Chemokine receptor expression in central nervous system (CNS) positive childhood acute lymphoblastic leukemia

Introduction:

CNS manifestation of ALL remains a rare condition in the pediatric population. Due to significant consequences for the therapy, diagnostic and prognostic markers however need to be established. Chemokine receptors (CRs) have been associated with CNS disease but comprehensive analyses of CR expression in CNS positive ALL patients have not been performed.

Methods:

mRNA expression levels of 10 CRs (CCR2, CCR3, CCR4, CCR5, CCR6, CCR8, CXCR3, CXCR4, CXCR5 and CXCR7) were measured in 127 BCP- (46 CNS+) and 117 T-ALL (24 CNS+) patient samples at initial diagnosis and correlated with clinical parameters.

Results:

Expression levels of CCR8 and CXCR4 were significantly elevated in CNS+ vs. CNS- T-ALL patients (p < 0.05, Mann-Whitney U-test). There were no such associations in BCP-ALL. In univariate regression analysis, CXCR4 expression in the highest quartile increased the likelihood of CNS positivity in T-ALL (odds ratio (OR)= 4.41, 95% CI 1.22 – 16.00, p < 0.05). This was also the case for CCR8 expression in the uppermost quartiles (OR = 4.41, 95% CI 1.04 – 18.71, p < 0.05). Expression of CCR6 in the highest quartile was associated with a reduction of the OR for CNS positivity in T-ALL (OR = 0.12, 95% CI 0.02 – 0.60, p = 0.01). In BCP-ALL, high expression of none of the chemokine receptors increased the likelihood of CNS positivity. In multivariate regression analysis including age and white blood cell count, the results for CXCR4 and CCR6, but not CCR8, in T-ALL were confirmed.

Conclusions:

Expression levels of several CRs were elevated in CNS+ vs. CNS- T-ALL but not BCP- ALL patients. Multivariate analysis showed that high CXCR4 and CCR8 expression levels were associated with higher rates of CNS positivity in T-ALL which needs to be validated via protein measurements, functional experiments and prospective testing.