The changing scenario of non-Down syndrome acute megakaryoblastic leukemia in children.

• Recent discovery of novel genetic lesions characterizing non-DS-AMKL. • A more refined genetic risk-assessment allowed a tailored treatment approach. • High-risk group: NUP98-KDM5 A, CBFA2T3-GLIS2, KMT2A -rearrangements and monosomy 7. • HSCT in first complete remission to avoid recurrence in high-risk non-DS-AMKL. • Intensive chemotherapy approach in standard-risk group, HSCT in case of poor response. Pediatric non-Down-syndrome acute megakaryoblastic leukemia (non-DS-AMKL) is a heterogeneous subtype of leukemia that has historically been associated with poor prognosis. Until the advent of large-scale genomic sequencing, the management of patients with non-DS-AMKL was very difficult due to the absence of reliable biological prognostic markers. The sequencing of large cohort of pediatric non-DS-AMKL samples led to the discovery of novel genetic aberrations, including high-frequency fusions, such as CBFA2T3-GLIS2 and NUP98-KDM5 A , as well as less frequent aberrations, such as HOX rearrangements. These new insights into the genetic landscape of pediatric non-DS-AMKL has allowed refining the risk-group stratification, leading to important changes in the prognostic scenario of these patients. This review summarizes the most important molecular pathogenic mechanisms of pediatric non-DS-AMKL. A critical discussion on how novel genetic abnormalities have refined the risk profile assessment and changed the management of these patients in clinical practice is also provided. [ABSTRACT FROM AUTHOR]