Aberrant polyploidization pathways in megakaryocytes as therapeutic targets in leukemia

Megakaryocyte polyploidization is a specialized process essential for platelet production, orchestrated by tightly regulated transcriptional programs, cell-cycle control, and signaling pathways. Disruption of this process – characterized by incomplete endomitosis, low ploidy, and maturation arrest – contributes to leukemic transformation, particularly in acute megakaryoblastic leukemia and related myeloid malignancies. Aberrant polyploidization arises from transcription factor dysregulation, cell-cycle abnormalities, hyperactive proliferative signaling, microenvironmental alterations, and genomic instability. These defects collectively promote proliferation, differentiation arrest, and malignant expansion of megakaryocytic progenitors. Therapeutic strategies targeting these pathways, including modulation of transcription factors, restoration of endomitotic progression, inhibition of JAK–STAT and RAS/MAPK signaling, epigenetic reprogramming, and niche-directed interventions, offer promising avenues to suppress leukemic growth and restore normal maturation. Understanding aberrant polyploidization as a driver of leukemogenesis provides a framework for developing precision therapies in megakaryocytic leukemia.