International Journal of Molecular Sciences

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19 pages, 2642 KB

Open AccessArticle

Novel NSAID Analogs Exhibit Anti-Leukemic Activity Through Modulation of Apoptotic and Survival Pathways

by Hind A. Alkhatabi, Mohammed Basabrain, Alaa G. Alahmadi, Shiekhah M. Alzahrani, Yosra A. Muhammad, Maha Almuhaiyawi, Maha M. Alreemi, Reem M. Alotibi, Roaa M. Alreemi, Heba A. Alkhattabi, Reem N. Hassan, Wedad M. Al-Bishri, Mohammed El-Mezgueldi and Abdelsattar M. Omar

Int. J. Mol. Sci. 2026, 27(9), 3850; https://doi.org/10.3390/ijms27093850 - 26 Apr 2026

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Abstract

Acute myeloid leukemia (AML) is a complex blood cancer that primarily affects relapsing or refractory patients receiving conventional chemotherapy. Nonsteroidal anti-inflammatory drugs (NSAIDs) have anticancer properties with restricted clinical efficacy attributable to cyclooxygenase (COX)-induced toxicities. To address this issue, a group of benzylamide [...] Read more.

Acute myeloid leukemia (AML) is a complex blood cancer that primarily affects relapsing or refractory patients receiving conventional chemotherapy. Nonsteroidal anti-inflammatory drugs (NSAIDs) have anticancer properties with restricted clinical efficacy attributable to cyclooxygenase (COX)-induced toxicities. To address this issue, a group of benzylamide analogs of the classical NSAIDs (NSI-1–NSI-9) were developed and synthesized to mask the carboxylic acid moiety and minimize COX-induced adverse effects while maintaining anticancer activity. The cytotoxic effect of such substances has been demonstrated in some leukemia cell lines (HL-60, MV4-11, KG1a, and K562). NSI-5 exerted the highest anti-leukemic activity among these sulindac analogs, as determined at a sub-micromolar level in all cell lines studied, by IC50. This mechanistic data also demonstrated that NSI-5 induced apoptosis that was dose-dependent, especially in HL-60 cell lines, and increased the sub-G1 cell fraction. This apoptotic process was also accompanied by a significant decrease in mitochondrial membrane potential, which is characteristic of the induction of the intrinsic apoptotic process. Interestingly, NSI-5 decreased the intracellular reactive oxygen species (ROS) and the expression of most antioxidants (catalase and glutathione synthetase), as well as the redox balance. Gene characterization in vitro also suggested activation of apoptotic pathways, where expression of Bax, Bak1, and Caspase-3 increased, suggesting a potential p53-independent apoptotic pathway, in contrast to control for Bcl-2 expression. Collectively, these findings indicate that NSI-5 is a promising in vitro anti-leukemic lead compound, with activity associated with mitochondrial dysfunction and altered redox regulation. The observed effects are consistent with previously reported COX-independent activity of structurally related NSAID derivatives, and support further investigation of NSI-5 in preclinical models. Full article

(This article belongs to the Special Issue Hematological Malignancies: Molecular Mechanisms and Therapy, 2nd Edition)

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13 pages, 5721 KB

Open AccessArticle

Intraclonal Enrichment of IL-23 Receptor Complex Expression in the Proliferative Fraction of Chronic Lymphocytic Leukemia

by Martina Cardillo, Fabiana Ferrero, Nadia Bertola, Ennio Nano, Rosanna Massara, Maria Cristina Capra, Daniele Reverberi, Monica Colombo, Vanessa Cossu, Fabio Ghiotto, Adalberto Ibatici, Emanuele Angelucci, Antonino Neri, Massimo Gentile, Fortunato Morabito, Andrea Nicola Mazzarello, Manlio Ferrarini, Franco Fais and Giovanna Cutrona

Int. J. Mol. Sci. 2026, 27(3), 1202; https://doi.org/10.3390/ijms27031202 - 25 Jan 2026

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Abstract

Chronic lymphocytic leukemia (CLL) is a dynamic malignancy in which intraclonal subfractions differ in activation history and responsiveness to microenvironmental signals. Here, we investigated the expression and inducibility of IL-12 family receptor subunits (IL-23R, IL-12Rβ1, IL-12Rβ2) and the related receptor complexes in recirculating [...] Read more.

Chronic lymphocytic leukemia (CLL) is a dynamic malignancy in which intraclonal subfractions differ in activation history and responsiveness to microenvironmental signals. Here, we investigated the expression and inducibility of IL-12 family receptor subunits (IL-23R, IL-12Rβ1, IL-12Rβ2) and the related receptor complexes in recirculating CLL cells, with a focus on CXCR4/CD5-defined fractions: the proliferative fraction (PF; CXCR4^dim/CD5^bright; most recently divided, tissue-emigrated cells) and the resting fraction (RF; CXCR4^bright/CD5^dim; older, quiescent cells). At baseline, IL-12Rβ1 was enriched in the PF and was associated with a higher proportion of cells expressing IL-23R and IL-12R receptor complexes. Concomitantly, RT-qPCR disclosed higher IL-12Rβ1 mRNA levels. Following antigen-independent activation with CpG or CpG + IL-15, there was a marked increase in IL-23R and IL-12Rβ1 but not in IL-12Rβ2 surface expression, resulting in preferential upregulation of the IL-23R complex over the IL-12R complex. Fraction-specific analyses showed stronger induction of IL-23R and IL-23R complex expression in PF compared with RF. These findings identify an intraclonal bias toward IL-23 responsiveness in the CLL cells with a phenotype of recently divided, tissue-emigrated cells and suggest the IL-23/IL-23R axis as a potential therapeutic target. Full article

(This article belongs to the Special Issue Hematological Malignancies: Molecular Mechanisms and Therapy, 2nd Edition)

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25 pages, 4020 KB

Open AccessArticle

Utility of a Digital PCR-Based Gene Expression Panel for Detection of Leukemic Cells in Pediatric Acute Lymphoblastic Leukemia

by Jesús García-Gómez, Dalia Ramírez-Ramírez, Rosana Pelayo, Octavio Martínez-Villegas, Lauro Fabián Amador-Medina, Juan Ramón González-García, Augusto Sarralde-Delgado, Luis Felipe Jave-Suárez and Adriana Aguilar-Lemarroy

Int. J. Mol. Sci. 2026, 27(2), 674; https://doi.org/10.3390/ijms27020674 - 9 Jan 2026

Cited by 1 | Viewed by 788

Abstract

Acute lymphoblastic leukemia (ALL) is a genetically heterogeneous disease where current clinical practice guidelines remain focused on traditional cytogenetic markers. Despite recent advances demonstrating excellent diagnostic accuracy for gene expression signatures, a discontinuity exists between biomarker validation and clinical implementation. This study aimed [...] Read more.

Acute lymphoblastic leukemia (ALL) is a genetically heterogeneous disease where current clinical practice guidelines remain focused on traditional cytogenetic markers. Despite recent advances demonstrating excellent diagnostic accuracy for gene expression signatures, a discontinuity exists between biomarker validation and clinical implementation. This study aimed to develop and validate a multiparametric gene expression signature using digital PCR (dPCR) to accurately diagnose pediatric ALL, with potential utility for monitoring measurable residual disease (MRD). We analyzed 130 bone marrow aspirates from pediatric patients from four clinical groups: non-leukemia, MRD-negative, MRD-positive and leukemia characterized by immunophenotype. Gene expression of an 8-gene panel (JUP, MYC, NT5C3B, GATA3, PTK7, CNP, ICOSLG, and SNAI1) was quantified by dPCR. The diagnostic performance of individual markers was assessed, and a Random Forest machine learning model was trained to classify active disease. The model was validated using a 5-fold stratified cross-validation approach. Individual markers, particularly JUP, MYC, and NT5C3B, showed good diagnostic accuracy for distinguishing leukemia from non-leukemia. However, integrating all eight markers into a multivariate Random Forest model significantly enhanced performance. The model achieved a mean cross-validated area under the curve (AUC) of 0.908 (±0.041) on receiver operator characteristic (ROC) analysis and 0.961 (±0.019) on Precision–Recall (PR) analysis, demonstrating high reliability and a favorable balance between sensitivity and precision. The integrated model achieved high sensitivity (88.9%) for detecting active disease, particularly at initial diagnosis. Although specificity was moderate (65.0%), the high positive predictive value (PPV 85.1%) and accuracy (81.5%) confirm the clinical utility of a positive result. While the panel showed promising performance for distinguishing MRD-positive from MRD-negative samples, the limited MRD-positive cohort size (n = 11) indicates that validation in larger MRD-focused studies is required before clinical implementation for treatment monitoring. This dPCR-based platform provides accessible, quantitative detection without requiring knowledge of clonal shifts or specific genomic landscape, offering potential advantages for resource-limited settings such as those represented in our Mexican pediatric cohort. Full article

(This article belongs to the Special Issue Hematological Malignancies: Molecular Mechanisms and Therapy, 2nd Edition)

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18 pages, 4497 KB

Open AccessArticle

NFE2 Truncation Mutants Protect Wild-Type NFE2 from ITCH-Dependent Degradation

by Mirjam Elisabeth Hoeness, Franziska Zell, Titiksha Basu, Katharina Gellrich, Albert Gründer, Jana Schulze, Anja Müller, Philipp Eble, Christoph Koellerer, Anne Marie Staehle, Sarolta Bojtine Kovacs, Heike L. Pahl and Hans Felix Staehle

Int. J. Mol. Sci. 2025, 26(24), 12112; https://doi.org/10.3390/ijms262412112 - 16 Dec 2025

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Abstract

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders characterized by the abnormal proliferation of myeloid cells. In addition to the main driver mutations in JAK2, MPL, and CALR, the transcription factor nuclear factor erythroid 2 (NFE2) has emerged as a key contributor to MPN [...] Read more.

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders characterized by the abnormal proliferation of myeloid cells. In addition to the main driver mutations in JAK2, MPL, and CALR, the transcription factor nuclear factor erythroid 2 (NFE2) has emerged as a key contributor to MPN pathophysiology. NFE2 expression is elevated in the majority of MPN patients, and augmented NFE2 activity in hematopoietic stem cells is sufficient to induce an MPN phenotype with spontaneous leukemic transformation in murine models. Moreover, NFE2 mutations, found in a subset of MPN patients, augment NFE2 activity and are associated with a markedly increased risk of progression to acute myeloid leukemia (AML). However, the molecular mechanism by which NFE2 mutations cause leukemogenesis is not understood. Here, we demonstrate that the E3 ubiquitin ligase ITCH mediates proteasomal degradation of wild-type (wt) NFE2 in HEK-293T cells. A gain-of-function truncation mutant, NFE2-226aa, retains the capacity to interact with ITCH but is no longer degraded. Rather, NFE2-226aa protects wt NFE2 from ITCH-dependent degradation, resulting in enhanced NFE2 activity. Full article

(This article belongs to the Special Issue Hematological Malignancies: Molecular Mechanisms and Therapy, 2nd Edition)

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9 pages, 219 KB

Open AccessArticle

Regeneration of Peripheral Blood T-Cell Subpopulations in Children After Completion of Acute Lymphoblastic Leukemia Treatment

by Bartosz Perkowski, Łukasz Słota, Aleksandra Lasia, Tomasz Szczepański and Łukasz Sędek

Int. J. Mol. Sci. 2025, 26(22), 11107; https://doi.org/10.3390/ijms262211107 - 17 Nov 2025

Viewed by 826

Abstract

Childhood acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, and while chemotherapy has significantly improved survival rates, it can also lead to long-term side effects, including immune system dysfunction. This study aimed to investigate in detail, using flow cytometry, the T-cell [...] Read more.

Childhood acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, and while chemotherapy has significantly improved survival rates, it can also lead to long-term side effects, including immune system dysfunction. This study aimed to investigate in detail, using flow cytometry, the T-cell subpopulations in the peripheral blood of children who have completed ALL treatment and compare them to a group of healthy children. The study group consisted of 20 patients, aged 5 to 18 years, with blood samples collected at least one year after treatment completion. Of the 52 T-cell subpopulations analyzed, 16 showed statistically significant differences. Children after ALL treatment had lower absolute values of TCRγδ+ and higher values of double-positive CD4+CD8+ and CD8+ T cells. They also had higher absolute numbers of memory T cells, including total CD45RO+ T cells, and the CD45RO+CD8+ and CD45RO+CD27+ subpopulations. Furthermore, post treatment patients showed higher absolute values of activated T cells (HLA-DR+, HLA-DR+CD8+, HLA-DR+CD57+, and CD25+CD8+), as well as CD57+ and CCR7+ T cells. The absolute leukocyte and granulocyte counts were lower in the study group, while the total lymphocyte count was significantly higher compared to the control group. The findings indicate persistent changes in T-cell subpopulations after ALL treatment, suggesting ongoing immune system rebuilding and chronic antigenic stimulation, possibly due to viral reactivation or chemotherapy-related tissue damage. The increased number of TCRγδ+ cells, which are responsible for eliminating cancer cells, may be a positive aspect of this rebuilding. Full article

(This article belongs to the Special Issue Hematological Malignancies: Molecular Mechanisms and Therapy, 2nd Edition)

13 pages, 860 KB

Open AccessArticle

Identification of Genetic Variants Using Next-Generation Sequencing in Pediatric Myelodysplastic Syndrome: From Disease Biology to Clinical Applications

by Viviane Lamim Lovatel, Gerson Moura Ferreira, Beatriz Ferreira da Silva, Rayane de Souza Torres, Rita de Cássia Barbosa da Silva Tavares, Ana Paula Silva Bueno, Eliana Abdelhay and Teresa de Souza Fernandez

Int. J. Mol. Sci. 2025, 26(14), 6907; https://doi.org/10.3390/ijms26146907 - 18 Jul 2025

Cited by 1 | Viewed by 1448

Abstract

This study aimed to identify genetic variants using a customized next-generation sequencing (NGS) panel for pediatric myelodysplastic syndrome (pMDS) and to explore their associations with cytogenetic and clinical characteristics. Cytogenetic analyses were conducted using G-banding and fluorescence in situ hybridization. NGS was performed [...] Read more.

This study aimed to identify genetic variants using a customized next-generation sequencing (NGS) panel for pediatric myelodysplastic syndrome (pMDS) and to explore their associations with cytogenetic and clinical characteristics. Cytogenetic analyses were conducted using G-banding and fluorescence in situ hybridization. NGS was performed with the Ion Torrent Personal Genome Machine for the following genes: GATA2, RUNX1, CEBPA, ANKRD26, ETV6, SAMD9, SAMD9L, PTPN11, NRAS, SETBP1, DDX41, TP53, FLT3, SRP72, and JAK3. Analyses were performed with Ion Reporter 5.20.8.0 software. Genetic variants were classified using the dbSNP, 1000 Genomes, COSMIC, and Varsome databases. We analyzed 25 cases of pMDS; 15 presented abnormal karyotypes, and 19 showed genetic variants. Among the 29 variants identified across 12/15 genes, 27% were pathogenic and 14% were likely pathogenic, with NRAS and GATA2 most frequently associated with disease progression. A new somatic variant of uncertain significance in SETBP1 was detected in seven patients showing heterogeneous clinical outcomes. Genetic variants were found in 7/10 patients with normal karyotypes, indicating that submicroscopic alterations can shed light on disease biology. Our results highlight the critical role of a targeted NGS panel in identifying molecular alterations associated with pMDS pathogenesis, thereby enhancing diagnostic precision, prognosis, and aiding in treatment selection. Full article

(This article belongs to the Special Issue Hematological Malignancies: Molecular Mechanisms and Therapy, 2nd Edition)

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21 pages, 5292 KB

Open AccessArticle

Downregulation of S6 Kinase and Hedgehog–Gli1 by Inhibition of Fatty Acid Synthase in AML with FLT3-ITD Mutation

by Maxim Kebenko, Ruimeng Zhuang, Konstantin Hoffer, Anna Worthmann, Stefan Horn, Malte Kriegs, Jan Vorwerk, Nikolas von Bubnoff, Cyrus Khandanpour, Niklas Gebauer, Sivahari Prasad Gorantla, Walter Fiedler, Carsten Bokemeyer and Manfred Jücker

Int. J. Mol. Sci. 2025, 26(12), 5721; https://doi.org/10.3390/ijms26125721 - 14 Jun 2025

Cited by 2 | Viewed by 1514

Abstract

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy associated with a poor prognosis. Activating mutations in the FLT3 gene occur in approximately 30% of AML cases, with internal tandem duplications in the juxtamembrane domain (FLT3-ITD; 75%) and mutations in the tyrosine kinase [...] Read more.

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy associated with a poor prognosis. Activating mutations in the FLT3 gene occur in approximately 30% of AML cases, with internal tandem duplications in the juxtamembrane domain (FLT3-ITD; 75%) and mutations in the tyrosine kinase domain (FLT3-TKD; 25%). FLT3-ITD mutations are linked to poor prognosis and offer significant clinical predictive value, whereas the implications of FLT3-TKD mutations are less understood. The Hedgehog–Gli pathway is an established therapeutic target in AML, and emerging evidence suggests crosstalk between FLT3-ITD signaling and Gli expression regulation via non-canonical mechanisms. Post-translational modifications involving myristic and palmitic acids regulate various cellular processes, but their role in AML remains poorly defined. In this study, we investigated the role of fatty acid synthase (FASN), which synthesizes myristic and palmitic acids and catalyzes palmitoyl-acyltransferation, in regulating FLT3-ITD-Gli signaling. FASN knockdown using shRNA and the FASN inhibitor TVB-3166 was performed in FLT3-ITD-mutated AML cell lines (MOLM13, MV411) and Baf3-FLT3-ITD cells. The impact of FASN inhibition was assessed through Western blot and kinome profiling, while biological implications were evaluated by measuring cell viability and proliferation. FASN inhibition resulted in reduced levels of phospho-Akt (pAkt) and phospho-S6 kinase (pS6) and decreased expression of Hedgehog–Gli1, confirming non-canonical regulation of Gli by FLT3-ITD signaling. Combining TVB-3166 with the Gli inhibitor GANT61 significantly reduced the survival of MOLM13 and MV411 cells. Full article

(This article belongs to the Special Issue Hematological Malignancies: Molecular Mechanisms and Therapy, 2nd Edition)

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20 pages, 5060 KB

Open AccessArticle

Acquired Resistance to Decitabine Associated with the Deoxycytidine Kinase A180P Mutation: Implications for the Order of Hypomethylating Agents in Myeloid Malignancies Treatment

by Kristina Simonicova, Lubos Janotka, Helena Kavcova, Ivana Borovska, Zdena Sulova, Albert Breier and Lucia Messingerova

Int. J. Mol. Sci. 2025, 26(11), 5083; https://doi.org/10.3390/ijms26115083 - 25 May 2025

Cited by 2 | Viewed by 1475

Abstract

The backbone of therapy for elderly patients with myelodysplastic syndromes and acute myeloid leukemia consists of hypomethylating agents 5-aza-2’-deoxycytidine (DAC) and 5-azacytidine (AZA). However, resistance frequently emerges during treatment. To investigate the mechanisms of resistance, we generated DAC-resistant variants of the acute myeloid [...] Read more.

The backbone of therapy for elderly patients with myelodysplastic syndromes and acute myeloid leukemia consists of hypomethylating agents 5-aza-2’-deoxycytidine (DAC) and 5-azacytidine (AZA). However, resistance frequently emerges during treatment. To investigate the mechanisms of resistance, we generated DAC-resistant variants of the acute myeloid leukemia cell lines, MOLM-13 and SKM-1, through their prolonged cultivation in increasing concentrations of DAC. The resistant cell variants, MOLM-13/DAC and SKM-1/DAC, exhibited cross-resistance to cytarabine and gemcitabine, but remained sensitive to AZA. Existing studies have suggested that the loss of deoxycytidine kinase (DCK) may play an important role in DAC resistance. DCK is critical for DAC activation, but the precise mechanisms of its downregulation remain incompletely understood. We identified a novel point mutation (A180P) in DCK, which results in acquired DAC resistance. Although the DCK mRNA was actively transcribed, the mutant protein was not detected in DAC-resistant cells. The transfection of HEK293 cells with the mutant DCK, combined with proteasomal inhibition, revealed rapid proteasomal degradation, establishing a mechanistic link between the A180P mutation and DCK loss, not previously described. This highlights the importance of also evaluating DCK at the protein and/or enzymatic activity levels in patients. The loss of functional DCK impairs the phosphorylation of deoxynucleosides, conferring resistance to DAC, gemcitabine, and cytarabine, but AZA, phosphorylated by uridine–cytidine kinase, remains effective and may represent a therapeutic alternative for patients with acquired DAC resistance. Full article

(This article belongs to the Special Issue Hematological Malignancies: Molecular Mechanisms and Therapy, 2nd Edition)

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Review

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29 pages, 1093 KB

Open AccessReview

Antibody–Drug Conjugates in Hematological Malignancies: Current Landscape and Future Perspectives

by Maria Chiara Montalbano, Matilde Micillo, Silvia Deaglio and Tiziana Vaisitti

Int. J. Mol. Sci. 2026, 27(2), 1025; https://doi.org/10.3390/ijms27021025 - 20 Jan 2026

Cited by 1 | Viewed by 1385

Abstract

The therapeutic landscape for hematological malignancies has been fundamentally revolutionized over the last decade by the introduction of targeted antibodies. Notably, antibody–drug conjugates (ADCs) have emerged as a critical breakthrough, significantly improving the efficacy of immune-based treatment. ADCs function as highly sophisticated delivery [...] Read more.

The therapeutic landscape for hematological malignancies has been fundamentally revolutionized over the last decade by the introduction of targeted antibodies. Notably, antibody–drug conjugates (ADCs) have emerged as a critical breakthrough, significantly improving the efficacy of immune-based treatment. ADCs function as highly sophisticated delivery systems: a selective monoclonal antibody recognizes a specific cell-surface target, guiding a potent toxic payload, attached via a chemical linker, directly into the cancer cell upon internalization. Intensive research has been dedicated to optimizing these components—improving antibody selectivity, enhancing linker stability, and utilizing highly effective payloads—which has resulted in a plethora of compounds that have reached patients’ bedsides and improved the clinical course of different tumors. This review provides a crucial overview of the current landscape of approved ADCs for hematological malignancies. It critically discusses their existing limitations and details the essential structural and chemical improvements that have yielded more potent and selective next-generation tools, finally presenting future strategies to generate highly effective “bullets” capable of decisively improving long-term disease prognosis. Full article

(This article belongs to the Special Issue Hematological Malignancies: Molecular Mechanisms and Therapy, 2nd Edition)

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29 pages, 2405 KB

Open AccessReview

Tumor Microenvironment, Inflammation, and Inflammatory Prognostic Indices in Diffuse Large B-Cell Lymphomas: A Narrative Review

by Zorica Cvetković, Olivera Marković, Gligorije Marinković, Snežana Pejić and Vesna Vučić

Int. J. Mol. Sci. 2025, 26(12), 5670; https://doi.org/10.3390/ijms26125670 - 13 Jun 2025

Cited by 11 | Viewed by 3517

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, characterized by significant variability in clinical outcomes. Emerging evidence highlights the pivotal role of inflammation in the pathogenesis and prognosis of DLBCL. This narrative review explores the interplay between the [...] Read more.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, characterized by significant variability in clinical outcomes. Emerging evidence highlights the pivotal role of inflammation in the pathogenesis and prognosis of DLBCL. This narrative review explores the interplay between the tumor microenvironment, inflammatory processes, and prognostic indices used in DLBCL, focusing on biomarkers, immune responses, and systemic inflammation. These indices show promise as predictive and prognostic tools comparable to molecular markers, such as gene expression profiling, which are currently considered gold standards in prognosis but are often costly and technically demanding. By synthesizing findings from the current literature, this article highlights the potential of inflammatory indices as accessible and cost-effective prognostic alternatives to molecular markers in DLBCL, while also underscoring the need for further research to validate their clinical utility. Full article

(This article belongs to the Special Issue Hematological Malignancies: Molecular Mechanisms and Therapy, 2nd Edition)

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8 pages, 1801 KB

Open AccessCase Report

Combining CAR T-Cell Therapy and Nivolumab to Overcome Immune Resistance in THRLBCL: A Case Report

by Daniel Munarriz, Oriana López-Godino, Nuria Martinez-Cibrian, Nil Albiol, Helena Brillembourg, Sergio Navarro-Velázquez, Marta Español-Rego, Sebastián Casanueva, Lucía García-Tomás, Guillermo Muñoz-Sanchez, Leticia Alserawan, Daniel Benitez-Ribas, Laura Magnano, Juan Gonzalo Correa, Andrea Rivero, Pablo Mozas, Eva Gine, Luis Gerardo Rodríguez-Lobato, Alexandra Martínez-Roca, Mercedes Montoro-Lorite, Pilar Ayora, Jordi Esteve, Laura Frutos, Olga Balagué-Ponz, Alvaro Urbano-Ispizua, Europa Azucena González-Navarro, Manel Juan, Julio Delgado and Valentín Ortiz-Maldonado Show full author list Hide full author list

Int. J. Mol. Sci. 2025, 26(19), 9265; https://doi.org/10.3390/ijms26199265 - 23 Sep 2025

Cited by 3 | Viewed by 1512

Abstract

T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare, aggressive subtype of diffuse large B-cell lymphoma characterized by a profoundly immunosuppressive tumor microenvironment. PD-L1 overexpression by tumor cells is a recognized immune escape mechanism and may underlie resistance to cellular therapies, including CAR T-cell [...] Read more.

T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare, aggressive subtype of diffuse large B-cell lymphoma characterized by a profoundly immunosuppressive tumor microenvironment. PD-L1 overexpression by tumor cells is a recognized immune escape mechanism and may underlie resistance to cellular therapies, including CAR T-cell therapy. We report a case of a 29-year-old woman with refractory stage IV-B THRLBCL treated with anti-CD19 CAR T-cell therapy (varnimcabtagene autoleucel), who achieved an initial response (day +28) but experienced disease progression by day +100 despite robust CAR T-cell expansion. Peripheral blood analysis revealed persistent absolute B-cell aplasia, while bone marrow biopsy confirmed CD19-positive disease. Comparative immunohistochemistry demonstrated markedly increased PD-L1 expression in post-CAR T-cell samples, suggesting adaptive immune resistance via PD-1/PD-L1-mediated CAR T-cell inhibition. Nivolumab was initiated at month +4 to overcome this checkpoint-mediated resistance. Notably, a complete metabolic response was documented on PET/CT after four doses of nivolumab (month +6). The patient remains in sustained remission, with persistent B-cell aplasia, four years post-intervention. This case provides clinical and pathological evidence supporting the use of immune checkpoint blockade to rescue CAR T-cell efficacy, highlighting the potential of this synergistic approach in THRLBCL and possibly other B-cell malignancies exhibiting similar immune evasion. Full article

(This article belongs to the Special Issue Hematological Malignancies: Molecular Mechanisms and Therapy, 2nd Edition)

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