Abstract
O-linked β-N-acetylglucosamine (O-GlcNAc) modification regulates the activity of hundreds of nucleocytoplasmic proteins involved in a wide variety of cellular processes, such as gene expression, signaling, and cell growth; however, the mechanism underlying the regulation of B cell development and function by O-GlcNAcylation remains largely unknown. Here, we demonstrate that changes in cellular O-GlcNAc levels significantly affected the growth of pre-B cells, which rapidly proliferate to allow expansion of functional clones that express successfully rearranged heavy chains at the pro-B stage during early B cell development. In our study, the overall O-GlcNAc levels in these proliferative pre-B cells, which are linked to the glucose uptake rate, were highly induced when compared with those in pro-B cells. Thus, pharmacologically, genetically, or nutritionally, inhibition of O-GlcNAcylation in pre-B cells markedly downregulated c-Myc expression, resulting in cell cycle arrest via blockade of cyclin expression. Importantly, the population of B cells after the pro-B cell stage in mouse bone marrow was severely impaired by the administration of an O-GlcNAc inhibitor. These results strongly suggest that O-GlcNAcylation-dependent expression of c-Myc represents a new regulatory component of pre-B cell proliferation, as well as a potential therapeutic target for the treatment of pre-B cell-derived leukemia.
Highlights
During the course of B cell development, immunoglobulin (Ig) genes become sequentially activated by the regulation of V(D)J recombination mediated by recombination activating gene (RAG)-encoded recombinases and nonhomologous end-joining proteins [1]
In contrast to the dynamic changes in c-Myc expression dependent on cellular O-GlcNAc levels, the activity of canonical molecules previously recognized as primary regulators of pre-B cell proliferation, including pre-BCR, IL-7R, and Wnt/β-catenin, were unaffected by O-GlcNAc changes. These results suggested that the induction of O-GlcNAcylation in large pre-B cells during early B cell development was essential for the rapid proliferation of functional pre-B cell clones according to the
Cells during early B cell development [26], we hypothesized that rapidly proliferating large pre-B cells might consume additional glucose to support their active cell metabolism and subsequently upregulate cellular O-GlcNAc levels
Summary
During the course of B cell development, immunoglobulin (Ig) genes become sequentially activated by the regulation of V(D)J recombination mediated by recombination activating gene (RAG)-encoded recombinases and nonhomologous end-joining proteins [1]. The functionally rearranged Ig-heavy chains in pro-B cells can be assembled with surrogate light chains (SLCs) encoded by VpreB and λ5 to express pre-B cell receptor (pre-BCR) on the membrane surface, which indicates successful differentiation from the pro-B to the pre-B cell stage [2]. Once pre-BCR is adequately expressed, the pre-BCR-expressing large pre-B cells are transiently induced to rapidly proliferate and expand their functional clones. This phenomenon is a critical checkpoint during early B cell development [1,2].
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