In this study, we identify IL-6 as a major player in Pax5-dependent B-ALL pathogenesis, and we demonstrate that Pax5 activity dictates the level of IL-6 produced by both mouse and human leukemic B-cells, regulating IL-6 mRNA levels through BCL6 and the STAT5 pathway, which are two well known transcriptional regulators of the IL-6 gene24,48. Here, PAX5 is linked to precursor B-cell acute lymphoblastic leukemia.