The role of ZAP70 kinase in acute lymphoblastic leukemia infiltration into the central nervous system

Abstract

C entral 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. Zetachain-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.

Involvement of the central nervous system in acute lymphoblastic leukemia: opinions on molecular mechanisms and clinical implications based on recent data

“…Moreover, knockdown of ZAP-70 in the BCP-ALL cell line 697 resulted in a significant decrease of CNS disease in vivo. High ZAP-70 expression in diagnostic BM samples of BCP-ALL patients was associated with a 7.5-fold increased risk for CNS disease [38]. Further data suggest that not only the pathway downstream of the preBCR is involved in CNS engraftment, but also the receptor complex itself.…”

“…Recently, evidence supporting the view that preBCR signaling is involved in CNS involvement of BCP-ALL has been accumulating. In BCP-ALL PDX cells xenografted into mice, high expression of the Zeta-chain-associated protein kinase 70 (ZAP-70) which acts directly downstream the preBCR was found to be associated with the ability to engraft in the CNS [38]. Moreover, knockdown of ZAP-70 in the BCP-ALL cell line 697 resulted in a significant decrease of CNS disease in vivo.…”

“…Studies have shown that one of the key regulators in CNS infiltration via IL15 and ZAP-70 is the mitogen-activated kinase (MAP-kinase) extracellular-signal regulated kinase (ERK) [35,38]. The RAS-RAF-MEK-ERK pathway represents one of the major axis for preBCR-mediated signaling transduction [41].…”

IL7R is associated with CNS infiltration and relapse in pediatric B-cell precursor acute lymphoblastic leukemia

“…These data suggest that increased IL7R expression levels in bone marrow (BM) leukemic cells are associated with and may predict CNS disease at initial diagnosis. IL7R expression also significantly correlated with z-chain-associated protein kinase 70 (ZAP70), which is another marker for CNS infiltration 15 (supplemental Figure 2A). However, combining both markers did not yield superior correlations (supplemental Figure 2B).…”

“…Chemotherapy was administered as previously published. 15,22 A total of 1 mg/kg anti-IL7R antibody (monoclonal mouse immunoglobulin G1 [IgG1], clone 40131; R&D Systems) or isotype control antibody were administered on days 0, 13, 17, 121, 135, 148, and 156 postinjection.…”