Alsadeq Ameera, Fedders Henning, Vokuhl Christian, Belau Nele M, Zimmermann Martin, Wirbelauer Tim, Spielberg Steffi, Vossen-Gajcy Michaela, Cario Gunnar, Schrappe Martin, Schewe Denis M
Department of General Pediatrics, ALL-BFM Study Group, Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
Kiel Pediatric Tumor Registry, Department of Pediatric Pathology, University Medical Center Schleswig-Holstein, Germany.
Haematologica. 2017 Feb;102(2):346-355. doi: 10.3324/haematol.2016.147744. Epub 2016 Sep 29.
Central nervous system infiltration and relapse are poorly understood in childhood acute lymphoblastic leukemia. We examined the role of zeta-chain-associated protein kinase 70 in preclinical models of central nervous system leukemia and performed correlative studies in patients. Zeta-chain-associated protein kinase 70 expression in acute lymphoblastic leukemia cells was modulated using short hairpin ribonucleic acid-mediated knockdown or ectopic expression. We show that zeta-chain-associated protein kinase 70 regulates CCR7/CXCR4 via activation of extracellular signal-regulated kinases. High expression of zeta-chain-associated protein kinase 70 in acute lymphoblastic leukemia cells resulted in a higher proportion of central nervous system leukemia in xenografts as compared to zeta-chain-associated protein kinase 70 low expressing counterparts. High zeta-chain-associated protein kinase 70 also enhanced the migration potential towards CCL19/CXCL12 gradients in vitro CCR7 blockade almost abrogated homing of acute lymphoblastic leukemia cells to the central nervous system in xenografts. In 130 B-cell precursor acute lymphoblastic leukemia and 117 T-cell acute lymphoblastic leukemia patients, zeta-chain-associated protein kinase 70 and CCR7/CXCR4 expression levels were significantly correlated. Zeta-chain-associated protein kinase 70 expression correlated with central nervous system disease in B-cell precursor acute lymphoblastic leukemia, and CCR7/CXCR4 correlated with central nervous system involvement in T-cell acute lymphoblastic leukemia patients. In multivariate analysis, zeta-chain-associated protein kinase 70 expression levels in the upper third and fourth quartiles were associated with central nervous system involvement in B-cell precursor acute lymphoblastic leukemia (odds ratio=7.48, 95% confidence interval, 2.06-27.17; odds ratio=6.86, 95% confidence interval, 1.86-25.26, respectively). CCR7 expression in the upper fourth quartile correlated with central nervous system positivity in T-cell acute lymphoblastic leukemia (odds ratio=11.00, 95% confidence interval, 2.00-60.62). We propose zeta-chain-associated protein kinase 70, CCR7 and CXCR4 as markers of central nervous system infiltration in acute lymphoblastic leukemia warranting prospective investigation.
儿童急性淋巴细胞白血病中枢神经系统浸润和复发的情况目前了解甚少。我们在中枢神经系统白血病的临床前模型中研究了ζ链相关蛋白激酶70的作用，并在患者中进行了相关性研究。使用短发夹核糖核酸介导的敲低或异位表达来调节急性淋巴细胞白血病细胞中ζ链相关蛋白激酶70的表达。我们发现ζ链相关蛋白激酶70通过激活细胞外信号调节激酶来调控CCR7/CXCR4。与低表达ζ链相关蛋白激酶70的急性淋巴细胞白血病细胞相比，高表达该激酶的细胞在异种移植中导致中枢神经系统白血病的比例更高。高表达ζ链相关蛋白激酶70还增强了体外向CCL19/CXCL12梯度的迁移潜能，CCR7阻断几乎消除了异种移植中急性淋巴细胞白血病细胞归巢至中枢神经系统的现象。在130例B细胞前体急性淋巴细胞白血病和117例T细胞急性淋巴细胞白血病患者中，ζ链相关蛋白激酶70与CCR7/CXCR4的表达水平显著相关。ζ链相关蛋白激酶70的表达与B细胞前体急性淋巴细胞白血病的中枢神经系统疾病相关，而CCR7/CXCR4与T细胞急性淋巴细胞白血病患者的中枢神经系统受累相关。在多变量分析中，ζ链相关蛋白激酶70表达水平处于上三分位数和上四分位数与B细胞前体急性淋巴细胞白血病的中枢神经系统受累相关（优势比分别为7.48，95%置信区间为2.06 - 27.17；优势比为6.86，95%置信区间为1.86 - 25.26）。上四分位数中CCR7的表达与T细胞急性淋巴细胞白血病的中枢神经系统阳性相关（优势比为11.00，95%置信区间为2.00 - 60.62）。我们提出ζ链相关蛋白激酶70、CCR7和CXCR4作为急性淋巴细胞白血病中枢神经系统浸润的标志物，值得进行前瞻性研究。
