Megakaryopoiesis and its dysregulation in paediatric acute megakaryoblastic leukaemia

Megakaryocytes (Mks) are haematopoietic cells responsible for platelet production. They arise from haematopoietic stem cells (HSCs) through a differentiation process known as megakaryopoiesis, which is classically viewed as occurring in a stepwise manner. However, recent studies have challenged this model, suggesting an alternative direct differentiation route producing functionally distinct Mk subtypes. Understanding this process is important, as dysregulation can lead to the development of diseases such as paediatric acute megakaryoblastic leukaemia (AMKL). This is a rare subtype of acute myeloid leukaemia (AML) that has a significantly worse prognosis compared to other AML subtypes. Accurate classification of AML increasingly relies on an integrated genetic and immunophenotypic diagnostic pathway. The poor prognosis of AML is largely driven by the presence of therapy-resistant leukaemia stem cells (LSCs). Furthermore, LSCs are often resistant to targeted therapies like the BCL-2 inhibitor venetoclax, yet they show a distinct dependency on other proteins within the same apoptosis pathway, notably BCL-XL. Therefore, this review aims to summarise current knowledge on normal megakaryopoiesis and explore how its dysregulation contributes to LSC emergence in paediatric AMKL, while also highlighting the therapeutic implications of both BCL-XL dependency and emerging subtype-specific therapies.