title: Identification of JAK2 as a mediator of FIP1L1-PDGFRA-induced eosinophil growth and function in CEL.
abstract: The Fip1-like1 (FIP1L1)-platelet-derived growth factor receptor alpha fusion gene (F/P) arising in the pluripotent hematopoietic stem cell (HSC),causes 14% to 60% of patients with hypereosinophilia syndrome (HES). These patients, classified as having F/P (+) chronic eosinophilic leukemia (CEL), present with clonal eosinophilia and display a more aggressive disease phenotype than patients with F/P (-) HES patients. The mechanisms underlying predominant eosinophil lineage targeting and the cytotoxicity of eosinophils in this leukemia remain unclear. Given that the Janus tyrosine kinase (JAK)/signal transducers and activators of transcription (Stat) signaling pathway is key to cytokine receptor-mediated eosinophil development and activated Stat3 and Stat5 regulate the expression of genes involved in F/P malignant transformation, we investigated whether and how JAK proteins were involved in the pathogenesis of F/P-induced CEL. F/P activation of JAK2, Stat3 and Stat5, were confirmed in all the 11 F/P (+) CEL patients examined. In vitro inhibition of JAK2 in EOL-1, primary F/P(+) CEL cells (PC) and T674I F/P Imatinib resistant cells(IR) by either JAK2-specific short interfering RNA (siRNA) or the tryphostin derivative AG490(AG490), significantly reduced cellular proliferation and induced cellular apoptosis. The F/P can enhance the IL-5-induced JAK2 activation, and further results indicated that JAK2 inhibition blocked IL-5-induced cellular migration and activation of the EOL-1 and PC cells in vitro. F/P-stimulation of the JAK2 suppressed cells led to a significantly reduction in Stat3 activation, but relatively normal induction of Stat5 activation. Interestingly, JAK2 inhibition also reduced PI3K, Akt and NF-κB activity in a dose-dependent manner, and suppressed expression levels of c-Myc and Survivin. These results strongly suggest that JAK2 is activated by F/P and is required for F/P stimulation of cellular proliferation and infiltration, possibly through induction of c-Myc and Survivin expression via activation of multiple signaling pathways, including NF-κB, Stat3, and PI3K/Akt.
authors.affiliation: Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, People's Republic of China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.forename: Guangsen
authors.initials: G
authors.lastname: Zhang
authors.forename: Cui
authors.initials: C
authors.lastname: Li
authors.forename: Dan
authors.initials: D
authors.lastname: He
authors.forename: Xinying
authors.initials: X
authors.lastname: Li
authors.forename: Chunfang
authors.initials: C
authors.lastname: Zhang
authors.forename: Faqing
authors.initials: F
authors.lastname: Tang
authors.forename: Xiyun
authors.initials: X
authors.lastname: Deng
authors.forename: Jingchen
authors.initials: J
authors.lastname: Lu
authors.forename: Youhong
authors.initials: Y
authors.lastname: Tang
authors.forename: Ruijuan
authors.initials: R
authors.lastname: Li
authors.forename: Zhuchu
authors.initials: Z
authors.lastname: Chen
authors.forename: Chaojun
authors.initials: C
authors.lastname: Duan
mesh_terms: D001549:Benzamides; D015536:Down-Regulation; D004789:Enzyme Activation; D004804:Eosinophils / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D000068877:Imatinib Mesylate; D015848:Interleukin-5 / Q000502:physiology; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D010879:Piperazines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000494:pharmacology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology; D039221:mRNA Cleavage and Polyadenylation Factors / Q000502:physiology*
chemical_list: D001549:Benzamides; D015848:Interleukin-5; D016328:NF-kappa B; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D011743:Pyrimidines; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D039221:mRNA Cleavage and Polyadenylation Factors; D000068877:Imatinib Mesylate; C479819:FIP1L1-PDGFRA fusion protein, human; D020796:Receptor, Platelet-Derived Growth Factor alpha; D053614:Janus Kinase 2