Rho kinase inhibition drives megakaryocyte polyploidization and proplatelet formation through MYC and NFE2 downregulation

Summary The processes of megakaryocyte polyploidization and demarcation membrane system (DMS) formation are crucial for platelet production, but the mechanisms controlling these processes are not fully determined. Inhibition of Rho kinase (ROCK) signalling leads to increased polyploidization in umbi...

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Veröffentlicht in:British journal of haematology Jg. 164; H. 6; S. 867 - 876
Hauptverfasser: Avanzi, Mauro P., Goldberg, Francine, Davila, Jennifer, Langhi, Dante, Chiattone, Carlos, Mitchell, William Beau
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Oxford Blackwell 01.03.2014
Schlagworte:
Biological and medical sciences
Blood Platelets - cytology
Blood Platelets - metabolism
Blood Platelets - physiology
Cell Culture Techniques
Cell Membrane - physiology
Down-Regulation
Genes, myc
Hematologic and hematopoietic diseases
Hematopoietic Stem Cell Transplantation - methods
Humans
Medical sciences
Megakaryocytes - drug effects
Megakaryocytes - metabolism
Megakaryocytes - physiology
megakaryocytopoiesis
MYC
NF-E2 Transcription Factor, p45 Subunit - biosynthesis
NF-E2 Transcription Factor, p45 Subunit - blood
NF-E2 Transcription Factor, p45 Subunit - genetics
NFE2
polyploidization
Polyploidy
proplatelet formation
Proto-Oncogene Proteins c-myc - biosynthesis
Proto-Oncogene Proteins c-myc - blood
Proto-Oncogene Proteins c-myc - genetics
Rho kinase
rho-Associated Kinases - antagonists & inhibitors
rho-Associated Kinases - blood
rho-Associated Kinases - genetics
Tumors
Transcription factor NF-E2
Megakaryocytopoiesis
NFE2
Polyploidy
Thrombopoiesis
Hematology
Rho kinase
Proplatelet
Megakaryocyte
proplatelet formation
polyploidization
Cancerology
Hematopoiesis
C-Onc gene
MYC
myc Gene
Inhibitor
Protooncogene
megakaryocytopoiesis
ISSN:0007-1048, 1365-2141, 1365-2141
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Zusammenfassung:Summary The processes of megakaryocyte polyploidization and demarcation membrane system (DMS) formation are crucial for platelet production, but the mechanisms controlling these processes are not fully determined. Inhibition of Rho kinase (ROCK) signalling leads to increased polyploidization in umbilical cord blood‐derived megakaryocytes. To extend these findings we determined the effect of ROCK inhibition on development of the DMS and on proplatelet formation. The underlying mechanisms were explored by analysing the effect of ROCK inhibition on the expression of MYC and NFE2, which encode two transcription factors critical for megakaryocyte development. ROCK inhibition promoted DMS formation, and increased proplatelet formation and platelet release. Rho kinase inhibition also downregulated MYC and NFE2 expression in mature megakaryocytes, and this down‐regulation correlated with increased proplatelet formation. Our findings suggest a model whereby ROCK inhibition drives polyploidization, DMS growth and proplatelet formation late in megakaryocyte maturation through downregulation of MYC and NFE2 expression.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0007-1048
1365-2141
1365-2141
DOI:10.1111/bjh.12709