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: 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, Tanja Nicole Hartmann
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 14 Pg. 12048-60 (May 20 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25895128 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CCL21 protein, human
• CXCL12 protein, human
• Chemokine CCL21
• Chemokine CXCL12
• Receptors, CXCR4

Topics

• Animals
• Chemokine CCL21 (genetics, metabolism)
• Chemokine CXCL12 (genetics, metabolism)
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (genetics)
• Mice
• Receptors, CXCR4 (genetics, metabolism)
• Signal Transduction