A predictive serum miRNA signature impacts diffuse large B‐cell lymphoma cell viability via inhibition of EGLN1 and TXNRD1 regulators of ferroptosis
Summary Diffuse large B‐cell lymphoma (DLBCL) is a heterogeneous disorder. Prognostic factors include genomic alterations and cell‐of‐origin (COO) subtypes, even though they cannot fully predict treatment response. MicroRNAs (miRNAs) deregulated in patient tumours and blood are promising non‐invasiv...
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| Published in | British journal of haematology Vol. 207; no. 3; pp. 802 - 812 |
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| Main Authors | , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
England
Blackwell Publishing Ltd
01.09.2025
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0007-1048 1365-2141 1365-2141 |
| DOI | 10.1111/bjh.70017 |
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| Abstract | Summary
Diffuse large B‐cell lymphoma (DLBCL) is a heterogeneous disorder. Prognostic factors include genomic alterations and cell‐of‐origin (COO) subtypes, even though they cannot fully predict treatment response. MicroRNAs (miRNAs) deregulated in patient tumours and blood are promising non‐invasive biomarkers. Several circulating miRNAs were found to be correlated with progression‐free survival (PFS), independently of other prognosticators. However, miRNA signatures, rather than individual miRNAs, represent more reliable biomarkers and a better mirror of the disease. In this study, we identified circulating miRNAs differentially expressed between R‐CHOP refractory and responding subjects by small‐RNA sequencing on serum from 33 DLBCL patients. Among the identified miRNAs, the combined expression of three of them improved the predictive performance and was correlated with PFS. Two out of three miRNAs, miR‐421 and miR‐324‐5p, were also differentially expressed in tumour tissues based on treatment response. Overexpressing these miRNAs reduced cell proliferation, viability and resistance to R‐CHOP in the germinal centre B‐like COO subtype. EGLN1 and TXNRD1, regulators of oxygen metabolism and redox homeostasis, were identified as miRNA targets and the silencing or inhibition of these genes impaired cell viability and induced ferroptosis. These results support the application of a two‐miRNA signature and its targets for novel combined therapeutic interventions in DLBCL.
Diffuse large B‐cell lymphoma is a heterogeneous and aggressive pathology. MicroRNAs, deregulated in patient tumours and blood, are promising non‐invasive predictive biomarkers for this pathology. We identified the circulating miR‐200c/421/324 signature both predictive of response to R‐CHOP and correlated with PFS. MiR‐421 and miR‐324‐5p were also altered in tumour tissues based on treatment response. Their overexpression reduced cell proliferation, viability and resistance to R‐CHOP in the germinal centre B‐like cell‐of‐origin subtype. The miR‐421/324 signature elicited its biological effects by induction of ferroptosis through the modulation of EGLN1 and TXNRD1 target genes, involved in the regulation of the redox homeostasis. |
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| AbstractList | Diffuse large B‐cell lymphoma (DLBCL) is a heterogeneous disorder. Prognostic factors include genomic alterations and cell‐of‐origin (COO) subtypes, even though they cannot fully predict treatment response. MicroRNAs (miRNAs) deregulated in patient tumours and blood are promising non‐invasive biomarkers. Several circulating miRNAs were found to be correlated with progression‐free survival (PFS), independently of other prognosticators. However, miRNA signatures, rather than individual miRNAs, represent more reliable biomarkers and a better mirror of the disease. In this study, we identified circulating miRNAs differentially expressed between R‐CHOP refractory and responding subjects by small‐RNA sequencing on serum from 33 DLBCL patients. Among the identified miRNAs, the combined expression of three of them improved the predictive performance and was correlated with PFS. Two out of three miRNAs, miR‐421 and miR‐324‐5p, were also differentially expressed in tumour tissues based on treatment response. Overexpressing these miRNAs reduced cell proliferation, viability and resistance to R‐CHOP in the germinal centre B‐like COO subtype. EGLN1 and TXNRD1, regulators of oxygen metabolism and redox homeostasis, were identified as miRNA targets and the silencing or inhibition of these genes impaired cell viability and induced ferroptosis. These results support the application of a two‐miRNA signature and its targets for novel combined therapeutic interventions in DLBCL. Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disorder. Prognostic factors include genomic alterations and cell-of-origin (COO) subtypes, even though they cannot fully predict treatment response. MicroRNAs (miRNAs) deregulated in patient tumours and blood are promising non-invasive biomarkers. Several circulating miRNAs were found to be correlated with progression-free survival (PFS), independently of other prognosticators. However, miRNA signatures, rather than individual miRNAs, represent more reliable biomarkers and a better mirror of the disease. In this study, we identified circulating miRNAs differentially expressed between R-CHOP refractory and responding subjects by small-RNA sequencing on serum from 33 DLBCL patients. Among the identified miRNAs, the combined expression of three of them improved the predictive performance and was correlated with PFS. Two out of three miRNAs, miR-421 and miR-324-5p, were also differentially expressed in tumour tissues based on treatment response. Overexpressing these miRNAs reduced cell proliferation, viability and resistance to R-CHOP in the germinal centre B-like COO subtype. EGLN1 and TXNRD1, regulators of oxygen metabolism and redox homeostasis, were identified as miRNA targets and the silencing or inhibition of these genes impaired cell viability and induced ferroptosis. These results support the application of a two-miRNA signature and its targets for novel combined therapeutic interventions in DLBCL.Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disorder. Prognostic factors include genomic alterations and cell-of-origin (COO) subtypes, even though they cannot fully predict treatment response. MicroRNAs (miRNAs) deregulated in patient tumours and blood are promising non-invasive biomarkers. Several circulating miRNAs were found to be correlated with progression-free survival (PFS), independently of other prognosticators. However, miRNA signatures, rather than individual miRNAs, represent more reliable biomarkers and a better mirror of the disease. In this study, we identified circulating miRNAs differentially expressed between R-CHOP refractory and responding subjects by small-RNA sequencing on serum from 33 DLBCL patients. Among the identified miRNAs, the combined expression of three of them improved the predictive performance and was correlated with PFS. Two out of three miRNAs, miR-421 and miR-324-5p, were also differentially expressed in tumour tissues based on treatment response. Overexpressing these miRNAs reduced cell proliferation, viability and resistance to R-CHOP in the germinal centre B-like COO subtype. EGLN1 and TXNRD1, regulators of oxygen metabolism and redox homeostasis, were identified as miRNA targets and the silencing or inhibition of these genes impaired cell viability and induced ferroptosis. These results support the application of a two-miRNA signature and its targets for novel combined therapeutic interventions in DLBCL. Summary Diffuse large B‐cell lymphoma (DLBCL) is a heterogeneous disorder. Prognostic factors include genomic alterations and cell‐of‐origin (COO) subtypes, even though they cannot fully predict treatment response. MicroRNAs (miRNAs) deregulated in patient tumours and blood are promising non‐invasive biomarkers. Several circulating miRNAs were found to be correlated with progression‐free survival (PFS), independently of other prognosticators. However, miRNA signatures, rather than individual miRNAs, represent more reliable biomarkers and a better mirror of the disease. In this study, we identified circulating miRNAs differentially expressed between R‐CHOP refractory and responding subjects by small‐RNA sequencing on serum from 33 DLBCL patients. Among the identified miRNAs, the combined expression of three of them improved the predictive performance and was correlated with PFS. Two out of three miRNAs, miR‐421 and miR‐324‐5p, were also differentially expressed in tumour tissues based on treatment response. Overexpressing these miRNAs reduced cell proliferation, viability and resistance to R‐CHOP in the germinal centre B‐like COO subtype. EGLN1 and TXNRD1, regulators of oxygen metabolism and redox homeostasis, were identified as miRNA targets and the silencing or inhibition of these genes impaired cell viability and induced ferroptosis. These results support the application of a two‐miRNA signature and its targets for novel combined therapeutic interventions in DLBCL. Diffuse large B‐cell lymphoma is a heterogeneous and aggressive pathology. MicroRNAs, deregulated in patient tumours and blood, are promising non‐invasive predictive biomarkers for this pathology. We identified the circulating miR‐200c/421/324 signature both predictive of response to R‐CHOP and correlated with PFS. MiR‐421 and miR‐324‐5p were also altered in tumour tissues based on treatment response. Their overexpression reduced cell proliferation, viability and resistance to R‐CHOP in the germinal centre B‐like cell‐of‐origin subtype. The miR‐421/324 signature elicited its biological effects by induction of ferroptosis through the modulation of EGLN1 and TXNRD1 target genes, involved in the regulation of the redox homeostasis. |
| Author | Palombi, Francesca Hohaus, Stefan Díaz Méndez, Ana Belén Papa, Elena Marchesi, Francesco Bertoni, Francesco Lulli, Valentina Goeman, Frauke Novello, Mariangela Mengarelli, Andrea Tomassi, Martina Rizzo, Maria Giulia Di Giuliani, Marta Vari, Giulia Regazzo, Giulia Sacconi, Andrea |
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| Keywords | ferroptosis regulators predictive biomarkers circulating microRNAs diffuse large B‐cell lymphoma |
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Diffuse large B‐cell lymphoma (DLBCL) is a heterogeneous disorder. Prognostic factors include genomic alterations and cell‐of‐origin (COO) subtypes,... Diffuse large B‐cell lymphoma (DLBCL) is a heterogeneous disorder. Prognostic factors include genomic alterations and cell‐of‐origin (COO) subtypes, even... Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disorder. Prognostic factors include genomic alterations and cell-of-origin (COO) subtypes, even... |
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| SubjectTerms | Adult Aged Antineoplastic Combined Chemotherapy Protocols - therapeutic use Biomarkers Biomarkers, Tumor - blood Cell Line, Tumor Cell proliferation Cell Survival - genetics Cell viability circulating microRNAs Cyclophosphamide - therapeutic use diffuse large B‐cell lymphoma Doxorubicin - therapeutic use Female Ferroptosis Ferroptosis - genetics ferroptosis regulators Gene Expression Regulation, Neoplastic Germinal centers Homeostasis Humans Lymphoma Lymphoma, Large B-Cell, Diffuse - blood Lymphoma, Large B-Cell, Diffuse - drug therapy Lymphoma, Large B-Cell, Diffuse - genetics Lymphoma, Large B-Cell, Diffuse - pathology Male Medical prognosis MicroRNAs MicroRNAs - blood MicroRNAs - genetics Middle Aged miRNA Neoplasm Proteins predictive biomarkers Prednisone - therapeutic use Prognosis Rituximab RNA, Neoplasm - blood Therapeutic applications Thioredoxin Reductase 1 - antagonists & inhibitors Thioredoxin Reductase 1 - genetics Thioredoxin Reductase 1 - metabolism Vincristine - therapeutic use |
| Title | A predictive serum miRNA signature impacts diffuse large B‐cell lymphoma cell viability via inhibition of EGLN1 and TXNRD1 regulators of ferroptosis |
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