title: Epigenetic alteration of SOCS family members is a possible pathogenetic mechanism in JAK2 wild type myeloproliferative diseases.
abstract: In polycythemia vera (PV) and essential thrombocythemia (ET) specific JAK2 mutations constitutively activate the JAK-STAT pathway, explaining biologic findings such as endogenous erythroid colony (EECs) growth or PRV-1 RNA overexpression. Since these markers are detected also in JAK2 wild type patients, we hypothesized that, in these cases, the activation of the JAK-STAT pathway could be produced by a deregulation of the suppressor of cytokine signaling (SOCS) protein system. Eighty-one patients with PV and ET (53 adults and 28 children) were investigated for the methylation status of the SOCS-1, SOCS-2 and SOCS-3 CpG islands and for several myeloproliferative markers (including JAK2 and MPL mutations and clonality of hematopoiesis). SOCS-1 or SOCS-3 hypermethylation was identified in 23 patients and was associated with a significant decrease of SOCS-1 or SOCS-3 RNA and protein levels. The gene expression was restored by exposing cells to the demethylating agent 2-deoxyazacytidin. Interestingly, SOCS-1 or SOCS-3 hypermethylation was detected in 6 female patients, proved negative for JAK2 or MPL mutations and exhibiting monoclonal hematopoiesis. In conclusion, SOCS-1 or SOCS-3 hypermethylation can activate the JAK-STAT signaling pathway in alternative or together with JAK2 mutations. These alterations might represent a potential therapeutic target.
authors.affiliation: Department of Haematology, Catholic University, Rome, Italy.
authors.forename: Luciana
authors.initials: L
authors.lastname: Teofili
authors.forename: Maurizio
authors.initials: M
authors.lastname: Martini
authors.forename: Tonia
authors.initials: T
authors.lastname: Cenci
authors.forename: Francesco
authors.initials: F
authors.lastname: Guidi
authors.forename: Lorenza
authors.initials: L
authors.lastname: Torti
authors.forename: Fiorina
authors.initials: F
authors.lastname: Giona
authors.forename: Robin
authors.initials: R
authors.lastname: Foà
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Leone
authors.forename: Luigi Maria
authors.initials: LM
authors.lastname: Larocca
mesh_terms: D000293:Adolescent; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D015153:Blotting, Western; D018899:CpG Islands; D019175:DNA Methylation; D017931:DNA Primers; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053614:Janus Kinase 2 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011087:Polycythemia Vera / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics*; D013920:Thrombocythemia, Essential / Q000201:enzymology / Q000235:genetics* / Q000473:pathology
chemical_list: D017931:DNA Primers; D050826:Suppressor of Cytokine Signaling Proteins; C507924:JAK2 protein, human; D053614:Janus Kinase 2