Glutathione‐Bioimprinted Nanoparticles Targeting of N6‐methyladenosine FTO Demethylase as a Strategy against Leukemic Stem Cells

Small, Journal Year: 2022, Volume and Issue: 18(13)

Published: Feb. 4, 2022

Abstract The N6‐methyladenosine (m 6 A) demethylase FTO plays an oncogenic role in acute myeloid leukemia (AML). Despite the promising recent progress for developing some small‐molecule inhibitors, clinical potential remains limited due to mild biological function, toxic side effects and low sensitivity and/or specificity leukemic stem cells (LSCs). Herein, inhibitor‐loaded GSH‐bioimprinted nanocomposites (GNPIPP12MA) are developed that achieves targeting of FTO/m A pathway synergized GSH depletion enhancing anti‐leukemogenesis. GNPIPP12MA can selectively target blasts, especially LSCs, induce ferroptosis by disrupting intracellular redox status. In addition, increases global m RNA modification decreases transcript levels LSCs. augments efficacy PD‐L1 blockade increasing infiltration cytotoxic T enhanced anti‐leukemia immunity. This study offers insights a nanoplatform methylation as synergistic treatment strategy against cancer may translate applications.

Language: Английский

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Safety and efficacy of CD33-targeted CAR-NK cell therapy for relapsed/refractory AML: preclinical evaluation and phase I trial

Experimental Hematology and Oncology, Journal Year: 2025, Volume and Issue: 14(1)

Published: Jan. 2, 2025

Abstract Background Due to the lack of effective treatment options, prognosis patients with relapsed/refractory acute myeloid leukemia (R/R AML) remains poor. Although chimeric antigen receptor (CAR)-T-cell therapy has shown promising effects in lymphoblastic (ALL) and lymphoma, its application R/R AML is limited by “off-target” effects, which lead severe bone marrow suppression limit clinical application. CAR-natural killer (NK) cells not only exhibit antitumor but also demonstrate increased safety universality. We have developed a new CAR construct that targets CD33 modified NK cells, specifically eliminating while reducing side on stem cells. Methods The CD33-targeting domain was selected CAR-T this optimized subsequently transduced into umbilical cord-derived via retroviral vector. Preclinical efficacy studies were conducted both vitro vivo. Ten eligible aged 18–65 years who received one or more infusions anti-CD33 CAR-NK following preconditioning regimen enrolled. assessed response rates treatment-related post-infusion, documenting long-term therapy. Results sequence basis CAR-T-cell demonstrated comparable showed toxicity hematopoietic (HSCs). patients, median five prior lines treatment, completed evaluation (range, 3–8). No grade 3–4 adverse events observed, except suppression, relieved within month. cases immune effector cell–associated neurotoxicity syndrome (ICANS) graft-versus-host disease (GVHD) reported cell infusion. Only patient experienced 2 cytokine release (CRS) presented persistent fever. By day 28, six ten had achieved minimal residual (MRD)-negative complete remission. Conclusions Our preclinical data primary for AML. Expanded samples longer follow-up periods are needed provide further data. Trial registration NCT05008575 ( https://clinicaltrials.gov/study/NCT05008575 ).

Language: Английский

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ILC1s control leukemia stem cell fate and limit development of AML

Nature Immunology, Journal Year: 2022, Volume and Issue: 23(5), P. 718 - 730

Published: April 29, 2022

Language: Английский

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A Bimetallic Metal–Organic‐Framework‐Based Biomimetic Nanoplatform Enhances Anti‐Leukemia Immunity via Synchronizing DNA Demethylation and RNA Hypermethylation

Advanced Materials, Journal Year: 2023, Volume and Issue: 35(16)

Published: Feb. 9, 2023

Epigenetic-alterations-mediated antigenicity reducing in leukemic blasts (LBs) is one of the critical mechanisms immune escape and resistance to T-cell-based immunotherapy. Herein, a bimetallic metal-organic framework (MOF)-based biomimetic nanoplatform (termed as AFMMB) that consists DNA hypomethylating agent, leukemia stem cell (LSC) membrane, pro-autophagic peptide fabricated. These AFMMB particles selectively target not only LBs but also LSCs due homing effect compatibility LSC induce autophagy by binding Golgi-apparatus-associated protein. The autophagy-triggered dissolution releases active components, resulting restoration stimulator interferon genes pathway inhibiting methylation, upregulation major histocompatibility complex class-I molecules, induction RNA-methylation-mediated decay programmed death protein ligand transcripts. dual epigenetic changes eventually enhance T-cell-mediated response increased cells. can suppress growth metastases solid tumor, which was suggestive pan-cancer effect. findings demonstrate may serve promising new for therapy against cancer warrants clinical validation.

Language: Английский

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Uncovering expression signatures of synergistic drug responses via ensembles of explainable machine-learning models

Nature Biomedical Engineering, Journal Year: 2023, Volume and Issue: 7(6), P. 811 - 829

Published: May 1, 2023

Language: Английский

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LILRB4 promotes tumor metastasis by regulating MDSCs and inhibiting miR-1 family miRNAs

OncoImmunology, Journal Year: 2022, Volume and Issue: 11(1)

Published: April 5, 2022

Myeloid-derived suppressor cells (MDSCs) are a population of immune suppressive that involved in tumor-associated immunosuppression, and dominate tumor progression metastasis. In this study, we report the leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4, murine ortholog gp49B) orchestrates polarization MDSCs to exhibit pro-tumor phenotypes. We found gp49B deficiency inhibited metastases cancer cells, reduced tumor-infiltration monocytic (M-MDSCs) tumor-bearing mice. Gp49B−/− responses, such as activation Treg promotion cell migration, stimulation angiogenesis. Treatment wild-type mice with gp49B−/− M-MDSCs Furthermore, knockout affected plasma exosome composition terms increased miR-1 family microRNAs (miRNAs) expression, which correlates upregulation MDSC-derived anti-tumor miRNAs. Collectively, our findings reveal LILRB4/gp49B promotes MDSC-mediated metastasis by regulating M2-polarization suppressing secretion miRNAs, facilitate migration invasion.AbbreviationsCTLA-4: cytotoxic T-lymphocyte-associated protein-4; FBS: fetal bovine serum; G-MDSCs: granulocytic-MDSCs; GP49B: glycoprotein 49B; HE: hematoxylin-eosin; ICI: checkpoint inhibitor; ITIM: immunoreceptor tyrosine-based inhibition motif; LILRB4: B4; M-CSF: macrophage colony stimulating factor; MDSC: myeloid-derived cell; M-MDSC: MDSC; MMP-9: metallopeptidase-9; mAb: monoclonal antibody; PBS: phosphate-buffered saline; PCR: polymerase chain reaction; PD-1: programmed death-1; PD-L1: death ligand-1; PMN-MDSC: polymorphonuclear-MDSC; qRT-PCR: quantitative reverse transcription PCR; TAM: associated macrophage; TME: microenvironment; TMM: trimmed mean M value; VEGFA: vascular endothelial growth factor A

Language: Английский

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Challenges and Advances in Chimeric Antigen Receptor Therapy for Acute Myeloid Leukemia

Cancers, Journal Year: 2022, Volume and Issue: 14(3), P. 497 - 497

Published: Jan. 19, 2022

The advent of chimeric antigen receptor (CAR) T-cell therapy has led to dramatic remission rates in multiple relapsed/refractory hematologic malignancies. While CAR been particularly successful as a treatment for B-cell malignancies, effectively treating acute myeloid leukemia (AML) with CARs posed larger challenge. AML not only creates an immunosuppressive tumor microenvironment that dampens responses, but it also lacks many unique tumor-associated antigens, making leukemic-specific targeting difficult. One advantage compared alternative options is the ability provide prolonged antigen-specific immune effector and surveillance functions. Since targets under investigation including CD33, CD117, CD123 are expressed on hematopoietic stem cells, can lead severe potentially lethal myeloablation. Novel strategies combat these issues include creation bispecific CARs, "safety switches", TCR-like NK universal all vary their sustained remission, consolidation allogeneic cell transplantation (allo-HCT) will be necessary most cases This review highlights delicate balance between eliminating blasts leukemic while preserving bone marrow regenerate. impact landscape changing scope allo-HCT discussed. Continued advances would great benefit disease still high morbidity mortality.

Language: Английский

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m6A-related lncRNAs predict prognosis and indicate immune microenvironment in acute myeloid leukemia

Scientific Reports, Journal Year: 2022, Volume and Issue: 12(1)

Published: Feb. 2, 2022

Abstract Acute myeloid leukemia (AML) is a complex hematologic malignancy. Survival rate of AML patients low. N 6-methyladenosine (m 6 A) and long non-coding RNAs (lncRNAs) play important roles in tumorigenesis progression. However, the relationship between lncRNAs biological characteristics AML, as well how influence prognosis patients, remain unclear. In this study. study, Pearson correlation analysis was used to identify related m A regulatory genes, namely A-related lncRNAs. And we analyzed their prognostic values AML. associated with patient were screened using univariate Cox regression analysis, followed by systematic these genes clinicopathologic biologic characteristics. Furthermore, examined tumor immune microenvironment (TIME) different IncRNA clustering models. Using LASSO regression, identified risk signals patients. We then constructed verified model based on for independent prediction overall survival Our results indicate that scores, calculated risk-related signaling, level infiltration. Finally, expression TRAF3IP2-AS1 samples through real-time polymerase chain reaction GEO datasets, interaction SRSF10 vitro assays. study shows lncRNAs, evaluated model, can potentially be predict design immunotherapy

Language: Английский

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Mutant U2AF1-Induced Mis-Splicing of mRNA Translation Genes Confers Resistance to Chemotherapy in Acute Myeloid Leukemia

Cancer Research, Journal Year: 2024, Volume and Issue: 84(10), P. 1583 - 1596

Published: Feb. 28, 2024

Abstract Patients with primary refractory acute myeloid leukemia (AML) have a dismal long-term prognosis. Elucidating the resistance mechanisms to induction chemotherapy could help identify strategies improve AML patient outcomes. Herein, we retrospectively analyzed multiomics data of more than 1,500 cases and found that patients spliceosome mutations had higher risk developing disease. RNA splicing analysis revealed mis-spliced genes in converged on translation-associated pathways, promoted mainly by U2AF1 mutations. Integrative analyses binding cell lines substantiated perturbations mRNA translation originated from both loss gain mutant binding. In particular, U2AF1S34F U2AF1Q157R mutants orchestrated inclusion exon 11 (encoding premature termination codon) eukaryotic initiation factor 4A2 (EIF4A2). This aberrant led reduced eIF4A2 protein expression via nonsense-mediated decay. Consequently, caused net decrease global induced integrated stress response (ISR) cells, which was confirmed single-cell sequencing. The ISR enhanced ability cells respond adapt stress, contributing chemoresistance. A pharmacologic inhibitor ISR, ISRIB, sensitized chemotherapy. These findings highlight mechanism drive chemoresistance provide therapeutic approach for through targeting pathway. Significance: induce disrupting improves fitness enable chemotherapy, can be targeted treatment.

Language: Английский

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Inhibition of pyrimidine biosynthesis targets protein translation in acute myeloid leukemia

EMBO Molecular Medicine, Journal Year: 2022, Volume and Issue: 14(7)

Published: May 6, 2022

Article6 May 2022Open Access Source DataTransparent process Inhibition of pyrimidine biosynthesis targets protein translation in acute myeloid leukemia Joan So orcid.org/0000-0001-6550-0637 The Peter MacCallum Cancer Centre, Melbourne, Vic., Australia Sir Department Oncology, University Parkville, Contribution: Data curation, ​Investigation, Methodology, Writing - original draft, Project administration, review & editing Search for more papers by this author Alexander C Lewis orcid.org/0000-0002-6253-5823 Lorey K Smith Methodology Kym Stanley Rheana Franich David Yoannidis orcid.org/0000-0001-9591-1349 Lizzy Pijpers Resources, ​Investigation Pilar Dominguez orcid.org/0000-0002-5775-4351 Simon J Hogg orcid.org/0000-0002-3170-839X Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Center, New York, NY, USA Stephin Vervoort Fiona Brown Australian Centre Blood Diseases, Monash University, Ricky W Johnstone orcid.org/0000-0001-7053-9237 Supervision, Gabrielle McDonald Servier Pharmaceuticals, Boston, MA, Danielle B Ulanet Josh Murtie Emily Gruber orcid.org/0000-0001-5990-036X Formal analysis, Lev M Kats Corresponding Author [email protected] orcid.org/0000-0001-8742-8138 Conceptualization, Funding acquisition, Information So1,2,†, Lewis1,†, Smith1,2, Stanley1, Franich1, Yoannidis1, Pijpers1,2, Dominguez1,2, Hogg3, Vervoort1,2, Brown4, Johnstone1,2, McDonald5, Ulanet5, Murtie5, Gruber1 *,1,2 1The 2The 3Human 4Australian 5Servier † These authors contributed equally to work *Corresponding author. Tel: +61 3 8559 5834; E-mail: EMBO Mol Med (2022)14:e15203https://doi.org/10.15252/emmm.202115203 See also: E Donato A Trumpp (July 2022) PDFDownload PDF article text main figures. Peer ReviewDownload a summary the editorial decision including letters, reviewer comments responses feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions Figures Info Abstract mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) catalyzes one rate-limiting steps de novo biosynthesis, pathway that provides essential metabolic precursors nucleic acids, glycoproteins, phospholipids. DHODH inhibitors (DHODHi) are clinically used autoimmune diseases emerging as novel class anticancer agents, especially (AML) where starvation was recently shown reverse characteristic differentiation block AML cells. Herein, we show blockade rapidly shuts down leukemic stem cells (LSCs) has potent selective activity against multiple subtypes. Moreover, find ablation CDK5, gene is recurrently deleted related disorders, increases sensitivity DHODHi. Our studies provide important molecular insights identify potential biomarker an strategy target AML. Synopsis This study reports AG636, inhibitor DHODH, excellent potency pre-clinical models. AG636 exhibits different subtypes vivo, promoting combination cell death effectively reducing inhibition moderate impact on normal blood development, but effects temporary with hematopoietic populations recovering after treatment cessation. Pyrimidine limits nascent synthesis, part through downregulating YY1. Loss subset patients aggressive disease, alters response their drug treatment. paper explained Problem low survival cancer 5-year overall rate < 30%. Selective dependencies offer significant promise development new therapeutic strategies. We explored cellular targeting synthesis using DHODH. Results found downregulates LSCs. YY1 its associated INO80 chromatin remodeling complex key sensor mediates response. also demonstrate loss have poor prognosis can be targeted existing drugs, sensitizes DHODHi Impact adds growing body evidence vivo. data into mechanism action identifying most likely respond Introduction malignancy few effective options extremely outcomes majority cases. less than 30%, large proportion who unfavorable prognostic factors, median 1 year (Papaemmanuil et al, 2016). Hence, there urgent unmet need develop strategies, particularly those engage mechanisms compared drugs current clinical use (Nair 2021). bases components many biological macromolecules DNA RNA growth. Although mammalian acquire pyrimidines from salvage pathways, rely predominantly meet requirements. flavoprotein localized inner membrane fourth step ubiquinone-mediated oxidation orotate. As electron transport chain, links nucleotide bioenergetics ROS production (Vyas Ghate, 2011; Sykes, 2018; Wang been proposed range human viral infection, autoimmunity FDA-approved leflunomide utilized immune-suppressant rheumatoid arthritis sclerosis, efficacy antiproliferative high-affinity T-cells (Klotz 2019). Leflunomide another DHODHi, brequinar, trialed various cancers, although occasional durable were observed, initial insufficient support further Notably, however, recent findings suggesting hematological malignancies prompted renewed interest spurred extensive efforts next-generation (Sykes 2016; Cao 2019; Christian Zhou 2020). Intriguingly, reported undergo maturation 2020), link between nutrient availability fate exploited form "differentiation therapy." To facilitate deployment remains comprehensive analysis responses, rare underpin disease progression therapy resistance (Pollyea Jordan, 2017). extensively validated biophysical profiling (McDonald characterize metabolism efficacy. prodifferentiation vivo By integrating across panel syngeneic mouse models lines, pathways directly triggered predictive strategy. antileukemic MLL-rearranged induce blasts vitro phenotypic remain unknown gain mode DHODH-targeting focused initially chemo-refractory murine model driven doxycycline-inducible expression MLL-AF9 constitutive oncogenic NrasG12D (hereafter referred MN) (Fig EV1A) (Zuber 2009, 2011). others previously addicted continued oncoprotein silencing it drives terminal Ghisi reasoned comparing depletion may aid distinguishing primary changes secondary occur consequence differentiation. Click here expand figure. Figure EV1. Efficacy MN Schematic model. Body weight tumor-bearing mice treated AG636. Gray bars denote Dotted line defines zero percent loss. Number recipient-derived (CD45.1+CD11b+Ly6G+) peripheral AG636- or doxycycline-treated recipients at conclusion 4 weeks (n = 8–10 mice/group). Representative FACS plots bone marrow no detectable (M#13) relapsed (M#15). Kaplan–Meier curve transplanted donor (M#15) control vehicle group (M#30). mice/group, 21.5 vehicle-treated M#30, 42 AG636-treated 23 M#15, not reached P value calculated log-rank test). spleen quantified flow cytometry 3–6 LSCs (CD11blowcKithighFcgR+) differentiated (CD182+Ly6G+) information: F-G presented mean ± SD; values one-tailed Student's unpaired t-test. *P 0.05, **P 0.01, Dox—doxycycline. available online Download figure PowerPoint first performed longitudinal monitoring status weekly intervals cytometric blood. administered dose 100 mg/kg b.i.d. days 1–5 7-day cycle, regimen well-tolerated EV1B). marginally reduced cycle treatment, observed indicated cKit increased Ly6G 1A B). Excitingly, following two, regression group, four cycles sufficient complete remission 10 out 12 1B C). 1. single-agent Frequency expressing immature marker mature 5 9–10 mice/group; 2% tumor burden any condition censored analysis). Absolute number cytometry. 11–12 16.5 doxycycline, 0.0001 showing induced doxycycline. Spleen weights (as percentage all cells) May-Grunwald-Giemsa-stained cytospins sorted Quantification functionally defined limiting dilution assay ELDA 4–8 E-G ***P 0.001, ****P 0.0001; [emmm202115203-sup-0012-SDataFig1.xlsx] After cycles, withdrawn surviving animals. assess myelopoiesis recovery, EV1C). differences either weeks. suggest did significantly exacerbate myelosuppression over above caused 3.5 Gy whole-body irradiation (used conditioning prior engraftment) itself. animals remained free 8 endpoint failed detect minimal residual 9 survivors. Two relapse, (M#15 M#16) other animal required euthanasia, detected EV1D). determine whether resistant inhibition, these cohort recipients. separate (M#30) had never exposed In both cohorts, (using 2-week regimen) effective, demonstrating even though could occasionally persist during therapy, they retained high degree relapse EV1E). observation 2 transplant M30 suggests extended duration additional benefit. underpins next short-term treatments. Mice bearing tumors doxycycline detailed immunophenotyping blood, spleen, compartments (Figs 1D–G EV1F G). expected, silenced cells, evidenced reduction frequency absolute phenotypically (CD11blowcKithighFcγR3+)(Krivtsov 2006) concomitant increase granulocyte-like 1G EV1G). similarly differentiation, notably, phenotype genetic MLL-AF9. particular, splenomegaly total drug-treated 1E–G Consistent data, morphological revealed presence doxycycline- 1H). Importantly, viable remaining possessed leukemia-initiating capacity re-transplant experiments, functional 1I). Overall, AML, LSCs, induces rapid broadly tested two carry distinct combinations driver genes Recipient engrafted established core-binding factor fusion RUNX1-RUNX1T1 (also known AML1-ETO) (Bots 2014) mutant alleles IDH1R132H, DNMT3AR882H, I1DN, see Appendix Fig S1A Methods details) randomized receive therapy. Both co-expressed fluorescent reporters, enabling precise compartment-specific quantification burden. contexts, 2A–C). model, reduced, comparable controls, fewer expressed CD11b 2A–D S1B). I1DN Unlike AMLs, marrow, predominant effect context inhibit proliferation and/or trigger 2E S1D). Interestingly, models, surface Sca1, only stemness Type I interferon (IFN) signaling (Essers 2009; S1C E). Taken together, our limited individual subsets. 2. inhibits A. days. B, C. (B) spleens (C) D, E. (D) (E) 6 n 5–6 mice/group model; 0.01. [emmm202115203-sup-0013-SDataFig2.xlsx] Effects hematopoiesis utility agents proteins nonmalignant dependent existence window. widely healthy sought non-tumor-bearing days, same stem, progenitor, three major lineages (lymphoid, myeloid, erythro-megakaryocytic) 3A Table EV1). minor-moderate reductions common progenitors, megakaryocyte-erythroid long-term 3B–D S2). erythroid compartment ProE, EryA, EryB fractions whereas EryC fraction burst (Appendix S3A). size, T NK multipotent unaffected S3B). It should noted progenitor potentially confounded upregulation Sca1 above. 3. minor B–D. Various (acute treatment) followed off (post-recovery). E–H. Peripheral red (E), platelets (F), (G), lymphoid (H) vehicle. prolonged recovery; two-tailed t-test; comparisons threshold 0.05 shown.

Language: Английский

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