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Abstract

Selective HDAC6 Inhibition Corrects Aberrant B Cell Development in the Bone Marrow of NZB/W F1 Mice

B cell development in the bone marrow is highly complex and includes vital regulatory checkpoints to maintain central tolerance. Defects in central tolerance are implicated in systemic lupus erythematosus (SLE) and aberrant B cell development has been reported in NZB/W mice. We hypothesized that altered B cell development in the bone marrow of lupus-prone NZB/W mice would be corrected after HDAC6 inhibition. B cell development was evaluated by flow cytometric analysis of Hardy fractions from bone marrow cells of NZB/W mice treated with an HDAC6 inhibitor or vehicle control. Additionally, deep sequence analysis of RNA from the bone marrow was utilized to identify potential targets of HDAC6. As NZB/W mice aged, there was an apparent shift in later stages of B cell development suggesting accelerated progression through maturation and potential to bypass key regulatory checkpoints. After HDAC6 inhibition, the alteration was corrected and RNAseq analysis revealed differential expression of 849 genes in the bone marrow. We focused on 6 genes related to B cell development and differentiation (ccr9, spib, pou2af1, nfil3, cebpb, and lgals1) and found that HDAC6 appears to have the most impact on expression of spiB, an early regulator of B cell development, and pou2af1, a regulator during later stages of B cell development. We conclude that HDAC6 inhibition helps correct aberrant B cell development and differentiation in the bone marrow of lupus-prone NZB/W mice. These results also identified new potential targets for HDAC6 regulation within the bone marrow, particularly spiB and pou2af1.


Author(s):

Miranda D Vieson, Xin M Luo, Song Li, Alexander M Gojmerac, Adrian Castaneda and Christopher M Reilly



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