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Biomedicines
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Innovative Approaches to Molecular Pathogenesis and Therapy of Lymphoid Malignancies
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Innovative Approaches to Molecular Pathogenesis and Therapy of Lymphoid Malignancies

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: 31 October 2025 | Viewed by 4405

Special Issue Editors

Dr. Dalia El-Gamal

E-Mail Website
Guest Editor
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
Interests: B-cell leukemia and lymphoma; tumor microenvironment; anti-tumor immunity; tumor induced T-cell dysfunction; signaling; novel targeted; therapies; BRD4/BET inhibitors; kinase and NF-kB inhibitors; preclinical drug testing
Special Issues, Collections and Topics in MDPI journals
Dr. Audrey Smith

E-Mail Website
Guest Editor
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center (UNMC), Omaha, NE, USA
Interests: chronic lymphocytic leukemia; T-cell exhaustion; BET protein inhibition

Special Issue Information

Dear Colleagues,

Lymphoid malignancies include an array of distinct and biologically complex neoplastic disorders of lymphoid (B-, T-, and NK-) cell origin. Basic, translational, and clinical research continues to enhance our understanding of lymphoid neoplasm pathogenesis, drug resistance, and relapse. Molecular dependencies identified in each of these processes have allowed clinicians to refine disease classification, diagnosis, and therapeutic strategies. However, there is still a great need for innovative approaches to targeted therapy development in order to actualize well-informed, personalized medicine for patients.

This Special Issue welcomes original research and review articles that address the molecular factors contributing to lymphoid malignancy pathogenesis and/or therapeutically targeting such factors. These include, but are not limited to, genetic, epigenetic, signalling, metabolic, and immune contributors. Topics of particular interest include the following:

  • Mechanistic studies of oncogenic events (genetic or epi-genetic) that contribute to disease pathogenesis;
  • Studies that characterize tumor microenvironment cancer cell dependencies (factors that support cancer cell survival/growth or contribute to evasion of anti-tumor immunity) or therapeutically targeting such factors;
  • Translational studies investigating novel therapeutic approaches including small molecule inhibitors or antibody therapies;
  • Studies that utilize drug-resistance models;
  • Innovative therapeutic formulations, delivery modes, or combination strategies;
  • Methods for early detection or improved classification of disease.

We look forward to your contributions to this Special Issue.

Dr. Dalia El-Gamal
Dr. Audrey Smith
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • lymphoma
  • leukemia
  • myeloma
  • lymphoproliferative disorders
  • B-cell neoplasms
  • T-cell neoplasms
  • pathogenesis
  • molecular targets
  • novel therapies
  • translational research
  • tumor microenvironment

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Published Papers (5 papers)

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Research

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12 pages, 708 KiB  
Article
Venetoclax-Based Regimens in CLL: Immunoglobulin G Levels, Absolute Neutrophil Counts, and Infectious Complications
by Wojciech Szlasa, Monika Kisielewska, Anna Sobczyńska-Konefał, Emilia Jaskuła, Monika Mordak-Domagała, Jacek Kwiatkowski, Katarzyna Tatara, Agnieszka Kuś, Mateusz Sawicki, Izabela Dereń-Wagemann, Mariola Sędzimirska, Ugo Giordano and Jarosław Dybko
Biomedicines 2025, 13(7), 1609; https://doi.org/10.3390/biomedicines13071609 - 30 Jun 2025
Viewed by 310
Abstract
Background: Chronic lymphocytic leukemia (CLL) is a prevalent hematologic malignancy that predominantly affects elderly individuals, posing significant clinical challenges due to patient comorbidities and inherent resistance to conventional chemotherapy. The emergence of targeted therapies combining venetoclax, a selective inhibitor of the anti-apoptotic protein [...] Read more.
Background: Chronic lymphocytic leukemia (CLL) is a prevalent hematologic malignancy that predominantly affects elderly individuals, posing significant clinical challenges due to patient comorbidities and inherent resistance to conventional chemotherapy. The emergence of targeted therapies combining venetoclax, a selective inhibitor of the anti-apoptotic protein BCL-2, with anti-CD20 monoclonal antibodies has dramatically transformed the treatment landscape. Methods: This retrospective observational study analyzed the differential impacts of first-line venetoclax-obinutuzumab (VenO) and second-line venetoclax-rituximab (VenR) on immunoglobulin G (IgG) levels and absolute neutrophil count (ANC) in CLL patients. Results: Our findings indicate that during first-line VenO therapy, a significant improvement in ANC levels from baseline was observed, whereas patients undergoing second-line VenR therapy demonstrated limited impact on ANC and the decreasing tendency in IgG levels. Patients treated with VenR had a longer disease history and previous exposure to other treatment regimens, primarily chemoimmunotherapy, which could negatively influence immune recovery, making direct comparisons between these two treatment lines challenging. Although this observational study did not directly compare infection rates, the observed enhancement of ANC levels in patients receiving VenO suggests a potential for lower infection risk compared to pretreated VenR patients. Conclusions: These results underscore the clinical significance of considering both the treatment line and the patient’s prior therapeutic history when selecting venetoclax-based regimens for CLL. The potential association of first-line VenO with improved immunological parameters and the complex impact of prior therapies on immunological recovery with second-line VenR warrant further prospective investigation into the correlation between treatment regimen, patient history, immune function, and infectious complications. Full article
(This article belongs to the Special Issue Innovative Approaches to Molecular Pathogenesis and Therapy of Lymphoid Malignancies)
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14 pages, 1712 KiB  
Article
Impact of Protein Kinase C Activation and Monoclonal Antibodies on Immune Checkpoint Regulation and B Cell Function in Patients with Chronic Lymphocytic Leukemia
by Aviwe Ntsethe, Phiwayinkosi Vusi Dludla and Bongani Brian Nkambule
Biomedicines 2025, 13(3), 741; https://doi.org/10.3390/biomedicines13030741 - 18 Mar 2025
Viewed by 538
Abstract
Background: Chronic lymphocytic leukemia (CLL) is characterized by the proliferation of dysfunctional B cells, resulting in significant immune dysregulation. Patients with CLL exhibit varied responses to B cell receptor (BCR) targeted therapies, emphasizing the need for tailored immunotherapy approaches. This study investigated [...] Read more.
Background: Chronic lymphocytic leukemia (CLL) is characterized by the proliferation of dysfunctional B cells, resulting in significant immune dysregulation. Patients with CLL exhibit varied responses to B cell receptor (BCR) targeted therapies, emphasizing the need for tailored immunotherapy approaches. This study investigated B cell function in untreated patients with CLL, and we further explored the effects of ex vivo protein kinase C activation on immune checkpoint expression and B cell profiles. Methods: Peripheral blood samples were collected from 21 untreated patients with CLL at King Edward Hospital in South Africa, between 2019 and 2022. B cells were stimulated with phorbol myristate acetate (PMA) and ionomycin. Using flow cytometry, the study explored the levels of B cell subsets and immune checkpoint proteins programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), programmed cell death-ligand 2 (PD-L2) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) expression on various B cell subsets. Results: PMA and ionomycin B cell stimulation upregulated PD-1, CTLA-4 and PD-L2 expression on B cell subsets (p < 0.01). As expected, monoclonal antibodies targeting PD-1, PD-L1 and CTLA-4 significantly downregulated the CTLA-4 expression of B cell subsets (p < 0.05), while PD-L2 exhibited varied responses in different B cell subsets. Moreover, PD-1 and PD-L1 expression on total B cells significantly declined following their blockage (p < 0.01). In addition, these monoclonal antibodies increased the levels of CD19+CD27+ B cells (p < 0.0128) and activated CD19+CD27+ B cells (p < 0.01). Conclusions: Protein kinase C activation on B cells stimulates immune checkpoint expression. The use of monoclonal antibodies on B cells plays a critical role in the B cell function through the reduction in CD38 expressing activated B cells and upregulation of CD19+CD27+ B cells. Moreover, the monoclonal antibody targeting PD-1, PD-L1 and CTLA-4 are effective in reducing the expression of CTLA-4 on B cell subsets, while PD-1 and PD-L1 blockage may be effective in reducing the expression of these immune checkpoints on total B cells. Full article
(This article belongs to the Special Issue Innovative Approaches to Molecular Pathogenesis and Therapy of Lymphoid Malignancies)
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13 pages, 3211 KiB  
Article
β-Catenin Regulates Glycolytic and Mitochondrial Function in T-Cell Acute Lymphoblastic Leukemia
by Ling Zhang, Yu Zhao, Shuoting Wang, Jian Zhang, Xiaohui Li, Shuangyin Wang, Taosheng Huang, Jinxing Wang and Jiajun Liu
Biomedicines 2025, 13(2), 292; https://doi.org/10.3390/biomedicines13020292 - 24 Jan 2025
Viewed by 997
Abstract
Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy characterized by a poor prognosis. β-catenin is implicated in the progression of T-ALL, yet the precise mechanisms of β-catenin involvement in the pathogenesis of T-ALL, particularly concerning metabolic processes, remain inadequately elucidated. [...] Read more.
Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy characterized by a poor prognosis. β-catenin is implicated in the progression of T-ALL, yet the precise mechanisms of β-catenin involvement in the pathogenesis of T-ALL, particularly concerning metabolic processes, remain inadequately elucidated. Methods: A β-catenin knockout cell line was generated in the human leukemic cell line Jurkat using the CRISPR-Cas9 technique. Subsequently, assays were performed to evaluate cell proliferation, apoptosis, and metabolic activity. Comparative transcriptomic analysis was conducted between control cells and β-catenin knockout cells. Finally, a mouse xenograft model was employed to assess whether β-catenin knockout attenuates tumor growth and infiltration in vivo. Results: The deletion of β-catenin significantly inhibited proliferation and induced apoptosis. Additionally, the silencing of β-catenin led to the inhibition of glycolysis and a reduction in both mitochondrial mass and membrane potential. These results indicate that β-catenin may play a crucial role in regulating cell proliferation and apoptosis through the modulation of glycolytic activity and mitochondrial function in T-ALL. Conclusions: In summary, our findings uncover a novel mechanism by which β-catenin influences glycolysis and mitochondrial function in the progression of T-ALL, thereby identifying a potential therapeutic target for patients with relapsed T-ALL. Full article
(This article belongs to the Special Issue Innovative Approaches to Molecular Pathogenesis and Therapy of Lymphoid Malignancies)
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17 pages, 2166 KiB  
Article
Immunogenic Cell Death Traits Emitted from Chronic Lymphocytic Leukemia Cells Following Treatment with a Novel Anti-Cancer Agent, SpiD3
by Elizabeth Schmitz, Abigail Ridout, Audrey L. Smith, Alexandria P. Eiken, Sydney A. Skupa, Erin M. Drengler, Sarbjit Singh, Sandeep Rana, Amarnath Natarajan and Dalia El-Gamal
Biomedicines 2024, 12(12), 2857; https://doi.org/10.3390/biomedicines12122857 - 16 Dec 2024
Cited by 1 | Viewed by 1551
Abstract
Background: Targeted therapies (e.g., ibrutinib) have markedly improved chronic lymphocytic leukemia (CLL) management; however, ~20% of patients experience disease relapse, suggesting the inadequate depth and durability of these front-line strategies. Moreover, immunotherapeutic success in CLL has been stifled by its pro-tumor microenvironment milieu [...] Read more.
Background: Targeted therapies (e.g., ibrutinib) have markedly improved chronic lymphocytic leukemia (CLL) management; however, ~20% of patients experience disease relapse, suggesting the inadequate depth and durability of these front-line strategies. Moreover, immunotherapeutic success in CLL has been stifled by its pro-tumor microenvironment milieu and low mutational burden, cultivating poor antigenicity and limited ability to generate anti-tumor immunity through adaptive immune cell engagement. Previously, we have demonstrated how a three-carbon-linker spirocyclic dimer (SpiD3) promotes futile activation of the unfolded protein response (UPR) in CLL cells through immense misfolded-protein mimicry, culminating in insurmountable ER stress and programmed CLL cell death. Method: Herein, we used flow cytometry and cell-based assays to capture the kinetics and magnitude of SpiD3-induced damage-associated molecular patterns (DAMPs) in CLL cell lines and primary samples. Result: SpiD3 treatment, in vitro and in vivo, demonstrated the capacity to propagate immunogenic cell death through emissions of classically immunogenic DAMPs (CALR, ATP, HMGB1) and establish a chemotactic gradient for bone marrow-derived dendritic cells. Conclusions: Thus, this study supports future investigation into the relationship between novel therapeutics, manners of cancer cell death, and their contributions to adaptive immune cell engagement as a means for improving anti-cancer therapy in CLL. Full article
(This article belongs to the Special Issue Innovative Approaches to Molecular Pathogenesis and Therapy of Lymphoid Malignancies)
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Review

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30 pages, 2234 KiB  
Review
A Comprehensive Review of Somatic and Germline Biomarkers Associated with Childhood B-Cell Precursor Acute Lymphoblastic Leukemia: From Biological Significance to Precision Medicine Opportunities
by Daniel Martínez Anaya, Johana Itzel Rodriguez Ruiz, María del Pilar Navarrete-Meneses and Patricia Pérez-Vera
Biomedicines 2025, 13(7), 1626; https://doi.org/10.3390/biomedicines13071626 - 2 Jul 2025
Viewed by 377
Abstract
B-cell precursor acute lymphoblastic leukemia (B-ALL) is characterized by a constellation of somatic pathogenic variants associated with malignant transformation. These variants have implications for clinical management by providing clinical biomarkers. Most B-ALL cases have a sporadic presentation. However, some patients may present the [...] Read more.
B-cell precursor acute lymphoblastic leukemia (B-ALL) is characterized by a constellation of somatic pathogenic variants associated with malignant transformation. These variants have implications for clinical management by providing clinical biomarkers. Most B-ALL cases have a sporadic presentation. However, some patients may present the disease as the neoplastic manifestation of cancer predisposition syndromes caused by germline pathogenic variants. In these cases, genetic counseling and personalized oncologic management is mandatory, considering the patient’s sensitivity to conventional therapies. In this review, we have summarized current knowledge on the biological role and clinical relevance of somatic and germline pathogenic variants associated with B-ALL, and discuss three aspects of their application as biomarkers: (1) their usefulness to determine specific molecular subtypes, predicting prognosis and response to specific therapies, (2) their influence in genetic counseling and therapy adaptation for B-ALL in the context of underlying cancer predisposition syndromes, and (3) their detection and interpretation through methodologies. We also included a brief discussion on the need to reclassify variants of uncertain significance to clarify their clinical relevance. Finally, we discuss cases illustrating the impact of somatic and germline pathogenic variants in personalized medicine. Full article
(This article belongs to the Special Issue Innovative Approaches to Molecular Pathogenesis and Therapy of Lymphoid Malignancies)
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