Iron homeostasis is critical for basic cellular functions and iron is used as a co-factor by many proteins that regulate transcription, proliferation and survival. Free iron is toxic to cells. Thus, iron homeostasis is tightly regulated. ABCB7 is an integral membrane protein found on mitochondrial inner membranes that belongs to the ABC (ATP-binding cassette) family of transporters. ABCB7 transports Fe-S-glutathione intermediates from the mitochondria to the cytoplasm for incorporation into ISCs (iron sulfur clusters). Inducible deletion of ABCB7 in Mx1-cre ABCB7 conditional knockout (cKO) mice resulted in rapid hematopoietic failure with multi-lineage defects in hematopoiesis. However, the function of ABCB7 in specific hematopoietic lineages has not been examined. We find that both mb1-cre ABCB7 conditional knockout (cKO) mice and CD2-icre ABCB7 cKO mice exhibit a severe block in B cell development with almost no IgM+ immature B cells produced. Deletion of ABCB7 using CD19-cre or CD23-cre had no effect on B cell development or peripheral B cell homeostasis, indicating a specific requirement for ABCB7 early in B cell development and demonstrating that ABCB7 is not simply required for survival. In mb1-cre or CD2-icre ABCB7 cKO mice, there is a decrease in B cell progenitors which express intracellular HC, and those present are unable to downregulate the surrogate light chain genes. Iron is a co-factor for many enzymes which regulate chromatin accessibility, including the Tet family of dioxygenases and most of the histone lysine demethylases (KDMs). Thus, the absence of ABCB7 may disrupt the function of these enzymes, altering the ability to appropriately regulate chromatin accessibility as B lymphocytes progress through key developmental checkpoints. We hypothesize that disruption of iron homeostasis by deletion of ABCB7 in B cell progenitors leads to a block in their development through dysregulation of iron-dependent chromatin-modifying enzymes, which will be examined in this proposal.
Iron metabolism is tightly regulated, as iron overload can be toxic yet it is a necessary co-factor in many enzymes including Tet dioxygenases and lysine demethylases. Disruption of iron homeostasis by deletion of ABCB7 in lymphocytes leads to a block in B lymphopoiesis. This proposal will examine the mechanisms behind the critical role for ABCB7 in regulating B cell development.
