Transcriptomic and phospho‐proteomic analyzes of erythroblasts expanded in vitro from normal donors and from patients with polycythemia vera. Issue 9 (3rd July 2013)

• Record Type: Journal Article
• Authors: Hricik, Todd; Federici, Giulia; Zeuner, Ann; Alimena, Giuliana; Tafuri, Agostino; Tirelli, Valentina; Varricchio, Lilian; Masiello, Francesca; Ciaffoni, Fiorella; Vaglio, Stefania; Petricoin, Emanuel F.; Girelli, Gabriella; Levine, Ross L.; Migliaccio, Anna Rita F.
• Is Part Of: American journal of hematology. Volume 88:Issue 9(2013:Sep.)
• Page Start: 723
• Page End: 729
• Publication Date: 2013-07-03
• Subjects: Hematology -- Periodicals; 616.15
• DOI: 10.1002/ajh.23487
• Languages: English
• ISSNs: 0361-8609

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 <italic>in vitro</italic> 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, <italic>GPR56</italic> and <italic>RAB4a</italic>, in PV‐derived ERYs along with reduced expression levels of transcription factor <italic>TAL1</italic> (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 <italic>TAL1</italic> 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. Am. J. Hematol. 88:723–729, 2013. © 2013 Wiley Periodicals, Inc.</p> </abstract>