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Molecular Pathogenesis and Molecular Therapy of Lymphoid Malignancies
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Molecular Pathogenesis and Molecular Therapy of Lymphoid Malignancies

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (15 May 2023) | Viewed by 11433

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
Dr. Christopher D'Angelo

E-Mail Website
Guest Editor
UNMC Department of Internal Medicine, Fred & Pamela Buffett Cancer Center, Omaha, NE 68198, USA
Interests: lymphoma; bone marrow transplant/cellular therapies; gut microbiome

Special Issue Information

Dear Colleagues,

Lymphoid malignancies represent a broad spectrum of neoplastic disorders of the immune system. These diseases are classified based upon the cell lineage (B-cell, T-cell, and natural killer cell), cell maturity (mature versus immature/precursor), and clinical behavior. Over the last decades, scientific advancements have greatly enhanced our understanding of the various pathogenetic pathways that contribute to the initiation and progression of lymphoid neoplasms and drug resistance. The novel insights generated from this collective effort have profoundly impacted disease classification, clinical diagnosis, and drug development, moving us closer to offering personalized medicine for patients.

This Special Issue welcomes Original Research articles, Reviews that address the complex pathogenesis and targeted molecular therapies of B-cell, T-cell or NK-cell malignancies. Manuscripts that highlight molecular disease factors (genetic and/or epigenetic), oncogenic pathways within the tumor and its microenvironment, and introduce or evaluate novel therapeutics (e.g., small molecule inhibitors or antibodies) targeting these pathways are invited. The following topics are of particular interest:

  • Studies that characterize cells (tumor and/or bystander cells), extracellular elements (matrices, soluble factors, metabolites), and their crosstalk within the microenvironment of lymphoid malignancies
  • Mechanistic studies of oncogenic events (genetic or epigenetic) that contribute to disease progression and/or drug resistance
  • Studies focusing on signaling pathways within the tumor microenvironment that support malignant cell growth and/or evasion of anti-tumor immunity 
  • Translational and studies investigating novel molecular-based therapeutic approaches
  • Other studies pertaining to the overarching theme of this Special Issue as outlined above

On behalf of the Editorial Board at IJMS, we look forward to your contributions to this Special Issue. 

Dr. Dalia El-Gamal
Dr. Christopher D'Angelo
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • B-cell neoplasms
  • T-cell neoplasms
  • NK-cell neoplasms
  • leukemia
  • lymphoma
  • myeloma
  • molecular subtypes
  • tumor microenvironment
  • T-cell exhaustion
  • (epi)genetic drivers
  • immune evasion
  • molecular targets
  • preclinical studies
  • targeted therapy
  • translational research

Published Papers (5 papers)

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Editorial

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4 pages, 162 KiB  
Editorial
Editorial for the IJMS Special Issue on Molecular Pathogenesis and Molecular Therapy of Lymphoid Malignancies
by Alexandria P. Eiken and Dalia El-Gamal
Int. J. Mol. Sci. 2024, 25(1), 557; https://doi.org/10.3390/ijms25010557 - 31 Dec 2023
Viewed by 493
Abstract
In the era of targeted therapies, researchers have aimed to uncover the molecular drivers of malignant pathogenesis in lymphoid malignancies in an endeavor to develop effective therapeutic strategies [...] Full article
(This article belongs to the Special Issue Molecular Pathogenesis and Molecular Therapy of Lymphoid Malignancies)

Research

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17 pages, 2754 KiB  
Article
A Novel Triple-Action Inhibitor Targeting B-Cell Receptor Signaling and BRD4 Demonstrates Preclinical Activity in Chronic Lymphocytic Leukemia
by Audrey L. Smith, Alexandria P. Eiken, Sydney A. Skupa, Dalia Y. Moore, Lelisse T. Umeta, Lynette M. Smith, Elizabeth R. Lyden, Christopher R. D’Angelo, Avyakta Kallam, Julie M. Vose, Tatiana G. Kutateladze and Dalia El-Gamal
Int. J. Mol. Sci. 2022, 23(12), 6712; https://doi.org/10.3390/ijms23126712 - 16 Jun 2022
Cited by 4 | Viewed by 2471
Abstract
B-cell chronic lymphocytic leukemia (CLL) results from intrinsic genetic defects and complex microenvironment stimuli that fuel CLL cell growth through an array of survival signaling pathways. Novel small-molecule agents targeting the B-cell receptor pathway and anti-apoptotic proteins alone or in combination have revolutionized [...] Read more.
B-cell chronic lymphocytic leukemia (CLL) results from intrinsic genetic defects and complex microenvironment stimuli that fuel CLL cell growth through an array of survival signaling pathways. Novel small-molecule agents targeting the B-cell receptor pathway and anti-apoptotic proteins alone or in combination have revolutionized the management of CLL, yet combination therapy carries significant toxicity and CLL remains incurable due to residual disease and relapse. Single-molecule inhibitors that can target multiple disease-driving factors are thus an attractive approach to combat both drug resistance and combination-therapy-related toxicities. We demonstrate that SRX3305, a novel small-molecule BTK/PI3K/BRD4 inhibitor that targets three distinctive facets of CLL biology, attenuates CLL cell proliferation and promotes apoptosis in a dose-dependent fashion. SRX3305 also inhibits the activation-induced proliferation of primary CLL cells in vitro and effectively blocks microenvironment-mediated survival signals, including stromal cell contact. Furthermore, SRX3305 blocks CLL cell migration toward CXCL-12 and CXCL-13, which are major chemokines involved in CLL cell homing and retention in microenvironment niches. Importantly, SRX3305 maintains its anti-tumor effects in ibrutinib-resistant CLL cells. Collectively, this study establishes the preclinical efficacy of SRX3305 in CLL, providing significant rationale for its development as a therapeutic agent for CLL and related disorders. Full article
(This article belongs to the Special Issue Molecular Pathogenesis and Molecular Therapy of Lymphoid Malignancies)
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Review

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34 pages, 768 KiB  
Review
Classical Hodgkin Lymphoma: From Past to Future—A Comprehensive Review of Pathophysiology and Therapeutic Advances
by Faryal Munir, Viney Hardit, Irtiza N. Sheikh, Shaikha AlQahtani, Jiasen He, Branko Cuglievan, Chitra Hosing, Priti Tewari and Sajad Khazal
Int. J. Mol. Sci. 2023, 24(12), 10095; https://doi.org/10.3390/ijms241210095 - 13 Jun 2023
Cited by 3 | Viewed by 2898
Abstract
Hodgkin lymphoma, a hematological malignancy of lymphoid origin that typically arises from germinal-center B cells, has an excellent overall prognosis. However, the treatment of patients who relapse or develop resistant disease still poses a substantial clinical and research challenge, even though current risk-adapted [...] Read more.
Hodgkin lymphoma, a hematological malignancy of lymphoid origin that typically arises from germinal-center B cells, has an excellent overall prognosis. However, the treatment of patients who relapse or develop resistant disease still poses a substantial clinical and research challenge, even though current risk-adapted and response-based treatment techniques produce overall survival rates of over 95%. The appearance of late malignancies after the successful cure of primary or relapsed disease continues to be a major concern, mostly because of high survival rates. Particularly in pediatric HL patients, the chance of developing secondary leukemia is manifold compared to that in the general pediatric population, and the prognosis for patients with secondary leukemia is much worse than that for patients with other hematological malignancies. Therefore, it is crucial to develop clinically useful biomarkers to stratify patients according to their risk of late malignancies and determine which require intense treatment regimens to maintain the ideal balance between maximizing survival rates and avoiding late consequences. In this article, we review HL’s epidemiology, risk factors, staging, molecular and genetic biomarkers, and treatments for children and adults, as well as treatment-related adverse events and the late development of secondary malignancies in patients with the disease. Full article
(This article belongs to the Special Issue Molecular Pathogenesis and Molecular Therapy of Lymphoid Malignancies)
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16 pages, 666 KiB  
Review
Defining the Role of the Gut Microbiome in the Pathogenesis and Treatment of Lymphoid Malignancies
by Shristi Upadhyay Banskota, Sydney A. Skupa, Dalia El-Gamal and Christopher R. D’Angelo
Int. J. Mol. Sci. 2023, 24(3), 2309; https://doi.org/10.3390/ijms24032309 - 24 Jan 2023
Cited by 5 | Viewed by 2574
Abstract
The gut microbiome is increasingly being recognized as an important immunologic environment, with direct links to the host immune system. The scale of the gut microbiome’s genomic repertoire extends the capacity of its host’s genome by providing additional metabolic output, and the close [...] Read more.
The gut microbiome is increasingly being recognized as an important immunologic environment, with direct links to the host immune system. The scale of the gut microbiome’s genomic repertoire extends the capacity of its host’s genome by providing additional metabolic output, and the close communication between gut microbiota and mucosal immune cells provides a continued opportunity for immune education. The relationship between the gut microbiome and the host immune system has important implications for oncologic disease, including lymphoma, a malignancy derived from within the immune system itself. In this review, we explore past and recent discoveries describing the role that bacterial populations play in lymphomagenesis, diagnosis, and therapy. We highlight key relationships within the gut microbiome-immune-oncology axis that present exciting opportunities for directed interventions intended to shape the microbiome for therapeutic effect. We conclude with a limited summary of active clinical trials targeting the microbiome in hematologic malignancies, along with future directions on gut microbiome investigations within lymphoid malignancies. Full article
(This article belongs to the Special Issue Molecular Pathogenesis and Molecular Therapy of Lymphoid Malignancies)
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17 pages, 1221 KiB  
Review
Targeting the Isoprenoid Biosynthetic Pathway in Multiple Myeloma
by Staci L. Haney and Sarah A. Holstein
Int. J. Mol. Sci. 2023, 24(1), 111; https://doi.org/10.3390/ijms24010111 - 21 Dec 2022
Cited by 5 | Viewed by 1549
Abstract
Multiple myeloma (MM) is a plasma cell malignancy for which there is currently no cure. While treatment options for MM have expanded over the last two decades, all patients will eventually become resistant to current therapies. Thus, there is an urgent need for [...] Read more.
Multiple myeloma (MM) is a plasma cell malignancy for which there is currently no cure. While treatment options for MM have expanded over the last two decades, all patients will eventually become resistant to current therapies. Thus, there is an urgent need for novel therapeutic strategies to treat MM. The isoprenoid biosynthetic pathway (IBP) is responsible for the post-translational modification of proteins belonging to the Ras small GTPase superfamily, such as Ras, Rho and Rab family members. Given the important roles these GTPase proteins play in various cellular processes, there is significant interest in the development of inhibitors that disturb their prenylation and consequently their activity in MM cells. Numerous preclinical studies have demonstrated that IBP inhibitors have anti-MM effects, including the induction of apoptosis in MM cells and inhibition of osteoclast activity. Some IBP inhibitors have made their way into the clinic. For instance, nitrogenous bisphosphonates are routinely prescribed for the management MM bone disease. Other IBP inhibitors, including statins and farnesyltransferase inhibitors, have been evaluated in clinical trials for MM, while there is substantial preclinical investigation into geranylgeranyl diphosphate synthase inhibitors. Here we discuss recent advances in the development of IBP inhibitors, assess their mechanism of action and evaluate their potential as anti-MM agents. Full article
(This article belongs to the Special Issue Molecular Pathogenesis and Molecular Therapy of Lymphoid Malignancies)
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