Premium
Epigenetic alteration of SOCS family members is a possible pathogenetic mechanism in JAK2 wild type myeloproliferative diseases
Author(s) -
Teofili Luciana,
Martini Maurizio,
Cenci Tonia,
Guidi Francesco,
Torti Lorenza,
Giona Fiorina,
Foà Robin,
Leone Giuseppe,
Larocca Luigi Maria
Publication year - 2008
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.23694
Subject(s) - jak stat signaling pathway , biology , dna methylation , socs3 , suppressor of cytokine signalling , cancer research , polycythemia vera , haematopoiesis , janus kinase , signal transduction , cytokine , stat , stat3 , immunology , gene , gene expression , genetics , stem cell , tyrosine kinase
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. © 2008 Wiley‐Liss, Inc.