High VLA-4 expression is associated with adverse outcome and distinct gene expression changes in childhood B-cell precursor acute lymphoblastic leukemia at first relapse
High VLA-4 expression is associated with adverse outcome and distinct gene expression changes in childhood B-cell precursor acute lymphoblastic leukemia at first relapse
复制标题
VLA-4 高表达与儿童 B 细胞前体急性淋巴细胞白血病首次复发时的不良后果和明显的基因表达变化相关
作者：
S. Shalapour;J. Hof;R. Kirschner;L. Bastian;C. Eckert;J. Prada;G. Henze;A. von Stackelberg;K. Seeger
背景：对治疗的耐药性和随后的复发仍然是复发儿童急性淋巴细胞白血病临床治疗的主要挑战。骨髓环境通过激活不同的信号通路，如vla4和PI3K/Akt通路，在白血病细胞的生存和化疗耐药中发挥重要作用，我们研究了vla4在复发的b细胞前体急性淋巴细胞白血病儿童白血病细胞中的预后和生物学影响及其对白血病细胞对药物敏感性的影响。设计与方法：采用实时聚合酶链反应（real-time polymerase chain reaction）对56例复发性急性淋巴细胞白血病患者的白血病细胞中vlad4的表达进行定量分析，这些患者参加了柏林-法兰克福-梅斯特研究组的ALL-REZ BFM 2002试验。通过基于微阵列的mRNA谱分析研究了与vla4表达相关的基因表达变化。在白血病细胞和基质细胞共培养中研究了VLA-4信号通路对白血病细胞增殖和耐药的影响。结果首次复发时高表达的vla4与不良预后因素相关，对治疗的分子反应较差，无事件和总生存的概率明显较差。VLA-4的表达是一个独立的预后参数。通过比较VLA-4高表达与低表达的白血病细胞的基因表达谱，我们鉴定出27个主要参与PI3K/Akt、ephrin和Rho GTPase通路的差异表达基因。阻断VLA-4信号通路联合阿糖胞苷治疗可消除基质细胞的生长支持作用。结论高表达的vla4是复发性急性淋巴细胞白血病患儿预后不良的标志和潜在的治疗靶点，证实了与vla4相关的细胞相互作用和生物学效应在白血病细胞存活和治疗应答中起决定性作用。
Background 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. Design and Methods 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. Results 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. Conclusions 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.
影响因子：
20.3
作者：
Kharas, MG;Deane, JA;Fruman, DA
通讯作者：
Fruman, DA
影响因子：
20.3
作者：
Becker, Pamela S.;Kopecky, Kenneth J.;Appelbaum, Frederick R.
通讯作者：
Appelbaum, Frederick R.
影响因子：
20.3
作者：
Kuang, Shao-Qing;Bai, Hao;Garcia-Manero, Guillermo
通讯作者：
Garcia-Manero, Guillermo