O-GlcNAcylation of c-Myc dynamically regulates pre-B cell proliferation

Abstract 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 is largely unknown. Here, we demonstrate that changes in cellular O-GlcNAc levels significantly affect the growth of large pre-B cells transiently expressing pre-B cell receptors on their surface membrane, which are known to rapidly proliferate for the expansion of functional clones that express successfully rearranged heavy chains during early B cell development. Our study first show that overall O-GlcNAc levels in these proliferative pre-B cells are highly induced compared to pro-B cells, depending on pre-B cell receptor expression. Mechanistically, inhibition of O-GlcNAcylation in pre-B cells markedly decreases c-Myc expression, which results in downregulation of cell proliferation through the blocking of E- and A-type cyclin expressions. In addition, restriction of glucose uptake in pre-B cells also reduces cellular O-GlcNAc levels as well as c-Myc expression and subsequently decreases cell proliferation. Furthermore, the population of large pre-B cells in the bone marrow is significantly reduced by the administration of O-GlcNAc inhibitor to mice. Thus, our study strongly suggests that O-GlcNAcylation dependent expression of c-Myc is a new component in regulation of pre-B cell proliferation and also a potential therapeutic target for the treatment of pre-B cell acute lymphoblastic leukemia.