We show that PAX2 and PAX5 exhibit transcriptional upregulation in response to hyperosmolarity in pre-B ALL cells, that PAX2 activation in lymphocytes, as in the kidney, is mediated by the tonicity response enhancer binding protein (TonEBP/NFAT5), and, finally, that hyperosmolarity-driven PAX2/5 activation correlates with changes in B cell developmental gene expression similar to those seen with exogenous PAX2/5/8 re-expression. The gene discussed is PAX5; the disease is acute lymphoblastic leukemia.