Abstract
Abstract Patients with iron overload disorders often develop lymphocyte deficiencies, indicating iron homeostasis is critical for lymphopoiesis. Loss of ABCB7, a mitochondrial iron transporter, leads to mitochondrial iron accumulation and rapid hematopoietic failure. We found that ABCB7 is required for lymphopoiesis, as CD2-icre ABCB7 cKO mice have a severe block in both T and B cell development. The block in T cell development occurs at the DN3 stage. This DN3 block is not due to aberrant β-selection, proliferation, or viability. The block in B cell development occurs at the Fr. C to Fr. C′ transition. Pre-BCR expression was reduced in developing B cells and they exhibited reduced proliferation compared to WT B cells. Because loss of ABCB7 causes mitochondrial iron accumulation, which is toxic to cells, we hypothesized that lymphoid cells increase heme synthesis in order to detoxify the accumulating iron. We found that HO-1, a surrogate marker for intracellular heme levels, was elevated in these lymphocytes. Currently, we are examining the mechanism responsible for the block in lymphocyte development upon loss of ABCB7.
Published Version
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