CD82 regulates STAT5/IL-10 and supports survival of acute myelogenous leukemia cells

We recently reported that adhesion molecule CD82 is aberrantly expressed in CD34(+)/CD38(-) leukemia stem cells (LSCs). Here, we report the results of a functional analysis of CD82 in CD34(+)/CD38(-) acute myelogenous leukemia (AML) cells. Short hairpin (sh)RNA-mediated downregulation of CD82 resulted in a decrease in the level of IL-10. In contrast, forced expression of CD82 in CD34(+)/CD38(+) AML cells by transduction with CD82-expressing lentiviral particles resulted in an increase in the levels of IL-10. Notably, exposure of CD34(+)/CD38(-) AML cells to IL-10 stimulated clonogenic growth of these cells. Moreover, downregulation of CD82 by a shRNA dephosphorylated STAT5 in CD34(+)/CD38(-) AML cells. On the other hand, forced expression of CD82 resulted in increase in the levels of p-STAT5 in CD34(+)/CD38(+) AML cells. Chromatin immunoprecipitation (ChIP) assay results indicated that STAT5A binds to the promoter region of the IL-10 gene, while reporter gene assay results indicated stimulation of IL-10 expression at the transcriptional level. These results suggest that CD82 positively regulates the STAT5/IL-10 signaling pathway. Moreover, shRNA-mediated downregulation of CD82 expression in CD34(+)/CD38(-) AML cells dephosphorylated STAT5 in immunodeficient mice. Taken together, our data suggest that the CD82/STAT5/IL-10 signaling pathway is involved in the survival of CD34(+)/CD38(-) AML cells and may thus be a promising therapeutic target for eradication of AML LSCs. What's new? The self-renewal capacity of leukemic stem cells (LSCs), which initiate and maintain acute myelogenous leukemia (AML), is dependent on signal transducer and activator of transcription 5 (STAT5). But while STAT5 is a key therapeutic target for AML, analysis of its function and cooperation with other molecules remains incomplete. Here, the surface protein CD82 was found to positively regulate STAT5/IL-10 signaling in CD34(+)/CD38(-) AML cells, suggesting that it is involved in overseeing the survival of this AML cell population. The data indicate that therapeutic disruption of the CD82/STAT5/IL-10 pathway could be key to the eradication of LSCs in AML.