title: JAK2 tyrosine kinase mediates integrin activation induced by CXCL12 in B-cell chronic lymphocytic leukemia.
abstract: Chemokines participate to B-cell chronic lymphocytic leukemia (B-CLL) pathogenesis by promoting cell adhesion and survival in bone marrow stromal niches and mediating cell dissemination to secondary lymphoid organs. In this study we investigated the role of JAK protein tyrosine kinases (PTK) in adhesion triggering by the CXC chemokine CXCL12 in normal versus CLL B-lymphocytes. We demonstrate that CXCL12 activates JAK2 in normal as well as CLL B-lymphocytes, with kinetics consistent with rapid adhesion triggering. By using complementary methodologies of signal transduction interference, we found that JAK2 mediates CXCL12-triggered activation of lymphocyte function-associated antigen-1 (LFA-1) and very late antigen-4 (VLA-4) integrins. We also show that JAK2 mediates the activation of the small GTP-binding protein RhoA, in turn controlling LFA-1 affinity triggering by CXCL12. Importantly, comparative analysis of 41 B-CLL patients did not evidence JAK2 functional variability between subjects, thus suggesting that JAK2, differently from other signaling events involved in adhesion regulation in B-CLL, is a signaling molecule downstream to CXCR4 characterized by a conserved regulatory role. Our results reveal JAK2 as critical component of chemokine signaling in CLL B-lymphocytes and indicate JAK inhibition as a potentially useful new pharmacological approach to B-CLL treatment.
authors.affiliation: Department of Pathology and Diagnostics, Division of General Pathology, Laboratory of Cell Trafficking and Signal Transduction, University of Verona, Verona 37134, Italy, EU.|The Center for Biomedical Computing (CBMC), University of Verona, Verona 37134, Italy, EU.
authors.forename: Alessio
authors.initials: A
authors.lastname: Montresor
authors.affiliation: Department of Pathology and Diagnostics, Division of General Pathology, Laboratory of Cell Trafficking and Signal Transduction, University of Verona, Verona 37134, Italy, EU.|The Center for Biomedical Computing (CBMC), University of Verona, Verona 37134, Italy, EU.
authors.forename: Lara
authors.initials: L
authors.lastname: Toffali
authors.affiliation: Department of Pathology and Diagnostics, Division of General Pathology, Laboratory of Cell Trafficking and Signal Transduction, University of Verona, Verona 37134, Italy, EU.
authors.forename: Michela
authors.initials: M
authors.lastname: Mirenda
authors.affiliation: Department of Medicine, Section of Hematology, Cancer Research & Cell Biology Laboratory, University of Verona, Verona 37134, Italy, EU.
authors.forename: Antonella
authors.initials: A
authors.lastname: Rigo
authors.affiliation: Department of Medicine, Section of Hematology, Cancer Research & Cell Biology Laboratory, University of Verona, Verona 37134, Italy, EU.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Vinante
authors.affiliation: Department of Pathology and Diagnostics, Division of General Pathology, Laboratory of Cell Trafficking and Signal Transduction, University of Verona, Verona 37134, Italy, EU.|The Center for Biomedical Computing (CBMC), University of Verona, Verona 37134, Italy, EU.
authors.forename: Carlo
authors.initials: C
authors.lastname: Laudanna
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes / Q000378:metabolism; D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology; D054377:Chemokine CXCL12 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D034741:RNA, Small Interfering; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: JAKs; adhesion; chemokines; chronic lymphocytic leukemia; integrin activation