Schematic representation of the crosstalk between the NOTCH and AKT pathways at the molecular and cellular levels. (A) Scheme of the molecular pathways. NOTCH pathway activation inhibits PTEN expression leading to AKT activation, FOXO phosphorylation, and enhanced RBPJ-mediated transcription. We hypothesize that this regulatory loop links cytokine receptor signaling and RBPJ-mediated transcription. (B) Scheme of the megakaryocyte lineage development pathways. Our results support the hypothesis that megakaryocyte can develop from immature hematopoietic cells through a NOTCH-induced AKT-independent pathway. Megakaryocyte can also develop from committed myeloid progenitor through an AKT-dependent pathway that is activated by cytokine receptor activation (eg, MPL) and may also be stimulated by the NOTCH signaling.