IKK?-mediated signaling circuitry regulates early B lymphopoiesis during hematopoiesis.

ABSTRACT: Multiple transcription factors regulate B-cell commitment, which is coordinated with myeloid-erythroid lineage differentiation. NF-?B has long been speculated to regulate early B-cell development; however, this issue remains controversial. I?B kinase-? (IKK?) 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? (KA/KA) knock-in mice. Markedly increased cytosolic p100, an NF-?B2-inhibitory form, and reduced nuclear NF-?B p65, RelB, p50, and p52, and IKK? were observed in KA/KA splenic and BM B cells. Several B- and myeloid-erythroid-cell regulators, including Pax5, were deregulated in KA/KA BM B cells. Using fetal liver and BM congenic transplantations and deleting IKK? from early hematopoietic cells in mice, this defect was identified as being B cell-intrinsic and an early event during hematopoiesis. Reintroducing IKK?, Pax5, or combined NF-?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? regulates B-lineage commitment via combined canonical and noncanonical NF-?B transcriptional activities to target Pax5 expression during hematopoiesis.

SUBMITTER: Balkhi MY 

PROVIDER: S-EPMC3369682 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature