Monomethylarsonous acid (MMA+3) inhibits IL-7 signaling in mouse pre-B cells

Abstract

Our previously published data show that As+3 in vivo and in vitro, at very low concentrations, inhibits lymphoid, but not myeloid stem cell development in mouse bone marrow. We also showed that the As+3 metabolite, monomethylarsonous acid (MMA+3), was responsible for the observed pre-B cell toxicity caused by As+3. Interleukin-7 (IL-7) is the primary growth factor responsible for pre-lymphoid development in mouse and human bone marrow, and Signal Transducer and Activator of Transcription 5 (STAT5) is a transcriptional factor in the IL-7 signaling pathway. We found that MMA+3 inhibited STAT5 phosphorylation at a concentration as low as 50 nM in mouse bone marrow pre-B cells. Inhibition of STAT5 phosphorylation by As+3 occurred only at a concentration of 500 nM. In the IL-7 dependent mouse pre-B 2E8 cell line, we also found selective inhibition of STAT5 phosphorylation by MMA+3, and this inhibition was dependent on effects on JAK3 phosphorylation. IL-7 receptor expression on 2E8 cell surface was also suppressed by 50 nM MMA+3 at 18 h. As further evidence for the inhibition of STAT5, we found that the induction of several genes required in B cell development, cyclin D1, E2A, EBF1, and PAX5, were selectively inhibited by MMA+3. Since 2E8 cells lack the enzymes responsible for the conversion of As+3 to MMA+3 in vitro, the results of these studies suggest that As+3 induced inhibition of pre-B cell formation in vivo is likely dependent on the formation of MMA+3 which in turn inhibits IL-7 signaling at several steps in mouse pre-B cells.