Oncotarget

Research Papers:

CXCL12-induced VLA-4 activation is impaired in trisomy 12 chronic lymphocytic leukemia cells: a role for CCL21

Sylvia Ganghammer, Evelyn Hutterer, Elisabeth Hinterseer, Gabriele Brachtl, Daniela Asslaber, Peter William Krenn, Tamara Girbl, Petra Berghammer, Roland Geisberger, Alexander Egle, Antonella Zucchetto, Anna Kruschinski, Valter Gattei, Alexandre Chigaev, Richard Greil and Tanja Nicole Hartmann _

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Oncotarget. 2015; 6:12048-12060. https://doi.org/10.18632/oncotarget.3660

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Abstract

Sylvia Ganghammer1,2,*, Evelyn Hutterer1,2,*, Elisabeth Hinterseer1,2,*, Gabriele Brachtl1,2, Daniela Asslaber1,2, Peter William Krenn1,2, Tamara Girbl1,2, Petra Berghammer1,2, Roland Geisberger1,2, Alexander Egle1,2, Antonella Zucchetto3, Anna Kruschinski4, Valter Gattei3, Alexandre Chigaev5, Richard Greil1,2, Tanja Nicole Hartmann1,2

1 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

2 Salzburg Cancer Research Institute, Salzburg, Austria

3 Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, Aviano, Italy

4 NOXXON Pharma AG, Berlin, Germany

5 Department of Pathology and Cancer Center, University of New Mexico, Albuquerque, NM, USA

* These authors have contributed equally to this work

Correspondence to:

Tanja Nicole Hartmann, email:

Keywords: trisomy 12, homing, CD49d, CXCR4, CCR7

Received: January 19, 2015 Accepted: February 27, 2015 Published: March 26, 2015

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.


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