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American Journal of Hematology May 2016A tight relationship between the acute myeloid leukemia (AML) population and the bone marrow (BM) microenvironment has been convincingly established. The AML clone... (Review)
Review
A tight relationship between the acute myeloid leukemia (AML) population and the bone marrow (BM) microenvironment has been convincingly established. The AML clone contains leukemic stem cells (LSCs) that compete with normal hematopoietic stem cells (HSCs) for niche occupancy and remodel the niche; whereas, the BM microenvironment might promote AML development and progression not only through hypoxia and homing/adhesion molecules, but also through genetic defects. Although it is still unknown whether the niche influences treatment results or contains any potential target for treatment, this dynamic AML-niche interaction might be a promising therapeutic objective to significantly improve the AML cure rate.
Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Benzylamines; Bone Marrow; Cell Hypoxia; Cell Lineage; Chemokine CXCL12; Clinical Trials as Topic; Combined Modality Therapy; Cord Blood Stem Cell Transplantation; Cyclams; Diphosphonates; Disease Models, Animal; Heterocyclic Compounds; Humans; Intercellular Signaling Peptides and Proteins; Leukemia, Myeloid, Acute; Mice; Molecular Targeted Therapy; Neoplasm Proteins; Neoplastic Stem Cells; Protein Kinase Inhibitors; Receptors, CXCR4; Stem Cell Niche; Stromal Cells; Transplantation, Heterologous; Tumor Microenvironment
PubMed: 26822317
DOI: 10.1002/ajh.24312 -
Experimental Hematology Feb 2019Granulocyte colony-stimulating factor (G-CSF)-stimulated peripheral blood progenitor cells (G-PBs) from either a related or unrelated donor continue to be the preferred... (Review)
Review
Granulocyte colony-stimulating factor (G-CSF)-stimulated peripheral blood progenitor cells (G-PBs) from either a related or unrelated donor continue to be the preferred donor source for most allogeneic hematopoietic cell transplantation (HCT). Recently, the American Society for Blood and Marrow Transplantation has recommended marrow instead of G-PBs as an unrelated graft source due to its lower rate of chronic graft-versus-host disease (cGVHD). However, the use of marrow is limited by both clinical considerations (slower rate of engraftment and increased donor morbidity) and logistical considerations (use of operating room resources and increased physician utilization), so this recommendation has not been widely adopted. An optimal donor source would include the rapid engraftment characteristic and the low donor morbidity associated with G-PBs and a rate of cGVHD similar to or lower than that of marrow. Recent data suggest that plerixafor mobilized PBs (P-PBs) have the rapid engraftment characteristics of G-PBs in allogeneic HCT with less cGVHD. The biologic mechanism of the lower rate of cGVHD appears to be through mobilization of regulator natural killer cells and plasmacytoid dendritic cell precursors that are associated with lower acute and chronic GVHD compared with G-PBs and rapid engraftment characterized by rapid myeloid-repopulating capacity. We suggest that, based on the experience of the two Phase II clinical trials and the unique biology of plerixafor-mobilized donor product, it should be evaluated in Phase III trials as an approach to replacing G-CSF mobilization for allogeneic HCT.
Topics: Allografts; Benzylamines; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cyclams; Filgrastim; Hematopoietic Stem Cell Mobilization; Heterocyclic Compounds; Humans; Peripheral Blood Stem Cell Transplantation; Peripheral Blood Stem Cells
PubMed: 30428338
DOI: 10.1016/j.exphem.2018.11.003 -
American Journal of Physiology. Renal... Oct 2014We examined whether antagonism of the CXCR₄receptor ameliorates the loss of renal function following ischemia-reperfusion. CXCR₄is ubiquitously expressed on...
We examined whether antagonism of the CXCR₄receptor ameliorates the loss of renal function following ischemia-reperfusion. CXCR₄is ubiquitously expressed on leukocytes, known mediators of renal injury, and on bone marrow hematopoietic stem cells (HSCs). Plerixafor (AMD3100, Mozobil) is a small-molecule CXCR₄antagonist that mobilizes HSCs into the peripheral blood and also modulates the immune response in in vivo rodent models of asthma and rheumatoid arthritis. Treatment with plerixafor before and after ischemic clamping ameliorated kidney injury in a rat model of bilateral renal ischemia-reperfusion. Serum creatinine and blood urea nitrogen were significantly reduced 24 h after reperfusion, as were tissue injury and cell death. Plerixafor prevented the renal increase in the proinflammatory chemokines CXCL1 and CXCL5 and the cytokine IL-6. Flow cytometry of kidney homogenates confirmed the presence of significantly fewer leukocytes with plerixafor treatment; additionally, myeloperoxidase activity was reduced. AMD3465, a monocyclam analog of plerixafor, was similarly renoprotective. Four weeks postreperfusion, long-term effects included diminished fibrosis, inflammation, and ongoing renal injury. The mechanism by which CXCR₄inhibition ameliorates AKI is due to modulation of leukocyte infiltration and expression of proinflammatory chemokines/cytokines, rather than a HSC-mediated effect. The data suggest that CXCR₄antagonism with plerixafor may be a potential option to prevent AKI.
Topics: Acute Kidney Injury; Animals; Benzylamines; Chemokine CXCL12; Cyclams; Flow Cytometry; Hematopoietic Stem Cells; Heterocyclic Compounds; Kidney Function Tests; Leukocytes; Male; Pyridines; Rats, Sprague-Dawley; Rats, Wistar; Receptors, CXCR4; Reperfusion Injury
PubMed: 25080523
DOI: 10.1152/ajprenal.00685.2013 -
Cell Communication and Signaling : CCS May 2018The CXCR4 receptor antagonist plerixafor (AMD3100) is raising interest as an anti-cancer agent that disrupts the CXCL12-CXCR4 chemokine - receptor interaction between...
BACKGROUND
The CXCR4 receptor antagonist plerixafor (AMD3100) is raising interest as an anti-cancer agent that disrupts the CXCL12-CXCR4 chemokine - receptor interaction between neoplastic cells and their microenvironment in tumor progression and metastasis. Here, we investigated plerixafor for anti-cancer activity in Ewing sarcoma, a rare and aggressive cancer of bone and soft tissues.
METHODS
We used a variety of methods such as cell viability and migration assays, flow cytometry, phospho-tyrosine arrays and western blotting to determine plerixafor effects on five characterized Ewing sarcoma cell lines and a low-passage culture in vitro.
RESULTS
Unexpectedly, plerixafor led to an increase in cell viability and proliferation in standard cell growth conditions, and to chemotactic migration towards plerixafor. Exploring potential molecular mechanisms underlying this effect, we found that Ewing sarcoma cell lines divided into classes of high- and low-level CXCR4 surface expression. Proliferative plerixafor responses were observed in both groups, maintained despite significant CXCR4 down-regulation or inhibition of Gαi-protein signal transduction, and involved activation of multiple receptor tyrosine kinases (DDR2, MERTK, MST1R, NTRK1, RET), the most prominent being platelet-derived growth factor receptor beta (PDGFRB). PDGFRB was activated in response to inhibition of the CXCL12-CXCR4 axis by plerixafor and/or pertussis toxin (Gαi-protein inhibitor). Dasatinib, a multi-kinase inhibitor of both PDGFRB and the CXCR4 downstream kinase SRC, counteracted this activation in some but not all cell lines.
CONCLUSION
These data suggest a feedback interaction between the CXCR4 chemokine receptor and RTK signaling cascades that elicits compensatory cell survival signaling and can shift the net effect of plerixafor towards proliferation. PDGFRB was identified as a candidate driver RTK and potential therapeutic co-target for CXCR4 in Ewing sarcoma. Although as yet limited to in vitro studies, these findings call for further investigation in the cancer - microenvironment interplay in vivo.
Topics: Benzylamines; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chemotaxis; Cyclams; Enzyme Activation; Gene Expression Regulation, Neoplastic; Heterocyclic Compounds; Humans; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptor Protein-Tyrosine Kinases; Receptors, CXCR4; Sarcoma, Ewing; Signal Transduction
PubMed: 29776413
DOI: 10.1186/s12964-018-0233-2 -
Scientific Reports Mar 2020Today, we face difficulty in generating new hypotheses and understanding oral lichen planus due to the large amount of biomedical information available. In this...
Today, we face difficulty in generating new hypotheses and understanding oral lichen planus due to the large amount of biomedical information available. In this research, we have used an integrated bioinformatics approach assimilating information from data mining, gene ontologies, protein-protein interaction and network analysis to predict candidate genes related to oral lichen planus. A detailed pathway analysis led us to propose two promising therapeutic targets: the stromal cell derived factor 1 (CXCL12) and the C-X-C type 4 chemokine receptor (CXCR4). We further validated our predictions and found that CXCR4 was upregulated in all oral lichen planus tissue samples. Our bioinformatics data cumulatively support the pathological role of chemokines and chemokine receptors in oral lichen planus. From a clinical perspective, we suggest a drug (plerixafor) and two therapeutic targets for future research.
Topics: Benzylamines; Chemokine CXCL12; Computational Biology; Cyclams; Female; Genetic Association Studies; Heterocyclic Compounds; Humans; Lichen Planus, Oral; Male; Molecular Targeted Therapy; Mouth Mucosa; Receptors, CXCR4; Up-Regulation
PubMed: 32214134
DOI: 10.1038/s41598-020-62258-7 -
Zhonghua Xue Ye Xue Za Zhi = Zhonghua... Jan 2021To analyze the effect and safety of plerixafor combined with G-CSF mobilization in plasma cell disease. The clinical baseline data, success rate of collection, and...
To analyze the effect and safety of plerixafor combined with G-CSF mobilization in plasma cell disease. The clinical baseline data, success rate of collection, and adverse reactions of consecutive cases of plasma cell disease were analyzed retrospectively, where the patients received plerixafor combined with G-CSF for autologous hematopoietic stem cell mobilization in Peking University People's Hospital from January 2018 to December 2019. Forty-nine patients with plasma disease were included, of which 39 (79.6% ) were multiple myeloma, 8 (16.3% ) were amyloidosis, and 2 (4.1% ) were monoclonal gammopathy of renal significance. A total of 16 patients (32.7% ) had renal insufficiency, and 7 patients (14.3% ) had previous collection failure. The median times of apheresis was 1 (1-3) , median days of apheresis was 2 (1-3) days, 47 patients (95.9% ) were successfully collected for once, and the success rate of collection for twice was 100% after using plerixafor for mobilization. In 16 patients with renal insufficiency, collection was successful in 5 patients (31.3% ) on the first day, while aphresis was required in 8 patients (50% ) on the second day and 3 (18.8% ) on the third day. The main adverse reactions were fatigue, insomnia, abdominal pain, diarrhea, dizziness, and arthralgia. A total of 37 patients underwent autologous hematopoietic stem cell transplantation with 11 (8-13) days for neutrophil engraftment, and 11 (9-26) days for platelet engraftment. Plerixafor combined with G-CSF has a high success rate in mobilizaion of autologous hematopoietic stem cells in patients with plasma cell disease with minimum side effects, even in patients with renal insufficiency.
Topics: Benzylamines; Cyclams; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Heterocyclic Compounds; Humans; Multiple Myeloma; Plasma Cells; Retrospective Studies; Transplantation, Autologous
PubMed: 33677864
DOI: 10.3760/cma.j.issn.0253-2727.2021.01.005 -
Scientific Reports Dec 2021Allograft-specific regulatory T cells (T cells) are crucial for long-term graft acceptance after transplantation. Although adoptive T cell transfer has been proposed,...
Allograft-specific regulatory T cells (T cells) are crucial for long-term graft acceptance after transplantation. Although adoptive T cell transfer has been proposed, major challenges include graft-specificity and stability. Thus, there is an unmet need for the direct induction of graft-specific T cells. We hypothesized a synergism of the immunotolerogenic effects of rapamycin (mTOR inhibition) and plerixafor (CXCR4 antagonist) for T cell induction. Thus, we performed fully-mismatched heart transplantations and found combination treatment to result in prolonged allograft survival. Moreover, fibrosis and myocyte lesions were reduced. Although less CD3 T cell infiltrated, higher T cell numbers were observed. Noteworthy, this was accompanied by a plerixafor-dependent plasmacytoid dendritic cells-(pDCs)-mobilization. Furthermore, in vivo pDC-depletion abrogated the plerixafor-mediated T cell number increase and reduced allograft survival. Our pharmacological approach allowed to increase T cell numbers due to pDC-mediated immune regulation. Therefore pDCs can be an attractive immunotherapeutic target in addition to plerixafor treatment.
Topics: Allografts; Animals; Benzylamines; Biomarkers; Cyclams; Dendritic Cells; Disease Models, Animal; Drug Synergism; Graft Rejection; Graft Survival; Heart Transplantation; Immunomodulation; Mice; Prognosis; Receptors, CXCR4; Sirolimus; T-Lymphocytes, Regulatory; Transplantation Immunology; Treatment Outcome
PubMed: 34893663
DOI: 10.1038/s41598-021-03115-z -
Communications Biology May 2021Following the FDA-approval of the hematopoietic stem cell (HSC) mobilizer plerixafor, orally available and potent CXCR4 antagonists were pursued. One such proposition...
Following the FDA-approval of the hematopoietic stem cell (HSC) mobilizer plerixafor, orally available and potent CXCR4 antagonists were pursued. One such proposition was AMD11070, which was orally active and had superior antagonism in vitro; however, it did not appear as effective for HSC mobilization in vivo. Here we show that while AMD11070 acts as a full antagonist, plerixafor acts biased by stimulating β-arrestin recruitment while fully antagonizing G protein. Consequently, while AMD11070 prevents the constitutive receptor internalization, plerixafor allows it and thereby decreases receptor expression. These findings are confirmed by the successful transfer of both ligands' binding sites and action to the related CXCR3 receptor. In vivo, plerixafor exhibits superior HSC mobilization associated with a dramatic reversal of the CXCL12 gradient across the bone marrow endothelium, which is not seen for AMD11070. We propose that the biased action of plerixafor is central for its superior therapeutic effect in HSC mobilization.
Topics: Aminoquinolines; Animals; Benzimidazoles; Benzylamines; Butylamines; COS Cells; Cell Line, Tumor; Chlorocebus aethiops; Cyclams; Drug Delivery Systems; Female; Granulocyte Colony-Stimulating Factor; HEK293 Cells; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cells; Humans; Mice; Mice, Inbred C57BL; Pharmaceutical Preparations; Receptors, CXCR3; Receptors, CXCR4; beta-Arrestins
PubMed: 33980979
DOI: 10.1038/s42003-021-02070-9 -
American Journal of Physiology.... Aug 2018The interaction between C-X-C chemokine receptor type 4 (CXCR4) and its cognate ligand C-X-C motif chemokine ligand 12 (CXCL12) plays a critical role in regulating...
The interaction between C-X-C chemokine receptor type 4 (CXCR4) and its cognate ligand C-X-C motif chemokine ligand 12 (CXCL12) plays a critical role in regulating hematopoietic stem cell activation and subsequent cellular mobilization. Extensive studies of these genes have been conducted in mammals, but much less is known about the expression and function of CXCR4 and CXCL12 in non-mammalian vertebrates. In the present study, we identify simultaneous expression of CXCR4 and CXCL12 orthologs in the epigonal organ (the primary hematopoietic tissue) of the little skate, Leucoraja erinacea. Genetic and phylogenetic analyses were functionally supported by significant mobilization of leukocytes following administration of Plerixafor, a CXCR4 antagonist and clinically important drug. Our results provide evidence that, as in humans, Plerixafor disrupts CXCR4/CXCL12 binding in the little skate, facilitating release of leukocytes into the bloodstream. Our study illustrates the value of the little skate as a model organism, particularly in studies of hematopoiesis and potentially for preclinical research on hematological and vascular disorders.
Topics: Animals; Benzylamines; Chemokine CXCL12; Cyclams; Fish Proteins; Gene Expression Regulation; Hematopoietic Stem Cells; Heterocyclic Compounds; Leukocytes; Leukopoiesis; Phylogeny; Receptors, CXCR4; Signal Transduction; Skates, Fish; Transcriptome
PubMed: 29641231
DOI: 10.1152/ajpregu.00322.2017 -
Journal of Clinical Apheresis Dec 2019The use of granulocyte-colony stimulating factor (G-CSF) with or without chemotherapy to mobilize hematopoietic progenitor cells (HPCs) can result in significant...
The use of granulocyte-colony stimulating factor (G-CSF) with or without chemotherapy to mobilize hematopoietic progenitor cells (HPCs) can result in significant morbidity in light chain (AL) amyloidosis patients. Plerixafor, a strong inducer and mobilizer of HPCs, can be used as an adjunct to G-CSF to improve mobilization efficiency. We describe the outcomes for combined G-CSF/plerixafor mobilized patients with AL amyloidosis. We reviewed data of 53 consecutive AL amyloidosis patients who underwent combined G-CSF/plerixafor HPC mobilization between May 2011 and October 2017 at our institution. We evaluated patients for HPC collection efficiency, perimobilization toxicity and postautologous hematopoietic cell transplantation (autoHCT) outcomes. Median CD34 cell collection was 12.4 × 10 cells/kg (range 2.5 × 10 to 34.1 × 10 cells/kg) and 45 (85%) patients had collections of ≥5.0 × 10 CD34 cells/kg. There were no mobilization failures or perimobilization mortality. During mobilization, 37 (70%) patients had weight gain (median 1.3 kg, range 0.1-4) but none >10% body weight, 5 (10%) patients had diarrhea, and one patient each had hypotension and cardiac arrhythmia. Among the 31 patients analyzed for CD34 collection efficiency (CE), the median CD34 CE was 47% (range 36-62). At 5 years follow-up 82% and 84% of patients were progression-free and alive, respectively. Our results suggest that G-CSF/plerixafor mobilization is safe, well tolerated, and effective in AL amyloidosis.
Topics: Adult; Antigens, CD34; Benzylamines; Cyclams; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Heterocyclic Compounds; Humans; Immunoglobulin Light-chain Amyloidosis; Male; Middle Aged; Retrospective Studies; Survival Analysis; Transplantation, Autologous; Treatment Outcome
PubMed: 31566813
DOI: 10.1002/jca.21747