaly with Schuffner 2, hemoglobin level 9.1 g/dL, leucocyte 7,200/uL, platelet 12,000/uL, erythrocyte sedimentation rate 22 mm/hour. The bone marrow was hemodiluted with 53% blasts dominated by large cells with a high nucleus cytoplasmic ratio, nucleoli were found, irregular fine chromatin, basophilic cytoplasm with prominent cytoplasmic projection/blebs consistent with megakaryoblast. These blasts were expressing CD45 dim, CD36, CD41a, CD33, HLA-DR and CD13 dim. A genetic test using fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) revealed lysine methyltransferase 2A/KMT2A/MLL positive. Therefore, the patient was confirmed as the Non-DS AMKL with positive KMT2A, which confers a dismal outcome compared to the GATA-binding factor1/GATA1/Erythroid transcription factor mutation.Conclusions: Non-DS AMKL is a challenging diagnosis in terms of morphology, immunophenotypic, signs, symptoms, and genetics. Genetic profile will contribute important scientific understanding to decide and improve AMKL treatment and prognosis, particularly unsatisfactory prognosis AMKL, such as a patient with KMT2Ar/MLL]]>
