High Interleukin 15 Expression Characterizes Childhood Acute Lymphoblastic Leukemia with Involvement of the Central Nervous System.
Authors: Cario Gunnar , Teichert Anja , Rhein Peter , Schrauder Andre , Skokowa Julia , Ludwig Wolf-Dieter , Izraeli Shai , Welte Karl , Schlegelberger Brigitte , Schrappe Martin , Stanulla Martin 
Published: October 2019

Abstract
Targeted but risk-adapted therapy to the central nervous system (CNS) has become a prerequisite for successful treatment of childhood acute lymphoblastic leukemia (ALL). Overt CNS involvement is a rare observation in childhood ALL and commonly associated with a poorer outcome when compared to CNS-negative patients. Although there are some known risk factors for CNS involvement of ALL such as T-cell-precursor immunophenotype and high initial white blood cell (WBC) count, the underlying biology leading to CNS disease is poorly understood. We hypothesized that leukemic cells crossing the blood-brain barrier early have distinct biological properties which are reflected in a specific gene expression pattern. To test this hypothesis, we generated leukemic gene expression profiles of 17 patients with CNS involvement using 26 CNS-negative patients as controls. Microarrays containing more than 39,000 distinct cDNA clones (SFGF, Stanford CA) were used. Data were analyzed applying Significance Analysis of Microarrays (PNAS2001, 98, 5116–5121). Our analytical approach identified several differentially expressed genes. To control for possible T-cell contamination of the samples, we purified leukemic cells from four samples and repeated the analysis. Interleukin 15 (IL-15) was one of the genes for which differential expression could be confirmed with an up to 10-fold higher expression in CNS-positive patients. IL-15 is a pro-inflammatory cytokine known to stimulate proliferation and activation of T-lymphocytes and polymorphonuclear cells. Of importance with regard to the CNS, IL-15 was described to be highly expressed in peripheral blood (PBL) mononuclear cells in multiple sclerosis. The high expression of IL-15 in patients with CNS involvement was confirmed in an independent set of 13 CNS-positive and 26 CNS-negative patients by quantitative RT-PCR in a similar range as described above (P Mann-Whitney U-Test = <0.001). Therefore, we postulated that inflammatory processes might be involved in the pathogenesis of CNS disease by increasing the permeability of the blood-brain-barrier and reviewed differential PBL smears of 134 CNS-positive and 335 CNS-negative ALL patients. We observed a significantly higher ratio of immature to total myeloid cells in CNS-positive samples (P = <0.001). Next, we compared IL-15 expression at initial diagnosis of CNS-negative patients subsequently relapsing with CNS involvement (n = 22) to those without CNS disease and being in long-term remission (n = 18). Again, a significantly higher IL-15 expression was detected in patients with CNS relapse (P = 0.01). We conclude that measurement of IL-15 expression could serve as an additional tool to further tailor CNS-directed therapy in children newly diagnosed with ALL. Our results support a role for inflammatory processes, but additional studies are needed to finally elucidate the role of IL-15 and inflammation in the pathogenesis of CNS disease in childhood ALL.