title: Proteomic analysis reveals heat shock protein 70 has a key role in polycythemia Vera.
abstract: JAK-STAT signaling through the JAK2V617F mutation is central to the pathogenesis of myeloproliferative neoplasms (MPN). However, other events could precede the JAK2 mutation. The aim of this study is to analyze the phenotypic divergence between polycytemia vera (PV) and essential thrombocytemia (ET) to find novel therapeutics targets by a proteomic and functional approach to identify alternative routes to JAK2 activation. Through 2D-DIGE and mass spectrometry of granulocyte protein from 20 MPN samples, showed differential expression of HSP70 in PV and ET besides other 60 proteins. Immunohistochemistry of 46 MPN bone marrow samples confirmed HSP70 expression. The median of positive granulocytes was 80% in PV (SD 35%) vs. 23% in ET (SD 34.25%). In an ex vivo model KNK437 was used as an inhibition model assay of HSP70, showed dose-dependent inhibition of cell growth and burst formation unit erythroid (BFU-E) in PV and ET, increased apoptosis in the erythroid lineage, and decreased pJAK2 signaling, as well as a specific siRNA for HSP70. These data suggest a key role for HSP70 in proliferation and survival of the erythroid lineage in PV, and may represent a potential therapeutic target in MPN, especially in PV.
authors.affiliation: Hematology Service, Hospital Universitario 12 de Octubre, Avenida, Córdoba, s/n, 28041, Madrid, Spain. miguelgallardodelgado@gmail.com.
authors.forename: Miguel
authors.initials: M
authors.lastname: Gallardo
authors.forename: Santiago
authors.initials: S
authors.lastname: Barrio
authors.forename: Marisol
authors.initials: M
authors.lastname: Fernandez
authors.forename: Alberto
authors.initials: A
authors.lastname: Paradela
authors.forename: Alicia
authors.initials: A
authors.lastname: Arenas
authors.forename: Oscar
authors.initials: O
authors.lastname: Toldos
authors.forename: Rosa
authors.initials: R
authors.lastname: Ayala
authors.forename: Enriqueta
authors.initials: E
authors.lastname: Albizua
authors.forename: Ana
authors.initials: A
authors.lastname: Jimenez
authors.forename: Santiago
authors.initials: S
authors.lastname: Redondo
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Garcia-Martin
authors.forename: Florinda
authors.initials: F
authors.lastname: Gilsanz
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Albar
authors.forename: Joaquin
authors.initials: J
authors.lastname: Martinez-Lopez
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D041905:Erythroid Cells / Q000166:cytology* / Q000378:metabolism; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011087:Polycythemia Vera / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics; D013920:Thrombocythemia, Essential / Q000097:blood / Q000235:genetics* / Q000378:metabolism*
chemical_list: D018840:HSP70 Heat-Shock Proteins