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Journal of Leukocyte Biology Jul 2023CR3 (CD11b/CD18; αmβ2 integrin) is a conserved phagocytic receptor. The active conformation of CR3 binds the iC3b fragment of complement C3 as well as many host and...
CR3 (CD11b/CD18; αmβ2 integrin) is a conserved phagocytic receptor. The active conformation of CR3 binds the iC3b fragment of complement C3 as well as many host and microbial ligands, leading to actin-dependent phagocytosis. There are conflicting reports about how CR3 engagement affects the fate of phagocytosed substrates. Using imaging flow cytometry, we confirmed that binding and internalization of iC3b-opsonized polystyrene beads by primary human neutrophils was CR3-dependent. iC3b-opsonized beads did not stimulate neutrophil reactive oxygen species, and most beads were found in primary granule-negative phagosomes. Similarly, Neisseria gonorrhoeae that does not express phase-variable Opa proteins suppresses neutrophil reactive oxygen species and delays phagolysosome formation. Here, binding and internalization of Opa-deleted (Δopa) N. gonorrhoeae by adherent human neutrophils was inhibited using blocking antibodies against CR3 and by adding neutrophil inhibitory factor, which targets the CD11b I-domain. No detectable C3 was deposited on N. gonorrhoeae in the presence of neutrophils alone. Conversely, overexpressing CD11b in HL-60 promyelocytes enhanced Δopa N. gonorrhoeae phagocytosis, which required the CD11b I-domain. Phagocytosis of N. gonorrhoeae was also inhibited in mouse neutrophils that were CD11b-deficient or treated with anti-CD11b. Phorbol ester treatment upregulated surface CR3 on neutrophils in suspension, enabling CR3-dependent phagocytosis of Δopa N. gonorrhoeae. Neutrophils exposed to Δopa N. gonorrhoeae had limited phosphorylation of Erk1/2, p38, and JNK. Neutrophil phagocytosis of unopsonized Mycobacterium smegmatis, which also resides in immature phagosomes, was CR3-dependent and did not elicit reactive oxygen species. We suggest that CR3-mediated phagocytosis is a silent mode of entry into neutrophils, which is appropriated by diverse pathogens to subvert phagocytic killing.
Topics: Mice; Animals; Humans; Neutrophils; Reactive Oxygen Species; Phagocytosis; Macrophage-1 Antigen; Complement C3b; Receptors, Complement
PubMed: 36882066
DOI: 10.1093/jleuko/qiad028 -
Liver Research Sep 2023Retinoic acid (RA) is a metabolite of vitamin A and is essential for development and growth as well as cellular metabolism. Through genomic and nongenomic actions, RA...
Retinoic acid (RA) is a metabolite of vitamin A and is essential for development and growth as well as cellular metabolism. Through genomic and nongenomic actions, RA regulates a variety of physiological functions. Dysregulation of RA signaling is associated with many diseases. Targeting RA signaling has been proven valuable to human health. All-trans retinoic acid (AtRA) and anthracycline-based chemotherapy are the standard treatment of acute promyelocytic leukemia (APL). Both human and animal studies have shown a significant relationship between RA signaling and the development and progression of nonalcoholic fatty liver disease (NAFLD). In this review article, we will first summarize vitamin A metabolism and then focus on the role of RA signaling in NAFLD. AtRA inhibits the development and progression of NAFLD via regulating lipid metabolism, inflammation, thermogenesis, etc.
PubMed: 37854944
DOI: 10.1016/j.livres.2023.07.002 -
European Journal of Haematology Oct 2023The prognostic value of the mutation types and dynamics of FLT3-ITD in acute myeloid leukemia (AML) and other known factors were studied.
OBJECTIVE
The prognostic value of the mutation types and dynamics of FLT3-ITD in acute myeloid leukemia (AML) and other known factors were studied.
METHODS
Initial and follow-up samples from 45 AML patients with FLT3-ITD mutations were analyzed by fragment length analysis, Sanger sequencing, and next-generation sequencing.
RESULTS
Some patients (13%) had multiple FLT3-ITD mutations, and many of them had acute promyelocytic leukemia (APL). FLT3-ITD mutations were classified according to mutation types, including duplication-only FLT3-ITD (52%) and FLT3-ITD with duplications and insertions (dup + ins) (48%). The dup + ins FLT3-ITD variant was independently associated with poor prognosis among non-APL patients (odds ratio, 2.92) in addition to FLT3-ITD with ≥50% variant allele frequency (VAF). The VAFs of FLT3-ITD were low (median 2.2%) when detected during morphologic complete remission (CR) after conventional chemotherapy; however, in two patients treated with gilteritinib after relapse, the VAFs of FLT3-ITD were much higher (>95% and 8.1%) in the morphologic CR state.
CONCLUSIONS
The type of FLT3-ITD mutation is important in prognosis, and the dup + ins type of FLT3-ITD can be an indicator of poor prognosis. In addition, the FLT3-ITD mutation status may unexpectedly not match the morphologic examination results after gilteritinib treatment.
Topics: Humans; Prognosis; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Mutation; fms-Like Tyrosine Kinase 3
PubMed: 37435718
DOI: 10.1111/ejh.14044 -
Blood Advances Sep 2023Acute promyelocytic leukemia (APL) is associated with a high risk of bleeding and thrombosis. APL patients have an activated coagulation system, hyperfibrinolysis, and...
Acute promyelocytic leukemia (APL) is associated with a high risk of bleeding and thrombosis. APL patients have an activated coagulation system, hyperfibrinolysis, and thrombocytopenia. APL cells express tissue factor (TF), a receptor and cofactor for factor VII/VIIa. This study had 2 goals. Firstly, we measured biomarkers of coagulation and fibrinolysis activation as well as platelet counts and bleeding in both mouse xenograft and allograft models of APL. Secondly, we determined the effect of inhibiting TF on the activation of coagulation in these models. We observed increased levels of plasma thrombin-antithrombin complexes (TAT), D-dimer, and plasmin-antiplasmin complexes, reduced platelet counts, and increased tail bleeding in both mouse models of APL. Fibrinogen levels decreased in the xenograft model but not in the allograft model. In contrast, the red blood cell count decreased in the allograft model but not in the xenograft model. Inhibition of APL-derived human TF with an anti-human TF monoclonal antibody reduced the level of TAT, increased platelet count, and normalized tail bleeding in a xenograft model. Inhibition of all sources of TF (APL cells and host cells) in the allograft model with a rat anti-mouse TF monoclonal antibody decreased the levels of TAT but did not affect the platelet count. Our study demonstrates that TF plays a central role in the activation of coagulation in both the xenograft and allograft mouse models of APL. These APL mouse models can be used to investigate the mechanisms of coagulopathy and thrombocytopenia in APL.
Topics: Humans; Animals; Rats; Leukemia, Promyelocytic, Acute; Thromboplastin; Blood Coagulation; Blood Coagulation Disorders; Hemorrhage; Thrombocytopenia; Antibodies, Monoclonal
PubMed: 37450381
DOI: 10.1182/bloodadvances.2023010466 -
Current Research in Pharmacology and... 2023Acute promyelocytic leukemia (APL)/blood cancer is M3 type of acute myeloid leukemia (AML) formed inside bone marrow through chromosomal translocation mutation usually... (Review)
Review
Acute promyelocytic leukemia (APL)/blood cancer is M3 type of acute myeloid leukemia (AML) formed inside bone marrow through chromosomal translocation mutation usually between chromosome 15 & 17. It accounts around 10% cases of AML worldwide. Trisenox (TX/ATO) is used in chemotherapy for treatment of all age group of APL patients with highest efficacy and survival rate for longer period. High concentration of TX inhibits growth of APL cells by diverse mechanism however, it cures only PML-RARα fusion gene/oncogene containing APL patients. TX resistant APL patients (different oncogenic make up) have been reported from worldwide. This review summarizes updated mechanism of TX action via PML nuclear bodies formation, proteasomal degradation, autophagy, p53 activation, telomerase activity, heteromerization of pRb & E2F, and regulation of signaling mechanism in APL cells. We have also provided important information of combination therapy of TX with other molecules mechanism of action in acute leukemia cells. It provides updated information of TX action for researcher which may help finding new target for further research in APL pathophysiology or new TX resistant APL patients drug designing.
PubMed: 38074774
DOI: 10.1016/j.crphar.2023.100166 -
Viruses Nov 2023Nuclear bodies (NBs) are dynamic structures present in eukaryotic cell nuclei. They are not bounded by membranes and are often considered biomolecular condensates,... (Review)
Review
Nuclear bodies (NBs) are dynamic structures present in eukaryotic cell nuclei. They are not bounded by membranes and are often considered biomolecular condensates, defined structurally and functionally by the localisation of core components. Nuclear architecture can be reorganised during normal cellular processes such as the cell cycle as well as in response to cellular stress. Many plant and animal viruses target their proteins to NBs, in some cases triggering their structural disruption and redistribution. Although not all such interactions have been well characterised, subversion of NBs and their functions may form a key part of the life cycle of eukaryotic viruses that require the nucleus for their replication. This review will focus on Cajal bodies (CBs) and the viruses that target them. Since CBs are dynamic structures, other NBs (principally nucleoli and promyelocytic leukaemia, PML and bodies), whose components interact with CBs, will also be considered. As well as providing important insights into key virus-host cell interactions, studies on Cajal and associated NBs may identify novel cellular targets for development of antiviral compounds.
Topics: Animals; Nuclear Proteins; Coiled Bodies; Cell Nucleus; Viruses; Virus Diseases; Promyelocytic Leukemia Protein
PubMed: 38140552
DOI: 10.3390/v15122311 -
Leukemia Research Jul 2023Accelerated phase (AP) CML at onset and have poorer prognosis than CP-CML. We hypothesize that off-license use of second generation TKI (TKI2) as front-line therapy... (Observational Study)
Observational Study
Accelerated phase (AP) CML at onset and have poorer prognosis than CP-CML. We hypothesize that off-license use of second generation TKI (TKI2) as front-line therapy might counterbalance this poor prognosis, with limited toxicity. In "real-life" conditions, newly diagnosed patients meeting the ELN cytological criteria for AP-CML or harboring ACA and treated with first-line TKI2 were included in this retrospective multicenter observational study. We enrolled 69 patients [69.5 % male, median age 49.5 years, median follow-up 43.5 months], segregated into hematologic AP [HEM-AP (n = 32)] and cytogenetically defined AP [ACA-AP (n = 37)]. Hematologic parameters were worse in HEM-AP [spleen size (p = 0.014), PB basophils (p < .001), PB blasts (p < .001), PB blasts+promyelocytes (p < .001), low hemoglobin levels (p < .001)]. Dasatinib was initiated in 56 % patients in HEM-AP and in 27 % in ACA-AP, nilotinib in 44 % and 73 % respectively. Response and survival do not differ, regardless of the TKI2: 81 % vs 84.3 % patients achieved CHR, 88 % vs 84 % CCyR, 73 % vs 75 % MMR respectively. The estimated 5-year PFS 91.5 % (95%CI: 84.51-99.06 %) and 5-year OS 96.84 % (95%CI: 92.61-100 %). Only BM blasts (p < 0.001) and BM blasts+promyelocytes (p < 0.001) at diagnosis negatively influenced OS. TKI2 as front-line therapy in newly diagnosed AP-CML induce excellent responses and survival, and counterbalance the negative impact of advanced disease phase.
Topics: Humans; Male; Middle Aged; Female; Imatinib Mesylate; Tyrosine Kinase Inhibitors; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Dasatinib; Pyrimidines; Treatment Outcome; Protein Kinase Inhibitors
PubMed: 37230027
DOI: 10.1016/j.leukres.2023.107308 -
Genome Biology Dec 2023Point mutations in histone variant H3.3 (H3.3K27M, H3.3G34R) and the H3.3-specific ATRX/DAXX chaperone complex are frequent events in pediatric gliomas. These H3.3 point...
BACKGROUND
Point mutations in histone variant H3.3 (H3.3K27M, H3.3G34R) and the H3.3-specific ATRX/DAXX chaperone complex are frequent events in pediatric gliomas. These H3.3 point mutations affect many chromatin modifications but the exact oncogenic mechanisms are currently unclear. Histone H3.3 is known to localize to nuclear compartments known as promyelocytic leukemia (PML) nuclear bodies, which are frequently mutated and confirmed as oncogenic drivers in acute promyelocytic leukemia.
RESULTS
We find that the pediatric glioma-associated H3.3 point mutations disrupt the formation of PML nuclear bodies and this prevents differentiation down glial lineages. Similar to leukemias driven by PML mutations, H3.3-mutated glioma cells are sensitive to drugs that target PML bodies. We also find that point mutations in IDH1/2-which are common events in adult gliomas and myeloid leukemias-also disrupt the formation of PML bodies.
CONCLUSIONS
We identify PML as a contributor to oncogenesis in a subset of gliomas and show that targeting PML bodies is effective in treating these H3.3-mutated pediatric gliomas.
Topics: Adult; Child; Humans; Brain Neoplasms; Glioma; Histones; Mutation; Promyelocytic Leukemia Nuclear Bodies
PubMed: 38066546
DOI: 10.1186/s13059-023-03122-5 -
Blood Oct 2023
Topics: Humans; Leukemia, Promyelocytic, Acute; Karyotyping; Karyotype; Translocation, Genetic
PubMed: 37824159
DOI: 10.1182/blood.2023021869 -
American Journal of Translational... 2023Arsenic is one of the greatest hazards as an environmental carcinogen. At the same time it is also a promising anticancer agent, that can be used to treat acute...
OBJECTIVES
Arsenic is one of the greatest hazards as an environmental carcinogen. At the same time it is also a promising anticancer agent, that can be used to treat acute promyelocytic leukemia (APL) and some other tumors. Arsenic trioxide (ATO) exerts its therapeutic effect by promoting degradation of an oncogenic protein that drives the growth of APL cells. However, the molecular mechanisms that govern these paradoxical effects of arsenic in bladder cancer remain unclear. We speculate that they share the common mechanism that arsenic binds to the target proteins and subsequently impacts the expression of downstream genes.
METHODS
To address this issue, three Gene Set Enrichments (GSE) were loaded from the Gene Expression Omnibus (GEO) database with four expression matrices. Three of them were mice samples at exposure times of 1, 2, and 12 weeks, and the last was a human urothelial cell (HUC1) sample. Differentially expressed genes (DEGs) from 4 expression groups were identified at iDEP and analyzed at Metascape and Cytoscape for signaling pathway analysis and protein-protein interaction (PPI) analysis. The web-portals UALCAN and GEPIA were used to analyze the role of DEGs in the crosstalk between carcinogenic and anticancer effects. The putative downstream genes of arsenic binding proteins were retrieved using the Cistrome Data Browser. Real-time PCR was used to validate the expression of DEGs.
RESULTS
The signaling pathways referred to lipid metabolism. Responses to various stimuli or hormones were overrepresented in 4 expression matrices. The PPI network emphasized the role of KRAS and TNF signaling in different groups. Furthermore, BDKRB2, FOS, NR4A1, PLAU, SH3BGRL, and F10 played an important role in the crosstalk between carcinogenic and anticancer effects in bladder cancer. Arsenic may impact the activity of ACTB, BACH1, NME2, RBBP4, PARP1, and PML by direct binding, and thus influence the expression of downstream genes such as PAX6, MLLT11, LTBP1, PCSK5, ZFP36, COL8A2, and IL1R2.
CONCLUSION
Arsenic exerted carcinogenic and anticancer functions by altering the expression of crosstalk genes such as BDKRB2, FOS, NR4A1, PLAU, SH3BGRL, and F10, and these were due to arsenic binding proteins.
PubMed: 37969188
DOI: No ID Found