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Cancers
Special Issues
Advanced Therapies for Hematological Cancers
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Advanced Therapies for Hematological Cancers

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 17709

Special Issue Editors

Dr. Brigitte Sola

E-Mail Website
Guest Editor
Université de Caen Normandie, Caen, France
Interests: B-cell lymphoma; mmetabolism; cell cycle; nucleo-cytoplasmic trafficking; tumor microenvironment; resistance; in vivo models;
Dr. Fabrice Gouilleux

E-Mail Website
Guest Editor
CNRS ERL 7001 LNOX, EA7501, Faculty of Medidine, Tours University, 37000 Tours, France
Interests: Signal transduction; JAK/STAT pathway; oncogenes; tumor suppressors; leukemogenesis; cancer stem cells; tumor microenvironment; pharmacological inhibitors; tumor resistance;

Special Issue Information

Dear Colleagues, 

Hematological cancers are tumors that affect the production and function of blood cells. According to their myeloid and/or lymphoid origin, they may affect children (e.g. acute lymphoblastic leukemias) or elderly patients (e.g. mantle cell lymphoma, acute myeloid leukemias). Hematopoietic malignancies display the hallmarks of cancer defined by Hanahan and Weinberg. Cancer cells sustain proliferative signaling, ignore growth suppressors, resist cell death, promote replicative immortality and genomic instability, support invasion, acquire reprogramming of energy metabolism, and induce angiogenesis, inflammation and/or immune escape. Genetic alterations of core signaling pathways are common hallmarks of cancer and multiple efforts have been made in the past to identify and target key effectors in these pathways. In some cases, these therapeutic strategies have been effective and have increased patient survival and quality of life. However, chemotherapy resistance often occurs due to additional alterations in tumor cell processes and/or interactions of cancer cells with their microenvironment. Moreover, some hematological diseases still remain incurable, indicating that new therapeutic strategies are needed.

This Special Issue is dedicated to preclinical studies reporting new efficient therapies assessed in various in vitro and in vivo models of leukemia, lymphoma, and myeloma.

Dr. Brigitte Sola
Dr. Fabrice Gouilleux
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. Cancers is an international peer-reviewed open access semimonthly 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 2900 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

  • leukemia
  • lymphoma
  • acute
  • chronic
  • signalization
  • inhibitor
  • modulator
  • epigenetics
  • microenvironment
  • therapy
  • targets

Published Papers (5 papers)

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Research

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12 pages, 3272 KiB  
Article
Diphenyleneiodonium Triggers Cell Death of Acute Myeloid Leukemia Cells by Blocking the Mitochondrial Respiratory Chain, and Synergizes with Cytarabine
by Hassan Dakik, Maya El Dor, Jérôme Bourgeais, Farah Kouzi, Olivier Herault, Fabrice Gouilleux, Kazem Zibara and Frédéric Mazurier
Cancers 2022, 14(10), 2485; https://doi.org/10.3390/cancers14102485 - 18 May 2022
Cited by 2 | Viewed by 1829
Abstract
Acute myeloid leukemia (AML) is characterized by the accumulation of undifferentiated blast cells in the bone marrow and blood. In most cases of AML, relapse frequently occurs due to resistance to chemotherapy. Compelling research results indicate that drug resistance in cancer cells is [...] Read more.
Acute myeloid leukemia (AML) is characterized by the accumulation of undifferentiated blast cells in the bone marrow and blood. In most cases of AML, relapse frequently occurs due to resistance to chemotherapy. Compelling research results indicate that drug resistance in cancer cells is highly dependent on the intracellular levels of reactive oxygen species (ROS). Modulating ROS levels is therefore a valuable strategy to overcome the chemotherapy resistance of leukemic cells. In this study, we evaluated the efficiency of diphenyleneiodonium (DPI)—a well-known inhibitor of ROS production—in targeting AML cells. Results showed that although inhibiting cytoplasmic ROS production, DPI also triggered an increase in the mitochondrial ROS levels, caused by the disruption of the mitochondrial respiratory chain. We also demonstrated that DPI blocks mitochondrial oxidative phosphorylation (OxPhos) in a dose-dependent manner, and that AML cells with high OxPhos status are highly sensitive to treatment with DPI, which synergizes with the chemotherapeutic agent cytarabine (Ara-C). Thus, our results suggest that targeting mitochondrial function with DPI might be exploited to target AML cells with high OxPhos status. Full article
(This article belongs to the Special Issue Advanced Therapies for Hematological Cancers)
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20 pages, 25437 KiB  
Article
Constitutive Activation of p62/Sequestosome-1-Mediated Proteaphagy Regulates Proteolysis and Impairs Cell Death in Bortezomib-Resistant Mantle Cell Lymphoma
by Grégoire Quinet, Wendy Xolalpa, Diana Reyes-Garau, Núria Profitós-Pelejà, Mikel Azkargorta, Laurie Ceccato, Maria Gonzalez-Santamarta, Maria Marsal, Jordi Andilla, Fabienne Aillet, Francesc Bosch, Felix Elortza, Pablo Loza-Alvarez, Brigitte Sola, Olivier Coux, Rune Matthiesen, Gaël Roué and Manuel S. Rodriguez
Cancers 2022, 14(4), 923; https://doi.org/10.3390/cancers14040923 - 12 Feb 2022
Cited by 5 | Viewed by 3180
Abstract
Protein ubiquitylation coordinates crucial cellular events in physiological and pathological conditions. A comparative analysis of the ubiquitin proteome from bortezomib (BTZ)-sensitive and BTZ-resistant mantle cell lymphoma (MCL) revealed an enrichment of the autophagy–lysosome system (ALS) in BTZ-resistant cells. Pharmacological inhibition of autophagy at [...] Read more.
Protein ubiquitylation coordinates crucial cellular events in physiological and pathological conditions. A comparative analysis of the ubiquitin proteome from bortezomib (BTZ)-sensitive and BTZ-resistant mantle cell lymphoma (MCL) revealed an enrichment of the autophagy–lysosome system (ALS) in BTZ-resistant cells. Pharmacological inhibition of autophagy at the level of lysosome-fusion revealed a constitutive activation of proteaphagy and accumulation of proteasome subunits within autophagosomes in different MCL cell lines with acquired or natural resistance to BTZ. Inhibition of the autophagy receptor p62/SQSTM1 upon verteporfin (VTP) treatment disrupted proteaphagosome assembly, reduced co-localization of proteasome subunits with autophagy markers and negatively impacted proteasome activity. Finally, the silencing or pharmacological inhibition of p62 restored the apoptosis threshold at physiological levels in BTZ-resistant cells both in vitro and in vivo. In total, these results demonstrate for the first time a proteolytic switch from the ubiquitin–proteasome system (UPS) to ALS in B-cell lymphoma refractory to proteasome inhibition, pointing out a crucial role for proteaphagy in this phenomenon and paving the way for the design of alternative therapeutic venues in treatment-resistant tumors. Full article
(This article belongs to the Special Issue Advanced Therapies for Hematological Cancers)
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20 pages, 3369 KiB  
Article
5,6-Epoxycholesterol Isomers Induce Oxiapoptophagy in Myeloma Cells
by Oumaima Jaouadi, Inès Limam, Mohamed Abdelkarim, Emna Berred, Ahlem Chahbi, Mélody Caillot, Brigitte Sola and Fatma Ben Aissa-Fennira
Cancers 2021, 13(15), 3747; https://doi.org/10.3390/cancers13153747 - 26 Jul 2021
Cited by 12 | Viewed by 2256
Abstract
Multiple myeloma (MM) is an incurable plasma cell malignancy with frequent patient relapse due to innate or acquired drug resistance. Cholesterol metabolism is reported to be altered in MM; therefore, we investigated the potential anti-myeloma activity of two cholesterol derivatives: the 5,6 α- [...] Read more.
Multiple myeloma (MM) is an incurable plasma cell malignancy with frequent patient relapse due to innate or acquired drug resistance. Cholesterol metabolism is reported to be altered in MM; therefore, we investigated the potential anti-myeloma activity of two cholesterol derivatives: the 5,6 α- and 5,6 β-epoxycholesterol (EC) isomers. To this end, viability assays were used, and isomers were shown to exhibit important anti-tumor activity in vitro in JJN3 and U266 human myeloma cell lines (HMCLs) and ex vivo in myeloma patients’ sorted CD138+ malignant cells. Moreover, we confirmed that 5,6 α-EC and 5,6 β-EC induced oxiapoptophagy through concomitant oxidative stress and caspase-3-mediated apoptosis and autophagy. Interestingly, in combination treatment a synergistic interaction was observed between 5,6 α-EC and 5,6 β-EC on myeloma cells. These data highlight a striking anti-tumor activity of 5,6 α-EC and 5,6 β-EC bioactive molecules against human myeloma cells, paving the way for their potential role in future therapeutic strategies in MM. Full article
(This article belongs to the Special Issue Advanced Therapies for Hematological Cancers)
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Review

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22 pages, 1071 KiB  
Review
Regulation of B-Cell Receptor Signaling and Its Therapeutic Relevance in Aggressive B-Cell Lymphomas
by Núria Profitós-Pelejà, Juliana Carvalho Santos, Ana Marín-Niebla, Gaël Roué and Marcelo Lima Ribeiro
Cancers 2022, 14(4), 860; https://doi.org/10.3390/cancers14040860 - 09 Feb 2022
Cited by 19 | Viewed by 5962
Abstract
The proliferation and survival signals emanating from the B-cell receptor (BCR) constitute a crucial aspect of mature lymphocyte’s life. Dysregulated BCR signaling is considered a potent contributor to tumor survival in different subtypes of B-cell non-Hodgkin lymphomas (B-NHLs). In the last decade, the [...] Read more.
The proliferation and survival signals emanating from the B-cell receptor (BCR) constitute a crucial aspect of mature lymphocyte’s life. Dysregulated BCR signaling is considered a potent contributor to tumor survival in different subtypes of B-cell non-Hodgkin lymphomas (B-NHLs). In the last decade, the emergence of BCR-associated kinases as rational therapeutic targets has led to the development and approval of several small molecule inhibitors targeting either Bruton’s tyrosine kinase (BTK), spleen tyrosine kinase (SYK), or phosphatidylinositol 3 kinase (PI3K), offering alternative treatment options to standard chemoimmunotherapy, and making some of these drugs valuable assets in the anti-lymphoma armamentarium. Despite their initial effectiveness, these precision medicine strategies are limited by primary resistance in aggressive B-cell lymphoma such as diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), especially in the case of first generation BTK inhibitors. In these patients, BCR-targeting drugs often fail to produce durable responses, and nearly all cases eventually progress with a dismal outcome, due to secondary resistance. This review will discuss our current understanding of the role of antigen-dependent and antigen-independent BCR signaling in DLBCL and MCL and will cover both approved inhibitors and investigational molecules being evaluated in early preclinical studies. We will discuss how the mechanisms of action of these molecules, and their off/on-target effects can influence their effectiveness and lead to toxicity, and how our actual knowledge supports the development of more specific inhibitors and new, rationally based, combination therapies, for the management of MCL and DLBCL patients. Full article
(This article belongs to the Special Issue Advanced Therapies for Hematological Cancers)
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27 pages, 1432 KiB  
Review
Targeting Reactive Oxygen Species Metabolism to Induce Myeloma Cell Death
by Mélody Caillot, Hassan Dakik, Frédéric Mazurier and Brigitte Sola
Cancers 2021, 13(10), 2411; https://doi.org/10.3390/cancers13102411 - 17 May 2021
Cited by 13 | Viewed by 3489
Abstract
Multiple myeloma (MM) is a common hematological disease characterized by the accumulation of clonal malignant plasma cells in the bone marrow. Over the past two decades, new therapeutic strategies have significantly improved the treatment outcome and patients survival. Nevertheless, most MM patients relapse [...] Read more.
Multiple myeloma (MM) is a common hematological disease characterized by the accumulation of clonal malignant plasma cells in the bone marrow. Over the past two decades, new therapeutic strategies have significantly improved the treatment outcome and patients survival. Nevertheless, most MM patients relapse underlying the need of new therapeutic approaches. Plasma cells are prone to produce large amounts of immunoglobulins causing the production of intracellular ROS. Although adapted to high level of ROS, MM cells die when exposed to drugs increasing ROS production either directly or by inhibiting antioxidant enzymes. In this review, we discuss the efficacy of ROS-generating drugs for inducing MM cell death and counteracting acquired drug resistance specifically toward proteasome inhibitors. Full article
(This article belongs to the Special Issue Advanced Therapies for Hematological Cancers)
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