Abstract
Abstract ABCB7 is a mitochondrial iron transporter critical for cellular iron homeostasis, as its loss results in mitochondrial iron accumulation. ABCB7 has been demonstrated to be critical for embryogenesis and hematopoiesis, though its role in specific hematopoietic lineages is unexplored. We found that ABCB7 is required for lymphopoiesis, as CD2-iCre ABCB7 cKO mice have a severe block in both T and B lymphocyte development. The block in B cell development occurs at the Fr. C to Fr. C’ transition, where we found reduced expression of intracellular μ and pre-BCR, as well as reduced proliferation. We observed reduced expression of E2A, Ikaros, and Pax5, transcription factors essential for B cell lineage development. Previous literature has shown that deletion of ABCB7 results in mitochondrial iron accumulation. Because this is toxic to cells, we hypothesized that B cells increase heme synthesis in order to detoxify accumulating iron. In support of this, we found that HO-1, a surrogate marker for intracellular heme concentration, was elevated in B cells lacking ABCB7. Interestingly, heme levels regulate Bach2, a transcriptional repressor important for B cell development as it suppresses myeloid program in lymphocytes. Bach2 expression was found to be decreased in ABCB7-deficient B cells. We are currently examining the role of Bach2 and the mechanism responsible for the block in B cell development upon loss of ABCB7.
Published Version
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