Laboratory for Immunological and Molecular Cancer Research, Third Medical Department with Hematology, Oncology, Hemostaseology, Infectiology and Rheumatology, Private Medical University Hospital, Salzburg, Austria.
PLoS One. 2011;6(8):e23758. doi: 10.1371/journal.pone.0023758. Epub 2011 Aug 18.
VLA-4 and CD38 predict a poor clinical outcome in chronic lymphocytic leukemia (CLL). We used CLL samples with discordant VLA-4/CD38 risk to address their individual roles in human bone marrow infiltration (BM), CLL cell homing to murine BM, and in supportive CLL cell-stromal cell interactions.
VLA-4, CD38, and Ki-67 expression was measured in CLL cells from peripheral blood (PB) and bone marrow (BM) aspirates. CLL BM infiltration rates, routinely determined by Pathology, were correlated to VLA-4 and CD38 expression. Short-term homing capacity of CLL cells was evaluated by adoptive transfer experiments. CLL cell viability and adhesion in stromal cell co-culture was determined.
About 20% of CLL samples in our cohort displayed discordant VLA-4 and CD38 risk, with either high VLA-4 and low CD38 risk or vice versa. Using particularly such samples, we observed that VLA-4, and not CD38, was responsible for recirculation of CLL cells to murine BM. Human BM infiltration was also significantly higher in patients with high VLA-4 risk but not high CD38 risk. However, both molecules acted as independent prognostic markers. While both VLA-4 and CD38 expression were increased in BM-derived CLL cells, and VLA-4+ and CD38+ subpopulations showed enriched Ki-67 expression, VLA-4 did not contribute to CLL cell protection by stromal cells in vitro.
Our data argue for a prominent role of VLA-4 but not CD38 expression in the homing of CLL cells to BM niches and in human BM infiltration, but only a limited role in their protection by stromal cells.
VLA-4 和 CD38 可预测慢性淋巴细胞白血病（CLL）的不良临床结局。我们使用具有不一致 VLA-4/CD38 风险的 CLL 样本，以解决它们在人类骨髓浸润（BM）、CLL 细胞归巢到小鼠 BM 以及支持性 CLL 细胞-基质细胞相互作用中的各自作用。
在来自外周血（PB）和骨髓（BM）抽吸物的 CLL 细胞中测量 VLA-4、CD38 和 Ki-67 的表达。通过病理学常规确定 CLL BM 浸润率，并将其与 VLA-4 和 CD38 表达相关联。通过过继转移实验评估 CLL 细胞的短期归巢能力。在基质细胞共培养中测定 CLL 细胞的活力和粘附。
在我们的队列中，约 20%的 CLL 样本显示出不一致的 VLA-4 和 CD38 风险，要么是高 VLA-4 和低 CD38 风险，要么相反。使用这些特定的样本，我们观察到 VLA-4 而不是 CD38 负责 CLL 细胞循环回到小鼠 BM。高 VLA-4 风险而非高 CD38 风险的患者中，人类 BM 浸润也显著更高。然而，这两个分子都是独立的预后标志物。尽管 VLA-4 和 CD38 表达在 BM 衍生的 CLL 细胞中均增加，并且 VLA-4+和 CD38+亚群显示出丰富的 Ki-67 表达，但 VLA-4 并没有在体外通过基质细胞来保护 CLL 细胞。
我们的数据表明 VLA-4 而不是 CD38 表达在 CLL 细胞归巢到 BM 龛位和人类 BM 浸润中起主要作用，但在它们由基质细胞保护方面作用有限。
