CXCR2 and CXCL4 regulate survival and self-renewal of hematopoietic stem/progenitor cells

Sinclair, Amy; Park, Laura; Shah, Mansi; Drotar, Mark E.; Calaminus, Simon D. J.; Hopcroft, Lisa; Kinstrie, Ross; Guitart, Amélie V.; Dunn, Kirsty; Abraham, Sheela A.; Sansom, Owen J.; Michie, Alison M.; Machesky, Laura M.; Kranc, Kamil R.; Graham, Gerard J.; Pellicano, Francesca; Holyoake, Tessa L.

doi:10.1182/blood-2015-08-661785

Cited by 55 publications

(36 citation statements)

References 58 publications

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“…4h ). Interestingly, the genes critical for the function of the BM niche on hematopoiesis, such as Vcam1, Cxcl1 33 , and Cxcl2 34 , were downregulated in Asxl1 −/− BMSCs (Fig. 4i ; Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Loss of ASXL1 in the bone marrow niche dysregulates hematopoietic stem and progenitor cell fates

Zhang

Chen

et al. 2018

Cell Discov

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Somatic or de novo mutations of Additional sex combs-like 1 (ASXL1) frequently occur in patients with myeloid malignancies or Bohring-Opitz syndrome, respectively. We have reported that global loss of Asxl1 leads to the development of myeloid malignancies and impairs bone marrow stromal cell (BMSC) fates in mice. However, the impact of Asxl1 deletion in the BM niche on hematopoiesis remains unclear. Here, we showed that BMSCs derived from chronic myelomonocytic leukemia patients had reduced expression of ASXL1, which impaired the maintaining cord blood CD34+ cell colony-forming capacity with a myeloid differentiation bias. Furthermore, Asxl1 deletion in the mouse BMSCs altered hematopoietic stem and progenitor cell (HSC/HPC) pool and a preferential myeloid lineage increment. Immunoprecipitation and ChIP-seq analyses demonstrated a novel interaction of ASXL1 with the core subunits of RNA polymerase II (RNAPII) complex. Convergent analyses of RNA-seq and ChIP-seq data revealed that loss of Asxl1 deregulated RNAPII transcriptional function and altered the expression of genes critical for HSC/HPC maintenance, such as Vcam1. Altogether, our study provides a mechanistic insight into the function of ASXL1 in the niche to maintain normal hematopoiesis; and ASXL1 alteration in, at least, a subset of the niche cells induces myeloid differentiation bias, thus, contributes the progression of myeloid malignancies.

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Section: Resultsmentioning

confidence: 99%

Loss of ASXL1 in the bone marrow niche dysregulates hematopoietic stem and progenitor cell fates

Zhang

Chen

et al. 2018

Cell Discov

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“…Regulation by CXCR2 and CXCR4 is reciprocal, and our data could explain why granulocyte colony-stimulating factor administration preferentially mobilizes GPI-AP − cells (Johnson, et al 1998). In a recent study, CXCR2-deficient HSCs/progenitor cells exhibited reduced self-renewal capacity as measured in serial transplantation assays (Sinclair, et al 2016). MIF, a functional noncognate ligand for CXCR2 and CXCR4, controls inflammatory leucocyte recruitment (Bernhagen, et al 2007).…”

Section: Resultsmentioning

confidence: 99%

Whole transcriptome sequencing identifies increased CXCR2 expression in PNH granulocytes

et al. 2017

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Summary The aetiology of paroxysmal nocturnal haemoglobinuria (PNH) is a somatic mutation in the X-linked phosphatidylinositol glycan class A gene (PIGA), resulting in global deficiency of glycosyl phosphatidylinositol–anchored proteins (GPI-APs). This study applied RNA-sequencing to examine functional effects of the PIGA mutation in human granulocytes. CXCR2 expression was increased in GPI-AP− compared to GPI-AP+ granulocytes. Macrophage migration inhibitory factor, a CXCR2 agonist, was significantly higher in plasma of PNH patients. Nuclear factor-κB phosphorylation was upregulated in GPI-AP− compared with GPI-AP+ granulocytes. Our data suggest novel mechanisms in PNH, not obviously predicted by decreased production of the GPI moiety.

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“…Therefore, the exact precursors that CXCL1 and CXCL2 act on remain to be further explored. Recently, CXCR2 was reported to be differentially expressed in CD34 + stem/progenitor cells, which may provide a possibility for further studies. In conclusion, our results show that the expression of CXCL1 and CXCL2 in tumor cells and tumor‐infiltrated CD11b + myeloid cells is critically involved in the promotion of the generation of mo‐MDSC from bone marrow cells.…”

Section: Discussionmentioning

confidence: 99%

Chemokine (C‐X‐C motif) ligand 1 and CXCL2 produced by tumor promote the generation of monocytic myeloid‐derived suppressor cells

et al. 2018

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Accumulation of myeloid‐derived suppressor cells (MDSC) in tumor‐bearing hosts is a hallmark of tumor‐associated inflammation, which is thought to be a barrier to immunosurveillance. Multiple factors secreted by tumor cells and tumor stromal cells are reported to be involved in promoting the expansion of MDSC. Herein, we showed that s.c. inoculation of tumor cells and i.v. injection of tumor‐conditioned medium increased the number of MDSC. Subsequent investigation elucidated that chemokine (C‐X‐C motif) ligand 1 (CXCL1) and CXCL2, which were originally characterized as the chemokines of neutrophils, specifically promoted the expansion of monocytic MDSC (mo‐MDSC), a subtype of MDSC, in the presence of granulocyte‐macrophage colony‐stimulating factor. Depletion of CXCL1 or CXCL2 in B16F10 cells or in B16F10‐bearing mice noticeably decreased the generation of mo‐MDSC in bone marrow. Moreover, we found that, in addition to the tumor cells, tumor‐infiltrated CD11b+ myeloid cells also expressed CXCL1 and CXCL2. Furthermore, CXCL1‐ and CXCL2‐induced increase of mo‐MDSC was not correlated with chemotaxis, proliferation or apoptosis of mo‐MDSC. These findings show a novel role of CXCL1 and CXCL2 in promoting mo‐MDSC generation by favoring the differentiation of bone marrow cells in tumor‐bearing conditions, which suggests that inhibition of CXCL1 and CXCL2 could decrease mo‐MDSC generation and improve host immunosurveillance.

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CXCR2 and CXCL4 regulate survival and self-renewal of hematopoietic stem/progenitor cells

Abstract: Key Points Chemokine ligands CXCL1-4, 6, 10, 11, and 13 are upregulated in human quiescent HSCs with CXCR2 and CXCL4 regulating their survival. Genetic ablation of Cxcr2 or Cxcl4 in murine models induces initial expansion but eventual exhaustion of HSC in transplantation assays.

Cited by 55 publications

References 58 publications

Loss of ASXL1 in the bone marrow niche dysregulates hematopoietic stem and progenitor cell fates

Loss of ASXL1 in the bone marrow niche dysregulates hematopoietic stem and progenitor cell fates

Whole transcriptome sequencing identifies increased CXCR2 expression in PNH granulocytes

Chemokine (C‐X‐C motif) ligand 1 and CXCL2 produced by tumor promote the generation of monocytic myeloid‐derived suppressor cells

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