Mammalian Target of Rapamycin Is Required for Thrombopoietin-Induced Proliferation of Megakaryocyte Progenitors

Drayer, A. Lyndsay; Olthof, Sandra; Vellenga, Edo

doi:10.1634/stemcells.2005-0062

Cited by 36 publications

(32 citation statements)

References 33 publications

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“…30 In addition, ectopic expression of eIF4E or rapamycin-resistant mutants of p70S6K partially rescues the rapamycininduced delay in cell cycle progression, indicating that p70S6K and eIF4E are important mediators of mTORdependent cell division. 30 It has been demonstrated that mTOR regulates the translation of proteins involved in G1/S transition during cell cycle progression, including retinoblastoma protein, cell-cycle inhibitors of the Cip/Kip family p21, p27, and cyclin D or E. [31][32][33][34][35][36] Thus, it is likely that mTOR also regulates hematopoietic progenitor expansion at the translational level by regulating translation of cellcycle modulating proteins.…”

Section: Discussionmentioning

confidence: 99%

Mammalian target of rapamycin activity is required for expansion of CD34+ hematopoietic progenitor cells

Geest¹,

Zwartkruis²,

Vellenga³

et al. 2009

Haematologica

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Section: Discussionmentioning

confidence: 99%

Mammalian target of rapamycin activity is required for expansion of CD34+ hematopoietic progenitor cells

Geest¹,

Zwartkruis²,

Vellenga³

et al. 2009

Haematologica

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“…16 Upon binding to its receptor, TPO induces conformational changes in the C-MPL molecule that lead to the activation of at least 3 intracellular signaling pathways: JAK-STAT, 17,18 ShcRas-MAPK, 19,20 and PI3K-AKT-mammalian target of rapamycin (mTOR). 21,22 The biologic relevance of these pathways has been dissected through the use of chemical inhibitors and/or the introduction of mutant kinases. However, results from these studies have been inconsistent and at times contradictory, likely reflecting some differences in experimental conditions, but mostly in the source of cells used: murine or human cell lines, primary murine MKs, or primary human MKs.…”

Section: Introductionmentioning

confidence: 99%

Developmental differences in megakaryocytopoiesis are associated with up-regulated TPO signaling through mTOR and elevated GATA-1 levels in neonatal megakaryocytes

Liu¹,

Italiano

Ferrer‐Marín³

et al. 2011

Blood

103

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Multiple observations support the existence of developmental differences in megakaryocytopoiesis. We have previously shown that neonatal megakaryocyte (MK) progenitors are hyperproliferative and give rise to MKs smaller and of lower ploidy than adult MKs. Based on these characteristics, neonatal MKs have been considered immature. The molecular mechanisms underlying these differences are unclear, but contribute to the pathogenesis of disorders of neonatal megakaryocytopoiesis. In the present study, we demonstrate that low-ploidy neonatal MKs, contrary to traditional belief, are more mature than adult lowploidy MKs. These mature MKs are generated at a 10-fold higher rate than adult MKs, and result from a developmental uncoupling of proliferation, polyploidization, and terminal differentiation. This pattern is associated with up-regulated thrombopoietin (TPO) signaling through mammalian target of rapamycin (mTOR) and elevated levels of full-length GATA-1 and its targets. Blocking of mTOR with rapamycin suppressed the maturation of neonatal MKs without affecting ploidy, in contrast to the synchronous inhibition of polyploidization and cytoplasmic maturation in adult MKs. We propose that these mechanisms allow fetuses/neonates to populate their rapidly expanding bone marrow and intravascular spaces while maintaining normal platelet counts, but also set the stage for disorders restricted to fetal/neonatal MK progenitors, including the Down syndrome-transient myeloproliferative disorder and the thrombocytopenia absent radius syndrome. IntroductionMegakaryocytopoiesis is the process by which hematopoietic stem cells undergo lineage commitment to become megakaryocyte (MK) progenitors, which proliferate and generate immature MKs. These immature MKs then undergo successive rounds of endomitosis that give rise to unique highly polyploid cells. The process of polyploidization is associated with the increasing production of proteins necessary for platelet formation and function, 1 including membrane receptors such as CD41/61 and CD42, and platelet granule components such as VWF, platelet factor 4, and P-selectin. Polyploidization is also accompanied by progressive ultrastructural changes, particularly the formation of a complex demarcation membrane system (DMS), which, together with an accumulation of ␣ granules, characterizes fully mature MKs. These events set the stage for the production of proplatelets and the release of platelets by mature MKs. 2 Over the last decades, a mounting body of evidence has supported the existence of substantial biologic differences between fetal/neonatal and adult MKs. Several in vitro studies have shown that MK progenitors from fetuses and neonates proliferate at a much higher rate than adult progenitors. [3][4][5] Neonatal MKs, however, are significantly smaller and of lower ploidy (and produce fewer platelets) than MKs from adults. [6][7][8] Based on these characteristics, MKs from fetuses and neonates have been considered to be immature compared with adult MKs. 9 Whereas the cellular and m...

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“…4,5 Signaling by thrombopoietin (TPO), the major megakaryocytic cytokine, induces PI3K activity, downstream of which lies the mammalian target of rapamycin pathway. 6 Mammalian target of rapamycin is a kinase that controls cell size and cell-cycle progression in mammals and Drosophila. 7,8 It also regulates key MK attributes (proliferation, cell size, cytoskeleton organization, and platelet formation) in part through control of G 1 /S cell-cycle progression.…”

Section: ;118(3):723-735) Introductionmentioning

confidence: 99%

SCL-mediated regulation of the cell-cycle regulator p21 is critical for murine megakaryopoiesis

Chagraoui

Kassouf

Banerjee

et al. 2011

Blood

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Megakaryopoiesis is a complex process that involves major cellular and nuclear changes and relies on controlled coordination of cellular proliferation and differentiation. These mechanisms are orchestrated in part by transcriptional regulators. The key hematopoietic transcription factor stem cell leukemia (SCL)/TAL1 is required in early hematopoietic progenitors for specification of the megakaryocytic lineage. These early functions have, so far, prevented full investigation of its role in megakaryocyte development in lossof-function studies. Here, we report that SCL critically controls terminal megakaryocyte maturation. In vivo deletion of Scl specifically in the megakaryocytic lineage affects all key attributes of megakaryocyte progenitors (MkPs), namely, proliferation, ploidization, cytoplasmic maturation, and platelet release. Genomewide expression analysis reveals increased expression of the cell-cycle regulator p21 in Scl-deleted MkPs. Importantly, p21 knockdown-mediated rescue of Sclmutant MkPs shows full restoration of cell-cycle progression and partial rescue of the nuclear and cytoplasmic maturation defects. Therefore, SCL-mediated transcriptional control of p21 is essential for terminal maturation of MkPs. Our study provides a mechanistic link between a major hematopoietic transcriptional regulator, cell-cycle progression, and megakaryocytic differentiation. (Blood. 2011;118(3):723-735) IntroductionMegakaryocytes (MKs) are specialized blood cells that release platelets, the effectors of coagulation processes. During megakaryopoiesis, megakaryocyte progenitors (MkPs) coordinately proliferate and differentiate to develop into mature MKs that, ultimately, shed platelets. This complex biologic process requires profound cellular and nuclear changes (cytoplasm remodeling, cell size increase, nuclear polyploidization, and cytoskeletal dynamics) relying on an exquisite coordination of key cellular and molecular mechanisms. 1 At an early stage in their development, MKs enter endomitosis (or abortive mitosis), during which DNA replicates without cell division. This process results in nuclear polyploidization, increase in cell size, and is linked to platelet formation. 2,3 Formation of the demarcation membrane system (DMS, a reservoir for proplatelet membranes) and secretory granules reflects some of the specific characteristics of the cytoplasmic maturation of MKs. 4,5 Signaling by thrombopoietin (TPO), the major megakaryocytic cytokine, induces PI3K activity, downstream of which lies the mammalian target of rapamycin pathway. 6 Mammalian target of rapamycin is a kinase that controls cell size and cell-cycle progression in mammals and Drosophila. 7,8 It also regulates key MK attributes (proliferation, cell size, cytoskeleton organization, and platelet formation) in part through control of G 1 /S cell-cycle progression. 6,9 This control is mediated by sequential action of the cell-cycle regulators cyclin D3 (CCND3) and P21 (cyclindependent cell-cycle inhibitor, CDKN1a). 9 In mouse MKs, cyclin D3 expression is hig...

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Mammalian Target of Rapamycin Is Required for Thrombopoietin-Induced Proliferation of Megakaryocyte Progenitors

Cited by 36 publications

References 33 publications

Mammalian target of rapamycin activity is required for expansion of CD34+ hematopoietic progenitor cells

Mammalian target of rapamycin activity is required for expansion of CD34+ hematopoietic progenitor cells

Developmental differences in megakaryocytopoiesis are associated with up-regulated TPO signaling through mTOR and elevated GATA-1 levels in neonatal megakaryocytes

SCL-mediated regulation of the cell-cycle regulator p21 is critical for murine megakaryopoiesis

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