Methylated Alteration of SHP1 Complements Mutation of JAK2 Tyrosine Kinase in Patients with Myeloproliferative Neoplasm

Yang, Jun-Jun; Chen, Hui; Zheng, Xiao-Qun; Li, Hai-Ying; Wu, Jian-Bo; Tang, Li-Yuan; Gao, Shen-Meng

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자료유형: 학술저널

저자정보: Yang, Jun-Jun (Department of Laboratory Medicine, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University) Chen, Hui (Department of Laboratory Medicine, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University) Zheng, Xiao-Qun (Department of Laboratory Medicine, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University) Li, Hai-Ying (Laboratory of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University) Wu, Jian-Bo (Laboratory of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University) Tang, Li-Yuan (Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University) Gao, Shen-Meng (Laboratory of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University)

저널정보: 아시아태평양암예방학회 Asian Pacific journal of cancer prevention : APJCP Asian Pacific journal of cancer prevention : APJCP 제16권 제6호

발행연도: 2015.1

수록면: 2,219 - 2,225 (7page)

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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, leukemias and other cancers. However, whether SHP1 hypermethylation occurs in MPNs, especially in Chinese patients, has remained unclear. Here, we report that aberrant hypermethylation of SHP1 was observed in several leukemic cell lines and bone marrow mononuclear cells from MPN patients. About 51 of 118 (43.2%) MPN patients including 23 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 MPN patients with both positive (34/81, 42%) and negative (17/37, 45.9%) JAK2V617F mutation. The levels of SHP1 mRNA were significantly lower in hypermethylated samples than unmethylated samples, suggesting SHP1 may be epigenetically inactivated in MPN patients. Furthermore, treatment with 5-aza-2'-deoxycytidine (AZA) in K562 cells showing hypermethylation of SHP1 led to progressive demethylation of SHP1, with consequently increased reexpression of SHP1. Meanwhile, phosphorylated JAK2 and STAT3 were progressively reduced. Finally, AZA increased the expression of SHP1 in primary MPN cells with hypermethylation of SHP1. Therefore, our data suggest 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.

#SHP1 #myeloproliferative neoplasm patients #hypermethylation

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Yang, Jun-Jun

소속기관 Department of Laboratory Medicine, The Second Affiliated Hospital & Yuying Children's Hospital o