SHP1 negatively regulates the Janus kinase 2/signal transducer and activator of transcription (JAK2/STAT)signaling pathway, which is constitutively activated in myeloproliferative neoplasms (MPNs) and leukemia.Promoter hypermethylation resulting in epigenetic inactivation of SHP1 has been reported in myelomas, leukemiasand other cancers. However, whether SHP1 hypermethylation occurs in MPNs, especially in Chinese patients, hasremained unclear. Here, we report that aberrant hypermethylation of SHP1 was observed in several leukemic celllines and bone marrow mononuclear cells from MPN patients. About 51 of 118 (43.2%) MPN patients including23 of 50 (46%) polycythaemia vera patients, 20 of 50 (40%) essential thrombocythaemia and 8 of 18 (44.4%)idiopathic myelofibrosis showed hypermethylation by methylation-specific polymerase chain reaction. However,SHP1 methylation was not measured in 20 healthy volunteers. Hypermethylation of SHP1 was found in MPNpatients with both positive (34/81, 42%) and negative (17/37, 45.9%) JAK2V617F mutation. The levels of SHP1mRNA were significantly lower in hypermethylated samples than unmethylated samples, suggesting SHP1 may beepigenetically inactivated in MPN patients. Furthermore, treatment with 5-aza-2’-deoxycytidine (AZA) in K562cells showing hypermethylation of SHP1 led to progressive demethylation of SHP1, with consequently increasedreexpression of SHP1. Meanwhile, phosphorylated JAK2 and STAT3 were progressively reduced. Finally, AZAincreased the expression of SHP1 in primary MPN cells with hypermethylation of SHP1. Therefore, our datasuggest that epigenetic inactivation of SHP1 contributes to the constitutive activation of JAK2/STAT signaling.Restoration of SHP1 expression by AZA may contribute to clinical treatment for MPN patients.
(2015). Methylated Alteration of SHP1 Complements Mutation of JAK2 Tyrosine Kinase in Patients with Myeloproliferative Neoplasm. Asian Pacific Journal of Cancer Prevention, 16(6), 2219-2225.
MLA
. "Methylated Alteration of SHP1 Complements Mutation of JAK2 Tyrosine Kinase in Patients with Myeloproliferative Neoplasm". Asian Pacific Journal of Cancer Prevention, 16, 6, 2015, 2219-2225.
HARVARD
(2015). 'Methylated Alteration of SHP1 Complements Mutation of JAK2 Tyrosine Kinase in Patients with Myeloproliferative Neoplasm', Asian Pacific Journal of Cancer Prevention, 16(6), pp. 2219-2225.
VANCOUVER
Methylated Alteration of SHP1 Complements Mutation of JAK2 Tyrosine Kinase in Patients with Myeloproliferative Neoplasm. Asian Pacific Journal of Cancer Prevention, 2015; 16(6): 2219-2225.