Ganghammer Sylvia, Hutterer Evelyn, Hinterseer Elisabeth, Brachtl Gabriele, Asslaber Daniela, Krenn Peter William, Girbl Tamara, Berghammer Petra, Geisberger Roland, Egle Alexander, Zucchetto Antonella, Kruschinski Anna, Gattei Valter, Chigaev Alexandre, Greil Richard, Hartmann Tanja Nicole
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.
Oncotarget. 2015 May 20;6(14):12048-60. doi: 10.18632/oncotarget.3660.
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.
归巢至不同的淋巴器官可使慢性淋巴细胞白血病（CLL）细胞接收促生存和增殖信号。细胞遗传学异常可显著影响CLL细胞的区室化。12号染色体三体（tri12）定义了一个具有特定临床特征且阴性预后标志物CD49d（整合素VLA - 4的α4亚基）水平升高的CLL亚组，CD49d是CLL细胞归巢至骨髓（BM）的关键调节因子。趋化因子诱导的VLA - 4由内向外激活，特别是通过CXCL12 - CXCR4轴，可增加各种细胞类型在表达VCAM - 1的内皮细胞上的滞留。在此，我们证明tri12 CLL中高CD49d表达伴随着CXCR4表达的降低。剖析这些改变的功能后果，我们观察到使用AMD3100或olaptesed pegol/NOX - A12阻断CXCR4 - CXCL12并不影响tri12 CLL细胞归巢至小鼠BM。同样，在血流条件下，CCL21 - CCR7而非CXCL12 - CXCR4相互作用触发了VLA - 4介导的tri12 CLL细胞与VCAM - 1的结合。与此一致，在实时动力学分析中，我们发现CCL21而非CXCL12能够在该CLL亚组中诱导VLA - 4由内向外的构象变化。我们的结果为tri12 CLL独特的临床生物学行为提供了新的见解，并强调了其在与微环境进行病理生理和治疗相关相互作用期间对特定趋化因子和整合素的利用。
