A CBFA2T3-GLIS2 fusion gene was identified in 31% of non–Down syndrome AMKL.

The NOTCH signaling pathway is implicated in a broad range of developmental processes, including cell fate decisions. However, the molecular basis for its role at the different steps of stem cell lineage commitment is unclear. We recently identified the NOTCH signaling pathway as a positive regulator of megakaryocyte lineage specification during hematopoiesis, but the developmental pathways that allow hematopoietic stem cell differentiation into the erythro-megakaryocytic lineages remain controversial. Here, we investigated the role of downstream mediators of NOTCH during megakaryopoiesis and report crosstalk between the NOTCH and PI3K/AKT pathways. We demonstrate the inhibitory role of phosphatase with tensin homolog and Forkhead Box class O factors on megakaryopoiesis in vivo. Finally, our data annotate developmental mechanisms in the hematopoietic system that enable a decision to be made either at the hematopoietic stem cell or the committed progenitor level to commit to the megakaryocyte lineage, supporting the existence of 2 distinct developmental pathways. (Blood. 2011;118(5):1264-1273) IntroductionDevelopmental pathways are generally viewed as a series of binary decisions with few opportunities for pleiotropy. However, this may limit adaptive decisions for development in adult tissues in response to environmental stressors.In the hematopoietic hierarchy, the various lymphoid and myeloid blood cell lineages originate from HSCs through successive cell fate decisions. 1,2 Purification of different progenitor populations that are based on multiple cellular markers and clonal analyses has yielded several potential models for hematopoietic development. [3][4][5][6][7] In particular, the origin of megakaryocyteerythrocyte progenitors (MEPs) is unclear. Several lines of evidence indicate that MEPs develop from committed myeloid progenitors, 5,7,8 whereas others have suggested that MEPs may arise directly from HSCs before their commitment to lymphoid/ myeloid lineages. 3,4,6 Of note, a number of genes involved in megakaryocyte-erythrocyte development, including Runx1, Tal1, or c-Myb, also play important roles in HSC biology. 9 The molecular basis for cell fate decisions made by HSCs for lineage commitment are not well understood. However, it is plausible that there are opportunities for MEP lineage commitment at more than 1 branch point in the hematopoietic developmental hierarchy. A precise understanding of the roadmap of hematopoietic development of MEPs may be of value both for the treatment of hematopoietic malignancies involving this lineage and in developing strategies to enhance regenerative platelet production.The NOTCH signaling pathway is highly conserved among multicellular organisms and has been shown to participate in a broad range of developmental processes in part through the regulation of cell fate decisions. 10 Several observations highlight the importance of tight regulation of NOTCH pathway activity during hematopoietic development. These include the causal role of Notch1-activating mutations in...