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Innovative Approaches to Molecular Pathogenesis and Therapy of Lymphoid Malignancies

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Special Issue Editors

Dr. Dalia El-Gamal

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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
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Dr. Audrey Smith

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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

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Published Papers (2 papers)

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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. 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

17 pages, 2166 KiB

Open AccessArticle

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

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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 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)

► Show Figures

Figure 1

Figure 1
CLL cells display ecto-CALR following SpiD3 treatment. HG-3 ((A,B); n = 3); OSU-CLL ((C,D); n = 3); or patient-derived CLL ((E,F); n = 5) cells were treated with vehicle (Veh), SpiD3 (0.25–2 µM), FeCl2 (160 μM), or the positive control, etoposide (Etop; 20 µM) for the indicated durations. Viable cells were analyzed by flow cytometry for changes in surface CALR expression (ecto-CALR). Primary patient-derived CLL cells were additionally designated as CD19+/CD5+ by flow cytometry. Data are presented as mean ± SEM. Comparisons across treatment groups were analyzed with respect to the vehicle by one-way ANOVA. Asterisks denote magnitude of significance: * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001. Full article ">Figure 2
SpiD3 treatment evokes extracellular ATP release. HG-3 (A); and OSU-CLL (B) cells were treated over 24 h (n = 3) with vehicle (Veh), SpiD3 (0.5–2 µM), or the positive control, etoposide (Etop; 20 µM). Extracellular ATP measurements at 8, 16, and 24 h were parsed out to evaluate the average extracellular ATP measured at these timepoints in comparison to the matched timepoint vehicle. Data are presented as mean ± SEM. Comparisons across treatment groups were analyzed with respect to the matched timepoint average vehicle by one-way ANOVA. Asterisks denote magnitude of significance: * p < 0.05, ** p < 0.01, **** p < 0.0001. Full article ">Figure 3
SpiD3-treated cells release extracellular HMGB1. Supernatant from HG-3 ((A,B); n = 3); OSU-CLL ((C,D); n = 3); and primary CLL ((E); n = 10) cells were evaluated for extracellular HMGB1 after 24 h or 48 h of treatment with the vehicle (Veh), SpiD3 (0.5–2 µM), ibrutinib (1 µM), or positive control, etoposide (Etop; 20 µM). Data are presented as mean ± SEM. Comparisons across treatment groups were analyzed with respect to the vehicle by one-way ANOVA. Asterisks denote magnitude of significance: * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001. Full article ">Figure 4
Chemotactic potential of SpiD3-treated cell supernatants. Bone marrow dendritic cells (BMDCs) were allowed to migrate for 6 h toward supernatant collected from HG-3 (A); and OSU-CLL (B) cells after 24 h treatment with the vehicle (Veh), SpiD3 (0.5–2 µM), or the positive control, etoposide (Etop; 20 µM). GM-CSF (20 ng/mL) stimulated media, and supernatant derived from heat-shocked CLL cells (HS) served as positive chemotactic controls. The number of migrated BMDCs were counted via flow cytometry analysis (n = 3). The chemotactic index is a comparison of the migrated events observed from treatment conditions to that of the vehicle condition. Data are represented as mean ± SEM. Comparisons across treatment groups were analyzed with respect to the vehicle by one-way ANOVA. Asterisks denote magnitude of significance: * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001. Full article ">Figure 5
In vivo SpiD3 treatment yields an immunostimulatory response. (A) Schematic of experiment design: Eµ-TCL1 mice with comparable leukemia burden were treated intravenously with SpiD3 prodrug (SpiD3_AP, 10 mg/kg; n = 6) or equivalent vehicle (Veh; 50% PEG400, 10% DMSO, 40% water; n = 5) once daily for 3 days, as previously reported [<a href="#B20-biomedicines-12-02857" class="html-bibr">20</a>]. Following treatment, spleen cells were collected for flow cytometry analysis and plasma was isolated from murine blood; (B) leukemic (CD19+/CD5+) cells from murine spleens were analyzed by flow cytometry for changes in surface CALR expression (ecto-CALR) and compared to the percentage of leukemic cells detected in spleens of the same mice (as reported in Eiken, et al. [<a href="#B20-biomedicines-12-02857" class="html-bibr">20</a>]). The concentrations of plasma inflammatory cytokines and chemokines were assessed using Mouse Anti-Virus Response (C,E); and Mouse Pro-Inflammatory Chemokine (D,F) LEGENDplex™ flow cytometry-based multiplex immunoassays. (C,D) Heatmaps display fold change in the plasma analyte concentration compared to the average of vehicle-treated mice. Columns represent individual mice per treatment group. (E,F) Raw plasma analyte concentration and correlation with the percentage of CD19+/CD5+ spleen-derived cells are shown for select analytes. Individual data points (Veh = black circles; SpiD3_AP = blue triangles) in addition to summary statistics (mean ± SEM) are shown. Comparisons between treatment groups were analyzed by unpaired t-test. Asterisks denote magnitude of significance: * p < 0.05, ** p < 0.01. Full article ">Figure 6
Illustrative summary of SpiD3 anti-leukemic activity. CLL cell cytotoxicity via SpiD3 is demonstrated by: (i) inhibition of NF-κB signaling; and (ii) accumulation of unfolded proteins, promoting ER stress, activating a futile UPR and, subsequently, the associated programmed cell death pathways. ER stress is a proposed prerequisite for immunogenic DAMP emissions; we hypothesize it is this facet of SpiD3-associated effects that result in detectable hallmarks of immunogenic cell death from CLL cells. This diagram is adapted from Eiken, et al. CLL, chronic lymphocytic leukemia; DC, dendritic cell; iDAMP, immunogenic damage-associated molecular pattern; ER, endoplasmic reticulum; UPR, unfolded protein response. Full article ">

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