RRC ID 53214
Author Sakurai K, Fujiwara T, Hasegawa S, Okitsu Y, Fukuhara N, Onishi Y, Yamada-Fujiwara M, Ichinohasama R, Harigae H.
Title Inhibition of human primary megakaryocyte differentiation by anagrelide: a gene expression profiling analysis.
Journal Int. J. Hematol.
Abstract Anagrelide is a treatment option for patients with essential thrombocythemia. Although the clinical efficacy of anagrelide has been established, there is limited knowledge of the molecular mechanism underlying its effect. Here, we evaluated the effect of anagrelide on primary megakaryocytic progenitors from cord blood-derived CD34-positive cells. Anagrelide treatment reduced the expression of megakaryocytic markers (CD41 and CD61). Microarray analysis was performed to characterize gene profiles altered by exposure to anagrelide. The analysis demonstrated upregulation and downregulation (>2-fold) of eight and 34 genes, respectively, in anagrelide-treated megakaryocyte progenitors. This included genes encoding prototypical megakaryocytic proteins, such as PPBP, PF4, and GP6. Gene ontology analysis of genes suppressed by anagrelide treatment revealed significant enrichment of genes involved in platelet activation and degranulation. Expression levels of transcription factors involved in megakaryocyte commitment/differentiation were further evaluated by quantitative RT-PCR, demonstrating significant downregulation of FLI1 and TAL1 in anagrelide-treated megakaryocyte progenitors. Knockdown of TAL1 in primary megakaryocyte progenitors confirmed significant downregulation of FLI1 and megakaryocytic genes. Anagrelide had no significant effect on the surface expression of erythroid markers or on the expression of transcription factors involved in erythroid commitment/differentiation. In conclusion, anagrelide suppresses megakaryocytic differentiation, partly through decreasing the expression of megakaryocytic transcription factors.
Volume 104(2)
Pages 190-9
Published 2016-8
DOI 10.1007/s12185-016-2006-2
PII 10.1007/s12185-016-2006-2
PMID 27084257
MeSH Cell Differentiation / drug effects* Cell Differentiation / genetics Cells, Cultured Fetal Blood / cytology Gene Expression Profiling* Humans Megakaryocyte Progenitor Cells / cytology Megakaryocytes / cytology* Platelet Aggregation Inhibitors / pharmacology Quinazolines / pharmacology* Transcription Factors / genetics
IF 1.942
Cord blood stem cells for research