Loss of IKKβ but not NF-κB p65 skews differentiation towards myeloid over erythroid commitment and increases myeloid progenitor self-renewal and functional long-term hematopoietic stem cells Public Deposited
- Creator
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Zhang, J.
- Other Affiliation: Johns Hopkins University
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Li, L.
- Other Affiliation: Johns Hopkins University
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Baldwin, A.S., Jr.
- Affiliation: College of Arts and Sciences, Department of Biology
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Friedman, A.D.
- Other Affiliation: Johns Hopkins University
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Paz-Priel, I.
- Other Affiliation: Johns Hopkins University
- Abstract
- NF-κB is an important regulator of both differentiation and function of lineage-committed hematopoietic cells. Targeted deletion of IκB kinase (IKK) β results in altered cytokine signaling and marked neutrophilia. To investigate the role of IKKβ in regulation of hematopoiesis, we employed Mx1-Cre mediated IKKβ conditional knockout mice. As previously reported, deletion of IKKβ in hematopoietic cells results in neutrophilia, and we now also noted decreased monocytes and modest anemia. Granulocyte-macrophage progenitors (GMPs) accumulated markedly in bone marrow of IKKβ deleted mice whereas the proportion and number of megakaryocyte-erythrocyte progenitors (MEP) decreased. Accordingly, we found a significantly reduced frequency of proerythroblasts and basophilic and polychromatic erythroblasts, and IKKβ-deficient bone marrow cells yielded a significantly decreased number of BFU-E compared to wild type. These changes are associated with elevated expression of C/EBPα, Gfi1, and PU.1 and diminished Gata1, Klf1, and SCL/Tal1 in IKKβ deficient Lineage-Sca1+c-Kit+ (LSK) cells. In contrast, no effect on erythropoiesis or expression of lineage-related transcription factors was found in marrow lacking NF-κB p65. Bone marrow from IKKβ knockout mice has elevated numbers of phenotypic long and short term hematopoietic stem cells (HSC). A similar increase was observed when IKKβ was deleted after marrow transplantation into a wild type host, indicating cell autonomous expansion. Myeloid progenitors from IKKβ- but not p65-deleted mice demonstrate increased serial replating in colony-forming assays, indicating increased cell autonomous self-renewal capacity. In addition, in a competitive repopulation assay deletion of IKKβ resulted in a stable advantage of bone marrow derived from IKKβ knockout mice. In summary, loss of IKKβ resulted in significant effects on hematopoiesis not seen upon NF-κB p65 deletion. These include increased myeloid and reduced erythroid transcription factors, skewing differentiation towards myeloid over erythroid differentiation, increased progenitor self-renewal, and increased number of functional long term HSCs. These data inform ongoing efforts to develop IKK inhibitors for clinical use.
- Date of publication
- 2015
- Keyword
- DOI
- Identifier
- PMID 26102347
- https://dx.doi.org/10.1371/journal.pone.0130441
- Resource type
- Article
- Rights statement
- In Copyright
- License
- Attribution 4.0 International
- Journal title
- PLoS ONE
- Journal volume
- 10
- Journal issue
- 6
- Language
- English
- Version
- Publisher
- ISSN
- 1932-6203
- Publisher
- Public Library of Science
- Parents:
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