IKKα-mediated signaling circuitry regulates early B lymphopoiesis during hematopoiesis

Multiple transcription factors regulate B-cell commitment, which is coordinated with myeloid-erythroid lineage differentiation. NF-kappa B has long been speculated to regulate early B-cell development; however, this issue remains controversial. I kappa B kinase-alpha (IKK alpha) is required for splenic B-cell maturation but not for BM B-cell development. In the present study, we unexpectedly found defective BM B-cell development and increased myeloid-erythroid lineages in kinase-dead IKK alpha (KA/KA) knock-in mice. Markedly increased cytosolic p100, an NF-kappa B2-inhibitory form, and reduced nuclear NF-kappa B p65, ReIB, p50, and p52, and IKK alpha were observed in KA/KA splenic and BM B cells. Several B-and myeloid-erythroid cell regulators, including Pax5, were de-regulated in KA/KA BM B cells. Using fetal liver and BM congenic transplantations and deleting IKK alpha from early hematopoietic cells in mice, this defect was identified as being B cell-intrinsic and an early event during hematopoiesis. Re-introducing IKK alpha, Pax5, or combined NF-kappa B molecules promoted B-cell development but repressed myeloid-erythroid cell differentiation in KA/KA BM B cells. The results of the present study demonstrate that IKK alpha regulates B-lineage commitment via combined canonical and noncanonical NF-kappa B transcriptional activities to target Pax5 expression during hematopoiesis. (Blood. 2012;119(23):5467-5477)