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Transcriptomic and phospho-proteomic analyzes of erythroblasts expanded in vitro from normal donors and from patients with polycythemia vera
- Publication Year :
- 2013
- Publisher :
- WILEY-BLACKWELL, 2013.
-
Abstract
- Erythropoiesis is a tightly regulated process which becomes decoupled from its normal differentiation program in patients with polycythemia vera (PV). Somatic mutations in JAK2 are commonly associated with this myeloid proliferative disorder. To gain insight into the molecular events that are required for abnormally developing erythroid cells to escape dependence on normal growth signals, we performed in vitro expansion of mature erythroblasts (ERY) from seven normal healthy donors and from seven polycythemic patients in the presence of IL3, EPO, SCF for 10, 11, or 13 days. Normal ERYs required exposure to the glucocorticoid dexamethasone (Dex) for expansion, while PV-derived ERYs expanded in the absence of dexamethasone. RNA expression profiling revealed enrichment of two known oncogenes, GPR56 and RAB4a, in PV-derived ERYs along with reduced expression levels of transcription factor TAL1 (ANOVA FDR < 0.05). While both normal and polycythemic-derived ERYs integrated signaling cascades for growth, they did so via different signaling pathways which are represented by their differential phospho-profiles. Our results show that normal ERYs displayed greater levels of phosphorylation of EGFR, PDGFRβ, TGFβ, and cKit, while PV-derived ERYs were characterized by increased phosphorylation of cytoplasmic kinases in the JAK/STAT, PI3K, and GATA1 pathways. Together these data suggest that PV erythroblast expansion and maturation may be maintained and enriched in the absence of dexamethasone through reduced TAL1 expression and by accessing additional signaling cascades. Members of this acquired repertoire may provide important insight into the pathogenesis of aberrant erythropoiesis in myeloproliferative neoplasms such as polycythemia vera.
- Subjects :
- Adult
Male
Proteomics
Myeloid
Erythroblasts
erythroid-differentiation
erythropoietin receptor
rich akt substrate
protein-kinase-c
factor gata-1
40 kda pras40
gene-expression
hematopoietic stem
phosphorylation
progenitor cells
Biology
Article
Dexamethasone
Receptors, G-Protein-Coupled
Polycythemia vera
erythroblasts expanded vitro polycythemia vera
Proto-Oncogene Proteins
hemic and lymphatic diseases
Basic Helix-Loop-Helix Transcription Factors
medicine
Humans
Erythropoiesis
Erythropoietin
Polycythemia Vera
Transcription factor
Cells, Cultured
T-Cell Acute Lymphocytic Leukemia Protein 1
Aged
Regulation of gene expression
Stem Cell Factor
rab4 GTP-Binding Proteins
Kinase
Gene Expression Profiling
GATA1
Hematology
Middle Aged
Phosphoproteins
medicine.disease
medicine.anatomical_structure
Gene Expression Regulation
Case-Control Studies
Cancer research
Female
Interleukin-3
Signal transduction
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....0f7c6d92d56fdc8540cbcc0aec906018