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

Zhang, Jing; Li, Li; Baldwin, Albert S.; Friedman, Alan D.; Paz‐Priel, Ido

doi:10.1371/journal.pone.0130441

Cited by 17 publications

(29 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Data in graphs on the right are means Ϯ standard deviations for three independent experiments. *, P Ͻ 0.05; **P Ͻ 0.01. has been reported that conditional knockout of p65 or IKK␤ induces cell cycling of hematopoietic stem cells and increases their number (76,77). These observations suggest that inhibition of the NF-B pathway is one potential cause of the SET-Nup214-induced block of the differentiation of hematopoietic progenitor cells observed in SET-Nup214 transgenic mice.…”

Section: Discussionmentioning

confidence: 91%

Leukemia-Associated Nup214 Fusion Proteins Disturb the XPO1-Mediated Nuclear-Cytoplasmic Transport Pathway and Thereby the NF-κB Signaling Pathway

Saito

Cigdem

Okuwaki

et al. 2016

Molecular and Cellular Biology

View full text Add to dashboard Cite

c Nuclear-cytoplasmic transport through nuclear pore complexes is mediated by nuclear transport receptors. Previous reports have suggested that aberrant nuclear-cytoplasmic transport due to mutations or overexpression of nuclear pore complexes and nuclear transport receptors is closely linked to diseases. Nup214, a component of nuclear pore complexes, has been found as chimeric fusion proteins in leukemia. Among various Nup214 fusion proteins, SET-Nup214 and DEKNup214 have been shown to be engaged in tumorigenesis, but their oncogenic mechanisms remain unclear. In this study, we examined the functions of the Nup214 fusion proteins by focusing on their effects on nuclear-cytoplasmic transport. We found that SET-Nup214 and DEK-Nup214 interact with exportin-1 (XPO1)/CRM1 and nuclear RNA export factor 1 (NXF1)/TAP, which mediate leucine-rich nuclear export signal (NES)-dependent protein export and mRNA export, respectively. SET-Nup214 and DEK-Nup214 decreased the XPO1-mediated nuclear export of NES proteins such as cyclin B and proteins involved in the NF-B signaling pathway by tethering XPO1 onto nuclear dots where Nup214 fusion proteins are localized. We also demonstrated that SET-Nup214 and DEK-Nup214 expression inhibited NF-B-mediated transcription by abnormal tethering of the complex containing p65 and its inhibitor, IB, in the nucleus. These results suggest that SETNup214 and DEK-Nup214 perturb the regulation of gene expression through alteration of the nuclear-cytoplasmic transport system. Biological macromolecules are transported between the nucleus and the cytoplasm in response to extracellular signals. Transport of molecules with a molecular mass greater than 40 kDa does not occur by simple diffusion but is generally facilitated by nuclear transport receptors (NTRs) through nuclear pore complexes (NPCs) embedded in the nuclear envelope (1-3). Controlled nuclear-cytoplasmic transport plays important roles in maintaining cellular integrity in eukaryotic cells. It is reported that aberrant subcellular localization of some proteins is associated with various cancer cases (4). p53 has nuclear localization signals (NLSs) and nuclear export signals (NESs), and the accumulation of p53 in the cytoplasm has been reported to be a prognostic indicator in cancer (5). The nuclear factor B (NF-B) transcription factor is observed mainly in the cytoplasm in normal cells, whereas in many cancer cells, it is localized largely in the nucleus (6).In addition to aberrant subcellular localization of proteins in cancer, mutations of genes encoding NTRs and NPC components are found in various types of cancer (7). Mutations of exportin-5 (XPO5) and exportin-1 (XPO1)/CRM1, members of export receptors (8-10), are found in solid cancer and leukemia, respectively. Four nucleoporins-Nup98, Nup214/CAN, Nup358/ RanBP2, and Tpr-have been reported to form chimeric proteins by chromosomal translocations mainly in leukemia (11-15). Nup214, located at the cytoplasmic filament of the NPC, interacts with NTRs to control macromolecular transport....

show abstract

Section: Discussionmentioning

confidence: 91%

Leukemia-Associated Nup214 Fusion Proteins Disturb the XPO1-Mediated Nuclear-Cytoplasmic Transport Pathway and Thereby the NF-κB Signaling Pathway

Saito

Cigdem

Okuwaki

et al. 2016

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…Because the critical biological function of c-Rel appears to be mainly restricted to the adaptive immune system, it may represent a more suitable target than IKKβ/p65 to enhance checkpoint-targeting immunotherapies [ 249 ]. In addition, IKKβ deletion in mouse bone-marrow derived hematopoietic cells results in significant defects in haematopoiesis not seen upon p65 deletion, suggesting NF-κB-independent pathways may mediate some of the hematopoietic defects associated with IKKβ deletion/inhibition [ 250 ]. This provides further rationale for targeting NF-κB subunits directly.…”

Section: Alternative Approaches To Targeting the Nf-κb Pathwaymentioning

confidence: 99%

Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors

Prescott

Cook

2018

Cells

112

View full text Add to dashboard Cite

Deregulated NF-κB signalling is implicated in the pathogenesis of numerous human inflammatory disorders and malignancies. Consequently, the NF-κB pathway has attracted attention as an attractive therapeutic target for drug discovery. As the primary, druggable mediator of canonical NF-κB signalling the IKKβ protein kinase has been the historical focus of drug development pipelines. Thousands of compounds with activity against IKKβ have been characterised, with many demonstrating promising efficacy in pre-clinical models of cancer and inflammatory disease. However, severe on-target toxicities and other safety concerns associated with systemic IKKβ inhibition have thus far prevented the clinical approval of any IKKβ inhibitors. This review will discuss the potential reasons for the lack of clinical success of IKKβ inhibitors to date, the challenges associated with their therapeutic use, realistic opportunities for their future utilisation, and the alternative strategies to inhibit NF-κB signalling that may overcome some of the limitations associated with IKKβ inhibition.

show abstract

“…5FU was chosen as its effects on murine blood counts are well-defined. 21 Five days later, at the 5FU-induced nadir of blood counts, we infused Luc-IMC, which were then visualized by IVIS after an additional 2 days ( figure 2D). Luc-IMC were evident in PCa and PDC tumors as well as the lungs, spleen, and femurs, but not in heart or liver; the bioluminescence signal in the PDC tumor was ~2.5 fold higher than that of lung or spleen (online supplementary figure S1C).…”

Section: Open Accessmentioning

confidence: 99%

“…20 IMCs were then infused, avoiding provision of mature macrophages that might less efficiently reach the tumor. We also evaluated pretreatment with 5-fluorouracil (5FU) at a dose that induces a nadir of host white blood cells starting 4 days later and lasts 1 week, 21 analogous to lymphodepletion prior to adoptive T cell transfer. In addition, 5FU targets immunosuppressive tumor myeloid cells 22 and may release PCa or PDC neoantigens to further enhance antitumor response.…”

Section: Introductionmentioning

confidence: 99%

NF-κB p50-deficient immature myeloid cell (p50-IMC) adoptive transfer slows the growth of murine prostate and pancreatic ductal carcinoma

Suresh

Barakat

Barberi

et al. 2020

J Immunother Cancer

View full text Add to dashboard Cite

BackgroundMacrophages and dendritic cells lacking the transcription factor nuclear factor kappa B p50 are skewed toward a proinflammatory phenotype, with increased cytokine expression and enhanced T cell activation; additionally, murine melanoma, fibrosarcoma, colon carcinoma, and glioblastoma grow slower in p50−/−mice. We therefore evaluated the efficacy of p50-negative immature myeloid cells (p50-IMCs) adoptively transferred into tumor-bearing hosts. Immature cells were used to maximize tumor localization, and pretreatment with 5-fluorouracil (5FU) was examined due to its potential to impair marrow production of myeloid cells, to target tumor myeloid cells and to release tumor neoantigens.MethodsWild-type (WT)-IMC or p50-IMC were generated by culturing lineage-negative marrow cells from WT or p50−/−mice in media containing thrombopoietin, stem cell factor and Flt3 ligand for 6 days followed by monocyte colony-stimulating factor for 1 day on ultralow attachment plates. Mice inoculated with Hi-Myc prostate cancer (PCa) cells or K-RasG12Dpancreatic ductal carcinoma (PDC)-luciferase cells received 5FU followed 5 days later by three doses of 107immature myeloid cells (IMC) every 3–4 days.ResultsPCa cells grew slower in p50−/−mice, and absence of host p50 prolonged the survival of mice inoculated orthotopically with PDC cells. IMC from Cytomegalovirus (CMV)-luciferase mice localized to tumor, nodes, spleen, marrow, and lung. 5FU followed by p50-IMC slowed PCa and PDC tumor growth, ~3-fold on average, in contrast to 5FU followed by WT-IMC, 5FU alone or p50-IMC alone. Slowed tumor growth was evident for 93% of PCa but only 53% of PDC tumors; we therefore focused on PCa for additional IMC analyses. In PCa, p50-IMC matured into F4/80+macrophages, as well as CD11b+F4/80−CD11c+conventional dendritic cells (cDCs). In both tumor and draining lymph nodes, p50-IMC generated more macrophages and cDCs than WT-IMC. Activated tumor CD8+T cells were increased fivefold by p50-IMC compared with WT-IMC, and antibody-mediated CD8+T cell depletion obviated slower tumor growth induced by 5FU followed by p50-IMC.Conclusions5FU followed by p50-IMC slows the growth of murine prostate and pancreatic carcinoma and depends on CD8+T cell activation. Deletion of p50 in patient-derived marrow CD34+cells and subsequent production of IMC for adoptive transfer may contribute to the therapy of these and additional cancers.

show abstract

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

Cited by 17 publications

References 55 publications

Leukemia-Associated Nup214 Fusion Proteins Disturb the XPO1-Mediated Nuclear-Cytoplasmic Transport Pathway and Thereby the NF-κB Signaling Pathway

Leukemia-Associated Nup214 Fusion Proteins Disturb the XPO1-Mediated Nuclear-Cytoplasmic Transport Pathway and Thereby the NF-κB Signaling Pathway

Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors

NF-κB p50-deficient immature myeloid cell (p50-IMC) adoptive transfer slows the growth of murine prostate and pancreatic ductal carcinoma

Contact Info

Product

Resources

About