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CD22 (also known as Siglec-2) is a member of the Siglec family of glycan-recognition proteins and functions as a negative regulator of the B-cell receptor-mediated calcium signaling. Although the low level of CD22 expression on the B cells in patients with chronic lymphocytic leukemia (CLL) has been documented, CD22's role and its downregulation mechanism in CLL are yet to be fully studied. In this study, we confirmed that the surface CD22 protein and its mRNA are downregulated in the B cells of CLL patients. We analyzed a public transcriptomic dataset and found that the CD22 mRNA level is negatively associated with the prognosis of patients with CLL. To investigate the mechanism of CD22 downregulation, we characterized the minimal promoter of the human CD22 gene required for its transcriptional activation in B cell lines. We employed an unbiased proteomic approach to identify several transcription factors binding to the minimal CD22 promoter, including PU.1, Spi-B, and IRF4. The chromatin immunoprecipitation-quantitative PCR revealed that PU.1 was enriched in a CD22-high cell line, while IRF4 was enriched in a CD22-low cell line. We then conducted overexpression/knockout/knockdown experiments, which validated that PU.1 and Spi-B positively, and IRF4 negatively, regulate CD22 transcription. Our study thus provides insights into the transcriptional regulation of CD22 and the mechanism by which CD22 expression is downregulated in the B cells of patients with CLL.
Enkhbayar et al. (Wed,) studied this question.