| First Author | Balkhi MY | Year | 2012 |
| Journal | Blood | Volume | 119 |
| Issue | 23 | Pages | 5467-77 |
| PubMed ID | 22544702 | Mgi Jnum | J:188639 |
| Mgi Id | MGI:5441384 | Doi | 10.1182/blood-2012-01-401547 |
| Citation | Balkhi MY, et al. (2012) IKKalpha-mediated signaling circuitry regulates early B lymphopoiesis during hematopoiesis. Blood 119(23):5467-77 |
| abstractText | Multiple transcription factors regulate B-cell commitment, which is coordinated with myeloid-erythroid lineage differentiation. NF-kappaB has long been speculated to regulate early B-cell development; however, this issue remains controversial. IkappaB kinase-alpha (IKKalpha) 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 IKKalpha (KA/KA) knock-in mice. Markedly increased cytosolic p100, an NF-kappaB2-inhibitory form, and reduced nuclear NF-kappaB p65, RelB, p50, and p52, and IKKalpha 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 IKKalpha from early hematopoietic cells in mice, this defect was identified as being B cell-intrinsic and an early event during hematopoiesis. Reintroducing IKKalpha, Pax5, or combined NF-kappaB 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 IKKalpha regulates B-lineage commitment via combined canonical and noncanonical NF-kappaB transcriptional activities to target Pax5 expression during hematopoiesis. |
