Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, Berlin, Germany.
Haematologica. 2011 Nov;96(11):1627-35. doi: 10.3324/haematol.2011.047993. Epub 2011 Aug 9.
Resistance to therapy and subsequent relapse remain major challenges in the clinical management of relapsed childhood acute lymphoblastic leukemia. As the bone marrow environment plays an important role in survival and chemotherapy resistance of leukemia cells by activating different signaling pathways, such as the VLA-4 and PI3K/Akt pathways, we studied the prognostic and biological impact of VLA-4 expression in leukemia cells from children with relapsed B-cell precursor acute lymphoblastic leukemia and its influence on the sensitivity of the leukemia cells to drugs.
VLA-4 expression was quantified by real-time polymerase chain reaction in leukemia cells from 56 patients with relapsed acute lymphoblastic leukemia enrolled in the ALL-REZ BFM 2002 trial of the Berlin-Frankfurt-Münster study group. Gene expression changes related to VLA-4 expression were investigated by microarray-based mRNA profiling. The effect of VLA-4 signaling on proliferation and drug resistance was studied in co-cultures of leukemia and stromal cells.
High expression of VLA-4 at first relapse was associated with adverse prognostic factors, poor molecular response to therapy and significantly worse probabilities of event-free and overall survival. VLA-4 expression was an independent prognostic parameter. Comparing gene expression profiles of leukemia cells with high versus low VLA-4 expression, we identified 27 differentially expressed genes primarily involved in the PI3K/Akt, ephrin and Rho GTPase pathways. Blocking of VLA-4 signaling in combination with cytarabine treatment abolished the growth supportive effect of stromal cells.
Our results show that high VLA-4 expression is a marker of poor prognosis and a potential therapeutic target in children with relapsed acute lymphoblastic leukemia and confirm that cellular interactions and biological effects related to VLA-4 play a decisive role in the survival of leukemia cells and response to therapy. (ClinicalTrials.gov identifier: NCT00114348).
治疗耐药和随后的复发仍然是儿童复发急性淋巴细胞白血病临床管理的主要挑战。由于骨髓微环境通过激活不同的信号通路（如 VLA-4 和 PI3K/Akt 通路）在白血病细胞的存活和化疗耐药中发挥重要作用，我们研究了 VLA-4 在复发 B 细胞前体急性淋巴细胞白血病患儿白血病细胞中的表达及其对白血病细胞对药物敏感性的影响的预后和生物学影响。
采用实时聚合酶链反应定量检测 56 例复发急性淋巴细胞白血病患儿白血病细胞中 VLA-4 的表达，这些患儿均参与柏林-法兰克福-明斯特研究组 ALL-REZ BFM 2002 试验。通过基于微阵列的 mRNA 谱分析研究与 VLA-4 表达相关的基因表达变化。在白血病细胞与基质细胞的共培养中研究 VLA-4 信号对增殖和耐药性的影响。
首次复发时 VLA-4 高表达与不良预后因素、治疗后分子反应不良以及无事件生存和总生存概率显著降低相关。VLA-4 表达是独立的预后参数。比较 VLA-4 高表达与低表达白血病细胞的基因表达谱，我们发现 27 个差异表达基因主要涉及 PI3K/Akt、ephrin 和 Rho GTPase 通路。VLA-4 信号阻断联合阿糖胞苷治疗可消除基质细胞的生长支持作用。
我们的结果表明，高 VLA-4 表达是儿童复发急性淋巴细胞白血病预后不良的标志物，也是潜在的治疗靶点，并证实与 VLA-4 相关的细胞相互作用和生物学效应在白血病细胞的存活和对治疗的反应中起决定性作用。（临床试验标识符：NCT00114348）。
