BCR-ABL1-driven exosome-miR130b-3p-mediated gap-junction Cx43 MSC intercellular communications imply therapies of leukemic subclonal evolution

Theranostics, Journal Year: 2023, Volume and Issue: 13(12), P. 3943 - 3963

Published: Jan. 1, 2023

Rationale:In the bone marrow microenvironment (BMME), mesenchymal stem/stromal cells (MSCs) control self-renewal of both healthy and cancerous hematopoietic stem/progenitor (HSPCs).We previously showed that in vivo leukemia-derived MSCs change neighbor into leukemia-permissive states boost leukemia cell proliferation, survival, chemotherapy resistance.But mechanisms behind how state changes are still not fully understood.Methods: Here, we took a reverse engineering approach to determine BCR-ABL1+ activated transcriptional factor c/EBPβ, resulting miR130a/b-3p production.Then, back-tracked from clinical specimen transcriptome sequencing co-culture, molecular cellular assays, flow cytometry, single-cell transcriptome, regulation BCR-ABL1-driven exosome-miR130b-3p-mediated gap-junction Cx43 MSC intercellular communications.Results: exosome-miR130a-3p mediated (a.k.a., GJA1) BMSC communications for subclonal evolution leukemic by targeting BMSCs-expressed HLAs, thereby potentially maintaining BMSCs with properties reduced immunogenicity.The low miR-130a/b high subsets differentiation could be reversed subclones higher stemness Cx43-overexpressed MSCs.Both miR-130a miR-130b might only inhibit translation or degrade proteins did affect mRNA stability.The was further confirmed profiling MSCs, which suggested regulated their played normal roles immunomodulation antigen processing.Thus, upregulated promoted osteogenesis adipogenesis BMSCs, decreasing cancer progression.Our data validated expression many genes human major histocompatibility negatively associated several immune checkpoint contributing escape tumors were overexpressed after either overexpression, such as CD274, LAG3, PDCD1, TNFRSF4.Not response-related cytokine-cytokine receptor interactions PI3K-AKT pathways, including EGR3, TNFRSF1B, but also NDRG2 leukemic-associated inflammatory factors, IFNB1, CXCL1, CXCL10, CCL7 manifest upon overexpression.Either BCR siRNAs ABL1 assay significantly decreased expression, chromatin immunoprecipitation is BCR-ABL1-dependent.BCR-ABL1 induces through upregulation C/EBPβ.C/EBPβ bind directly Ivyspring International Publisherpromoter region miR-130b-3p, miR-130a-3p.BCR-ABL1-driven interact Cx43, impact GJIC TME.Conclusion: Our findings shed light on exosome-miR130b-3p TME, implications therapies evolution.

Language: Английский

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CD73: a new immune checkpoint for leukemia treatment

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: March 6, 2025

Recent studies on the pathogenesis of leukemia have led to remarkable advances in disease treatment. Numerous shown potential and viability immune responses against leukemia. In classical pathway, this process is often initiated by upstream activity CD39, which hydrolyzes extracellular adenosine triphosphate (ATP) diphosphate (ADP) AMP. Subsequently, CD73 acts AMP generate adenosine, contributing an immunosuppressive microenvironment. However, can also utilize substrates derived from other molecules through non-canonical NAD + specifically via CD38/CD203a/CD73 axis, further enhancing production facilitating escape. Targeting has disrupting these pathways, thereby anti-leukemic improving patient outcomes. Inhibiting not only reduces levels but increases efficacy existing immunotherapies, such as PD-1/PD-L1 inhibitors, making it a versatile therapeutic target This review discusses emphasizes its unique position escape mechanism Moreover, provides overview current research progress future trends, emphasizing clinical significance targeting strategies

Language: Английский

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MMP14 from BM-MSCs facilitates progression and Ara-C resistance in acute myeloid leukemia via the JAK/STAT pathway

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

Published: March 22, 2025

Abstract Growing evidence underscores the pivotal impact of crosstalk between leukemic stem cells (LSCs) and mesenchymal stromal (MSCs) within their niche on leukemia initiation, progression, therapy response. Although MMP14 plays an important role in inflammation cancer, regulation MSC-derived acute myeloid (AML) are largely unknown. Here, we found that AML patient-derived MSCs (AML-MSCs) were more supportive cell growth compared to healthy donor-derived (HD-MSCs). Moreover, AML-MSCs HD-MSCs showed significant differences gene expression protein profiles. Knockdown inhibited CFU-F ability MSC increased proportion G0 phase, thereby inhibiting proliferation. Co-culture with proliferation cycle progression cells, while increasing apoptosis rate, thus impairing leukemogenic potential both vitro vivo. Mechanistic studies revealed MMP14-mediated alterations microenvironment driven by PGE2 secretion activation JAK-STAT pathway, promoting progression. Notably, inhibition can attenuate chemotherapy resistance induced cytarabine (Ara-C). Together, our study, for first time, demonstrates critical chemoresistance. Targeting signaling pathways may offer novel therapeutic options AML.

Language: Английский

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Bone Marrow Microenvironment as a Source of New Drug Targets for the Treatment of Acute Myeloid Leukaemia

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 24(1), P. 563 - 563

Published: Dec. 29, 2022

Acute myeloid leukaemia (AML) is a heterogeneous disease with one of the worst survival rates all cancers. The bone marrow microenvironment increasingly being recognised as an important mediator AML chemoresistance and relapse, supporting stem cell through interactions among stromal, haematopoietic progenitor leukaemic cells. Traditional therapies targeting cells have failed to improve long term rates, such, niche has become promising new source potential therapeutic targets, particularly for relapsed refractory AML. This review briefly discusses role in development progression, novel targets main focus this on drugs that modulate/target been examined vivo models or clinically.

Language: Английский

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Bone Marrow Aging and the Leukaemia-Induced Senescence of Mesenchymal Stem/Stromal Cells: Exploring Similarities

Journal of Personalized Medicine, Journal Year: 2022, Volume and Issue: 12(5), P. 716 - 716

Published: April 29, 2022

Bone marrow aging is associated with multiple cellular dysfunctions, including perturbed haematopoiesis, the propensity to haematological transformation, and maintenance of leukaemia. It has been shown that instructive signals from different leukemic cells are delivered stromal remodel bone into a supportive niche. In particular, senescence, physiological program both beneficial deleterious effects on health organisms, may be responsible for increased incidence malignancies in elderly survival diverse cells. Here, we will review connection between BM senescence role these processes play leukaemia progression. Specifically, discuss mesenchymal stem as central component Due specificity genetic defects present leukaemia, one would think alterations also have particular changes, making it difficult envisage shared therapeutic use. We tried summarize coincident features during two leukaemias, acute myeloid high frequency elderly, B-acute lymphoblastic mainly childhood disease. propose similarly affected changes observed terms function, redox balance, genetics epigenetics, soluble factor repertoire stemness equivalent those occurring senescence. These used explore strategies useful treat various malignancies.

Language: Английский

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Inhibition of CCCTC Binding Factor-Programmed Cell Death Ligand 1 Axis Suppresses Emergence of Chemoresistance Induced by Gastric Cancer-Derived Mesenchymal Stem Cells

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: April 27, 2022

Gastric cancer (GC) is the third leading cause of cancer-associated deaths worldwide. Stromal cells, especially mesenchymal stem cells (MSCs), play significant roles in development therapy resistance depending on their paracrine function. The PD-1/PD-L1 crosstalk between and immune has been well studied. Emerging evidence suggests that PD-L1 also contributes to tumor therapy. Cell survival apoptosis were assessed using CCK-8, colony formation, flow cytometry assays. Protein alterations analyzed via Western blot. Gene knockdown overexpression achieved with siRNA/shRNA lentiviral infection, respectively. Drug effects tumors vivo xenografts nude mice. In addition, GC patient samples after chemotherapy treatment collected observe relationship effect CTCF or PD-L1. response 5-fluorouracil paclitaxel treatment, GCMSC-CM enhanced cell viability decreased rate. Furthermore, blocking prevented GCMSC-induced drug accompanied by a decline stemness. Consistent these vitro observations, mice treated showed lower sensitivity 5-fluorouracil. high expression was associated poor progression clinic. Study results demonstrate mechanism where promotes chemoresistance upregulating CTCF-PD-L1 provide strong support targeting signaling as strategy prevent

Language: Английский

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Harnessing Immune Response in Acute Myeloid Leukemia

Journal of Clinical Medicine, Journal Year: 2023, Volume and Issue: 12(18), P. 5824 - 5824

Published: Sept. 7, 2023

Despite the results achieved with evolution of conventional chemotherapy and inclusion targeted therapies in treatment acute myeloid leukemia (AML), survival is still not satisfying, particular setting relapsed/refractory (R/R) disease or elderly/unfit patients. Among most innovative therapeutic options, cellular therapy has shown great different hematological malignancies such as lymphoblastic lymphomas, several products already approved for clinical use. However, despite interest also expanding application these new treatments to R/R AML, no product been yet application. Furthermore, could indeed represent a powerful tool an appealing alternative allogeneic hematopoietic stem cell transplantation ineligible In this review, we aim provide overview recent research exploring effectiveness moving from consolidated approaches post- transplant donor’s lymphocytes infusion, modern adoptive immunotherapies alloreactive NK infusions, engineered T cells (CAR-T, CAR-NK) novel platforms engaging (i.e., BiTEs, DARTs ANKETTM).

Language: Английский

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The role of exosomes in the stemness maintenance and progression of acute myeloid leukemia

Biochemical Pharmacology, Journal Year: 2023, Volume and Issue: 212, P. 115539 - 115539

Published: April 4, 2023

Language: Английский

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Spatiotemporal evolution of AML immune microenvironment remodeling and RNF149-driven drug resistance through single-cell multidimensional analysis

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: Oct. 27, 2023

Abstract Background The composition of the bone marrow immune microenvironment in patients with acute myeloid leukaemia (AML) was analysed by single-cell sequencing and evolutionary role different subpopulations T cells development AML driving drug resistance explored conjunction E3 ubiquitin ligase-related genes. Methods To elucidate mechanisms underlying AML-NR Ara-C resistance, we analyzed integrating multiple RNA datasets. When compared to disease remission (AML-CR) cohort, displayed distinct cellular interactions alterations ratios CD4 + T, Treg, CD8 cell populations. Results Our findings indicate that ligase RNF149 accelerates progression, modifies milieu, triggers dysfunction, influences transformation Navie.T Exh , culminating diminished responsiveness chemotherapeutic agents. Experiments both vivo vitro revealed RNF149’s enhancing drug-resistant line proliferation apoptotic inhibition, fostering Ara-C. Conclusion In essence, microenvironments AML-CR diverge considerably, spotlighting tumorigenic function cementing its status as a potential prognostic indicator innovative therapeutic avenue for countering resistance. Graphical

Language: Английский

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In Vitro and In Vivo Modeling of Normal and Leukemic Bone Marrow Niches: Cellular Senescence Contribution to Leukemia Induction and Progression

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(13), P. 7350 - 7350

Published: July 1, 2022

Cellular senescence is recognized as a dynamic process in which cells evolve and adapt context dependent manner; consequently, senescent can exert both beneficial deleterious effects on their surroundings. Specifically, mesenchymal stromal (MSC) the bone marrow (BM) have been linked to generation of supporting microenvironment that enhances malignant cell survival. However, study MSC’s role leukemia development has straitened not only by availability suitable models faithfully reflect structural complexity biological diversity events triggered BM, but also lack universal, standardized method measure senescence. Despite these constraints, two- three dimensional vitro continuously improved terms culture techniques, support materials analysis methods; addition, research animal tends focus techniques allow tracking leukemic living organism, well modify available mice strains generate individuals mimic human BM characteristics. Here, we present main advances niche modeling, discussing advantages limitations different systems, focusing contribution MSC progression.

Language: Английский

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