title: IKKα-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-κB has long been speculated to regulate early B-cell development; however, this issue remains controversial. IκB kinase-α (IKKα) 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 IKKα (KA/KA) knock-in mice. Markedly increased cytosolic p100, an NF-κB2-inhibitory form, and reduced nuclear NF-κB p65, RelB, p50, and p52, and IKKα 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 IKKα from early hematopoietic cells in mice, this defect was identified as being B cell-intrinsic and an early event during hematopoiesis. Reintroducing IKKα, Pax5, or combined NF-κB 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 IKKα regulates B-lineage commitment via combined canonical and noncanonical NF-κB transcriptional activities to target Pax5 expression during hematopoiesis.
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21701, USA.
authors.forename: Mumtaz Yaseen
authors.initials: MY
authors.lastname: Balkhi
authors.forename: Jami
authors.initials: J
authors.lastname: Willette-Brown
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
authors.forename: Zhisong
authors.initials: Z
authors.lastname: Chen
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
authors.forename: Denis C
authors.initials: DC
authors.lastname: Guttridge
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: Yinling
authors.initials: Y
authors.lastname: Hu
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D041905:Erythroid Cells / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D006410:Hematopoiesis; D051550:I-kappa B Kinase / Q000235:genetics* / Q000276:immunology; D050835:Interferon Regulatory Factors / Q000235:genetics; D038041:Lymphopoiesis; D051379:Mice; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology; D051757:PAX5 Transcription Factor / Q000235:genetics; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D000099218:Interferon Regulatory Factor-4
chemical_list: D051550:I-kappa B Kinase; D050835:Interferon Regulatory Factors; D016328:NF-kappa B; D051757:PAX5 Transcription Factor; D000099218:Interferon Regulatory Factor-4