title: CXCL12-induced VLA-4 activation is impaired in trisomy 12 chronic lymphocytic leukemia cells: a role for CCL21.
abstract: Homing to distinct lymphoid organs enables chronic lymphocytic leukemia (CLL) cells to receive pro-survival and proliferative signals. Cytogenetic aberrations can significantly affect CLL cell compartmentalization. Trisomy 12 (tri12) defines a CLL subgroup with specific clinical features and increased levels of the negative prognostic marker CD49d, the α4-subunit of the integrin VLA-4, which is a key regulator of CLL cell homing to bone marrow (BM). Chemokine-induced inside-out VLA-4 activation, particularly via the CXCL12-CXCR4 axis, increases the arrest of various cell types on VCAM-1 presenting endothelium. Here, we demonstrate that high CD49d expression in tri12 CLL is accompanied by decreased CXCR4 expression. Dissecting functional consequences of these alterations, we observed that tri12 CLL cell homing to murine BM is not affected by CXCR4-CXCL12 blockage using AMD3100 or olaptesed pegol/NOX-A12. In line, CCL21-CCR7 rather than CXCL12-CXCR4 interactions triggered VLA-4-mediated arrests of tri12 CLL cells to VCAM-1 under blood flow conditions. Concordantly, in real-time kinetic analyses we found CCL21 but not CXCL12 being capable to induce inside-out VLA-4 conformational changes in this CLL subgroup. Our results provide novel insights into the peculiar clinico-biological behaviour of tri12 CLL and emphasize its specific chemokine and integrin utilization during pathophysiologically and therapeutically relevant interactions with the microenvironment.
authors.affiliation: Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases and Rheumatology, Oncologic Center, Paracelsus Medical University Salzburg, Austria.|Salzburg Cancer Research Institute, Salzburg, Austria.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Ganghammer
authors.affiliation: Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases and Rheumatology, Oncologic Center, Paracelsus Medical University Salzburg, Austria.|Salzburg Cancer Research Institute, Salzburg, Austria.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Hutterer
authors.affiliation: Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases and Rheumatology, Oncologic Center, Paracelsus Medical University Salzburg, Austria.|Salzburg Cancer Research Institute, Salzburg, Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Hinterseer
authors.affiliation: Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases and Rheumatology, Oncologic Center, Paracelsus Medical University Salzburg, Austria.|Salzburg Cancer Research Institute, Salzburg, Austria.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Brachtl
authors.affiliation: Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases and Rheumatology, Oncologic Center, Paracelsus Medical University Salzburg, Austria.|Salzburg Cancer Research Institute, Salzburg, Austria.
authors.forename: Daniela
authors.initials: D
authors.lastname: Asslaber
authors.affiliation: Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases and Rheumatology, Oncologic Center, Paracelsus Medical University Salzburg, Austria.|Salzburg Cancer Research Institute, Salzburg, Austria.
authors.forename: Peter William
authors.initials: PW
authors.lastname: Krenn
authors.affiliation: Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases and Rheumatology, Oncologic Center, Paracelsus Medical University Salzburg, Austria.|Salzburg Cancer Research Institute, Salzburg, Austria.
authors.forename: Tamara
authors.initials: T
authors.lastname: Girbl
authors.affiliation: Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases and Rheumatology, Oncologic Center, Paracelsus Medical University Salzburg, Austria.|Salzburg Cancer Research Institute, Salzburg, Austria.
authors.forename: Petra
authors.initials: P
authors.lastname: Berghammer
authors.affiliation: Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases and Rheumatology, Oncologic Center, Paracelsus Medical University Salzburg, Austria.|Salzburg Cancer Research Institute, Salzburg, Austria.
authors.forename: Roland
authors.initials: R
authors.lastname: Geisberger
authors.affiliation: Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases and Rheumatology, Oncologic Center, Paracelsus Medical University Salzburg, Austria.|Salzburg Cancer Research Institute, Salzburg, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Egle
authors.affiliation: Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, Aviano, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Zucchetto
authors.affiliation: NOXXON Pharma AG, Berlin, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Kruschinski
authors.affiliation: Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, Aviano, Italy.
authors.forename: Valter
authors.initials: V
authors.lastname: Gattei
authors.affiliation: Department of Pathology and Cancer Center, University of New Mexico, Albuquerque, NM, USA.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Chigaev
authors.affiliation: Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases and Rheumatology, Oncologic Center, Paracelsus Medical University Salzburg, Austria.|Salzburg Cancer Research Institute, Salzburg, Austria.
authors.forename: Richard
authors.initials: R
authors.lastname: Greil
authors.affiliation: Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases and Rheumatology, Oncologic Center, Paracelsus Medical University Salzburg, Austria.|Salzburg Cancer Research Institute, Salzburg, Austria.
authors.forename: Tanja Nicole
authors.initials: TN
authors.lastname: Hartmann
mesh_terms: D000818:Animals; D054421:Chemokine CCL21 / Q000235:genetics* / Q000378:metabolism*; D054377:Chemokine CXCL12 / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D051379:Mice; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C515478:CCL21 protein, human; C515255:CXCL12 protein, human; D054421:Chemokine CCL21; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4
keywords: CCR7; CD49d; CXCR4; homing; trisomy 12