Crosstalk between NOTCH and AKT signaling during murine megakaryocyte lineage specification

Abstract

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...

PEAR1 attenuates megakaryopoiesis via control of the PI3K/PTEN pathway

“…25 Hence, even when embryonic development is not affected by the PTENa MO, megakaryopoiesis and thrombocyte formation depend on Pear1, at least in part, via the regulation of Ptena. Recent studies in MKs 22 and in thymocytes 23 have revealed that Hes1 is a negative regulator of Pten expression. We presently found evidence of HES1 upregulation in the PEAR1 knockdown in CD34 1 cells, but not in zebrafish.…”

Endoreplication and polyploidy: insights into development and disease

“…Recent work in this Drosophila model tissue suggests that chromatin modifications may accompany the Notch-regulated mitosis-to-endoreplication switch (Domanitskaya and Schüpbach, 2012). The involvement of Notch in regulating endoreplication appears conserved, as mammalian megakaryocyte differentiation is regulated in part by Notch, although the nature of this regulation (positive versus negative) may differ between humans and mice (Cornejo et al, 2011;Mercher et al, 2008;Poirault-Chassac et al, 2010).…”

NOTCH1 activation clinically antagonizes the unfavorable effect of PTEN inactivation in BFM-treated children with precursor T-cell acute lymphoblastic leukemia

“…While the importance of NOTCH1 activity in T-cell development has been known for some time, [38][39][40] NOTCH has recently emerged to also function in myeloid, megakaryocyte and erythroid development. [41][42][43] Gain of NOTCH1 function is a hallmark of 50%-60% of children with T-ALL, 9,44 and is thought to function as an initiating event and a progression factor in T-ALL. [45][46][47] Therefore, one might have predicted that activating NOTCH1 mutations should have an unfavorable effect on treatment response and long-term outcome.…”