Cancers

Editorial

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4 pages, 177 KiB

Open AccessEditorial

Advances and Perspectives in the Treatment of B-Cell Malignancies

by Marta Cuenca and Victor Peperzak

Cancers 2021, 13(9), 2266; https://doi.org/10.3390/cancers13092266 - 8 May 2021

Cited by 4 | Viewed by 2686

Abstract

B-cell malignancies arise from different stages of B-cell differentiation and constitute a heterogeneous group of cancers including B-cell lymphomas, B-cell leukemias, and plasma cell dyscrasias [...] Full article

(This article belongs to the Special Issue B Cell Malignancies (including B Cell Lymphoma, Multiple Myeloma and B-CLL))

Research

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16 pages, 4158 KiB

Open AccessArticle

CD229 (Ly9) a Novel Biomarker for B-Cell Malignancies and Multiple Myeloma

by Giovanna Roncador, Joan Puñet-Ortiz, Lorena Maestre, Luis Gerardo Rodríguez-Lobato, Scherezade Jiménez, Ana Isabel Reyes-García, Álvaro García-González, Juan F. García, Miguel Ángel Piris, Santiago Montes-Moreno, Manuel Rodríguez-Justo, Mari-Pau Mena, Carlos Fernández de Larrea and Pablo Engel

Cancers 2022, 14(9), 2154; https://doi.org/10.3390/cancers14092154 - 26 Apr 2022

Cited by 6 | Viewed by 3285

Abstract

CD229 (Ly9) homophilic receptor, which belongs to the SLAM family of cell-surface molecules, is predominantly expressed on B and T cells. It acts as a signaling molecule, regulating lymphocyte homoeostasis and activation. Studies of CD229 function indicate that this receptor functions as a [...] Read more.

CD229 (Ly9) homophilic receptor, which belongs to the SLAM family of cell-surface molecules, is predominantly expressed on B and T cells. It acts as a signaling molecule, regulating lymphocyte homoeostasis and activation. Studies of CD229 function indicate that this receptor functions as a regulator of the development of marginal-zone B cells and other innate-like T and B lymphocytes. The expression on leukemias and lymphomas remains poorly understood due to the lack of CD229 monoclonal antibodies (mAb) for immunohistochemistry application (IHC). In this study, we used a new mAb against the cytoplasmic region of CD229 to study the expression of CD229 on normal tissues and B-cell malignancies, including multiple myeloma (MM), using tissue microarrays. We showed CD229 to be restricted to hematopoietic cells. It was strongly expressed in all cases of MM and in most marginal-zone lymphomas (MZL). Moderate CD229 expression was also found in chronic lymphocyte leukemia (CLL), follicular (FL), classic mantle-cell (MCL) and diffuse large B-cell lymphoma. Given the high expression on myeloma cells, we also analyzed for the presence of soluble CD229 in the sera of these patients. Serum levels of soluble CD229 (sCD229) at the time of diagnosis in MM patients could be useful as a prognostic biomarker. In conclusion, our results indicate that CD229 represents not only a useful biomarker but also an attractive therapeutic target. Full article

(This article belongs to the Special Issue B Cell Malignancies (including B Cell Lymphoma, Multiple Myeloma and B-CLL))

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17 pages, 2334 KiB

Open AccessArticle

Role of ETS1 in the Transcriptional Network of Diffuse Large B Cell Lymphoma of the Activated B Cell-Like Type

by Valdemar Priebe, Giulio Sartori, Sara Napoli, Elaine Yee Lin Chung, Luciano Cascione, Ivo Kwee, Alberto Jesus Arribas, Afua Adjeiwaa Mensah, Andrea Rinaldi, Maurilio Ponzoni, Emanuele Zucca, Davide Rossi, Dimitar Efremov, Georg Lenz, Margot Thome and Francesco Bertoni

Cancers 2020, 12(7), 1912; https://doi.org/10.3390/cancers12071912 - 15 Jul 2020

Cited by 6 | Viewed by 4093

Abstract

Diffuse large B cell lymphoma (DLBCL) is a heterogenous disease that has been distinguished into at least two major molecular entities, the germinal center-like B cell (GCB) DLBCL and activated-like B cell (ABC) DLBCL, based on transcriptome expression profiling. A recurrent ch11q24.3 gain [...] Read more.

Diffuse large B cell lymphoma (DLBCL) is a heterogenous disease that has been distinguished into at least two major molecular entities, the germinal center-like B cell (GCB) DLBCL and activated-like B cell (ABC) DLBCL, based on transcriptome expression profiling. A recurrent ch11q24.3 gain is observed in roughly a fourth of DLBCL cases resulting in the overexpression of two ETS transcription factor family members, ETS1 and FLI1. Here, we knocked down ETS1 expression by siRNA and analyzed expression changes integrating them with ChIP-seq data to identify genes directly regulated by ETS1. ETS1 silencing affected expression of genes involved in B cell signaling activation, B cell differentiation, cell cycle, and immune processes. Integration of RNA-Seq (RNA sequencing) data and ChIP-Seq (chromatin immunoprecipitation sequencing) identified 97 genes as bona fide, positively regulated direct targets of ETS1 in ABC-DLBCL. Among these was the Fc receptor for IgM, FCMR (also known as FAIM3 or Toso), which showed higher expression in ABC- than GCB-DLBCL clinical specimens. These findings show that ETS1 is contributing to the lymphomagenesis in a subset of DLBCL and identifies FCMR as a novel target of ETS1, predominantly expressed in ABC-DLBCL. Full article

(This article belongs to the Special Issue B Cell Malignancies (including B Cell Lymphoma, Multiple Myeloma and B-CLL))

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20 pages, 2241 KiB

Open AccessArticle

The miR-26b-5p/KPNA2 Axis Is an Important Regulator of Burkitt Lymphoma Cell Growth

by Fubiao Niu, Marta Kazimierska, Ilja M. Nolte, Miente Martijn Terpstra, Debora de Jong, Jasper Koerts, Tineke van der Sluis, Bea Rutgers, Ryan M. O’Connell, Klaas Kok, Anke van den Berg, Agnieszka Dzikiewicz-Krawczyk and Joost Kluiver

Cancers 2020, 12(6), 1464; https://doi.org/10.3390/cancers12061464 - 4 Jun 2020

Cited by 25 | Viewed by 4171

Abstract

The expression of several microRNAs (miRNAs) is known to be changed in Burkitt lymphoma (BL), compared to its normal counterparts. Although for some miRNAs, a role in BL was demonstrated, for most of them, their function is unclear. In this study, we aimed [...] Read more.

The expression of several microRNAs (miRNAs) is known to be changed in Burkitt lymphoma (BL), compared to its normal counterparts. Although for some miRNAs, a role in BL was demonstrated, for most of them, their function is unclear. In this study, we aimed to identify miRNAs that control BL cell growth. Two BL cell lines were infected with lentiviral pools containing either 58 miRNA inhibitors or 44 miRNA overexpression constructs. Eighteen constructs showed significant changes in abundance over time, indicating that they affected BL growth. The screening results were validated by individual green fluorescent protein (GFP) growth competition assays for fifteen of the eighteen constructs. For functional follow-up studies, we focused on miR-26b-5p, whose overexpression inhibited BL cell growth. Argonaute 2 RNA immunoprecipitation (Ago2-IP) in two BL cell lines revealed 47 potential target genes of miR-26b-5p. Overlapping the list of putative targets with genes showing a growth repression phenotype in a genome-wide CRISPR/Cas9 knockout screen, revealed eight genes. The top-5 candidates included EZH2, COPS2, KPNA2, MRPL15, and NOL12. EZH2 is a known target of miR-26b-5p, with oncogenic properties in BL. The relevance of the latter four targets was confirmed using sgRNAs targeting these genes in individual GFP growth competition assays. Luciferase reporter assay confirmed binding of miR-26b-5p to the predicted target site for KPNA2, but not to the other genes. In summary, we identified 18 miRNAs that affected BL cell growth in a loss- or gain-of-function screening. A tumor suppressor role was confirmed for miR-26b-5p, and this effect could at least in part be attributed to KPNA2, a known regulator of OCT4, c-jun, and MYC. Full article

(This article belongs to the Special Issue B Cell Malignancies (including B Cell Lymphoma, Multiple Myeloma and B-CLL))

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15 pages, 2086 KiB

Open AccessArticle

Iron Causes Lipid Oxidation and Inhibits Proteasome Function in Multiple Myeloma Cells: A Proof of Concept for Novel Combination Therapies

by Jessica Bordini, Federica Morisi, Fulvia Cerruti, Paolo Cascio, Clara Camaschella, Paolo Ghia and Alessandro Campanella

Cancers 2020, 12(4), 970; https://doi.org/10.3390/cancers12040970 - 14 Apr 2020

Cited by 25 | Viewed by 4966

Abstract

Adaptation to import iron for proliferation makes cancer cells potentially sensitive to iron toxicity. Iron loading impairs multiple myeloma (MM) cell proliferation and increases the efficacy of the proteasome inhibitor bortezomib. Here, we defined the mechanisms of iron toxicity in MM.1S, U266, H929, [...] Read more.

Adaptation to import iron for proliferation makes cancer cells potentially sensitive to iron toxicity. Iron loading impairs multiple myeloma (MM) cell proliferation and increases the efficacy of the proteasome inhibitor bortezomib. Here, we defined the mechanisms of iron toxicity in MM.1S, U266, H929, and OPM-2 MM cell lines, and validated this strategy in preclinical studies using Vk*MYC mice as MM model. High-dose ferric ammonium citrate triggered cell death in all cell lines tested, increasing malondialdehyde levels, the by-product of lipid peroxidation and index of ferroptosis. In addition, iron exposure caused dose-dependent accumulation of polyubiquitinated proteins in highly iron-sensitive MM.1S and H929 cells, suggesting that proteasome workload contributes to iron sensitivity. Accordingly, high iron concentrations inhibited the proteasomal chymotrypsin-like activity of 26S particles and of MM cellular extracts in vitro. In all MM cells, bortezomib-iron combination induced persistent lipid damage, exacerbated bortezomib-induced polyubiquitinated proteins accumulation, and triggered cell death more efficiently than individual treatments. In Vk*MYC mice, addition of iron dextran or ferric carboxymaltose to the bortezomib-melphalan-prednisone (VMP) regimen increased the therapeutic response and prolonged remission without causing evident toxicity. We conclude that iron loading interferes both with redox and protein homeostasis, a property that can be exploited to design novel combination strategies including iron supplementation, to increase the efficacy of current MM therapies. Full article

(This article belongs to the Special Issue B Cell Malignancies (including B Cell Lymphoma, Multiple Myeloma and B-CLL))

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Review

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13 pages, 1058 KiB

Open AccessFeature PaperReview

Biology and Clinical Applicability of Plasma Thymus and Activation-Regulated Chemokine (TARC) in Classical Hodgkin Lymphoma

by Eline A. M. Zijtregtop, Iris van der Strate, Auke Beishuizen, Christian M. Zwaan, Marijn A. Scheijde-Vermeulen, Arianne M. Brandsma and Friederike Meyer-Wentrup

Cancers 2021, 13(4), 884; https://doi.org/10.3390/cancers13040884 - 20 Feb 2021

Cited by 15 | Viewed by 4342

Abstract

Thymus and activation-regulated chemokine (TARC) is produced by different cell types and is highly expressed in the thymus. It plays an important role in T cell development, trafficking and activation of mature T cells after binding to its receptor C-C chemokine receptor type [...] Read more.

Thymus and activation-regulated chemokine (TARC) is produced by different cell types and is highly expressed in the thymus. It plays an important role in T cell development, trafficking and activation of mature T cells after binding to its receptor C-C chemokine receptor type 4 (CCR4) and consecutive signal transducer and activator of transcription 6 (STAT6) activation. Importantly, TARC is also produced by malignant Hodgkin and Reed–Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL). In cHL, HRS cells survive and proliferate due to the micro-environment consisting primarily of type 2 T helper (Th2) cells. TARC-mediated signaling initiates a positive feedback loop that is crucial for the interaction between HRS and T cells. The clinical applicability of TARC is diverse. It is useful as diagnostic biomarker in both children and adults with cHL and in other Th2-driven diseases. In adult cHL patients, TARC is also a biomarker for treatment response and prognosis. Finally, blocking TARC signaling and thus inhibiting pathological Th2 cell recruitment could be a therapeutic strategy in cHL. In this review, we summarize the biological functions of TARC and focus on its role in cHL pathogenesis and as a biomarker for cHL and other diseases. We conclude by giving an outlook on putative therapeutic applications of antagonists and inhibitors of TARC-mediated signaling. Full article

(This article belongs to the Special Issue B Cell Malignancies (including B Cell Lymphoma, Multiple Myeloma and B-CLL))

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21 pages, 2561 KiB

Open AccessReview

Follicular Lymphoma Microenvironment: An Intricate Network Ready for Therapeutic Intervention

by Cèlia Dobaño-López, Ferran Araujo-Ayala, Neus Serrat, Juan G. Valero and Patricia Pérez-Galán

Cancers 2021, 13(4), 641; https://doi.org/10.3390/cancers13040641 - 5 Feb 2021

Cited by 10 | Viewed by 4768

Abstract

Follicular Lymphoma (FL), the most common indolent non-Hodgkin’s B cell lymphoma, is a paradigm of the immune microenvironment’s contribution to disease onset, progression, and heterogeneity. Over the last few years, state-of-the-art technologies, including whole-exome sequencing, single-cell RNA sequencing, and mass cytometry, have precisely [...] Read more.

Follicular Lymphoma (FL), the most common indolent non-Hodgkin’s B cell lymphoma, is a paradigm of the immune microenvironment’s contribution to disease onset, progression, and heterogeneity. Over the last few years, state-of-the-art technologies, including whole-exome sequencing, single-cell RNA sequencing, and mass cytometry, have precisely dissected the specific cellular phenotypes present in the FL microenvironment network and their role in the disease. In this already complex picture, the presence of recurring mutations, including KMT2D, CREBBP, EZH2, and TNFRSF14, have a prominent contributory role, with some of them finely tuning this exquisite dependence of FL on its microenvironment. This precise characterization of the enemy (FL) and its allies (microenvironment) has paved the way for the development of novel therapies aimed at dismantling this contact network, weakening tumor cell support, and reactivating the host’s immune response against the tumor. In this review, we will describe the main microenvironment actors, together with the current and future therapeutic approaches targeting them. Full article

(This article belongs to the Special Issue B Cell Malignancies (including B Cell Lymphoma, Multiple Myeloma and B-CLL))

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32 pages, 8225 KiB

Open AccessReview

Primary Pulmonary B-Cell Lymphoma: A Review and Update

by Francesca Sanguedolce, Magda Zanelli, Maurizio Zizzo, Alessandra Bisagni, Alessandra Soriano, Giorgia Cocco, Andrea Palicelli, Giacomo Santandrea, Cecilia Caprera, Matteo Corsi, Giulia Cerrone, Raffaele Sciaccotta, Giovanni Martino, Linda Ricci, Francesco Sollitto, Domenico Loizzi and Stefano Ascani

Cancers 2021, 13(3), 415; https://doi.org/10.3390/cancers13030415 - 22 Jan 2021

Cited by 42 | Viewed by 6302

Abstract

Primary pulmonary B-cell lymphomas (PP-BCLs) comprise a group of extranodal non-Hodgkin lymphomas of B-cell origin, which primarily affect the lung without evidence of extrapulmonary disease at the time of diagnosis and up to 3 months afterwards. Primary lymphoid proliferations of the lung are [...] Read more.

Primary pulmonary B-cell lymphomas (PP-BCLs) comprise a group of extranodal non-Hodgkin lymphomas of B-cell origin, which primarily affect the lung without evidence of extrapulmonary disease at the time of diagnosis and up to 3 months afterwards. Primary lymphoid proliferations of the lung are most often of B-cell lineage, and include three major entities with different clinical, morphological, and molecular features: primary pulmonary marginal zone lymphoma of mucosa-associated lymphoid tissue (PP-MZL, or MALT lymphoma), primary pulmonary diffuse large B cell lymphoma (PP-DLBCL), and lymphomatoid granulomatosis (LYG). Less common entities include primary effusion B-cell lymphoma (PEL) and intravascular large B cell lymphoma (IVLBCL). A proper workup requires a multidisciplinary approach, including radiologists, pneumologists, thoracic surgeons, pathologists, hemato-oncologists, and radiation oncologists, in order to achieve a correct diagnosis and risk assessment. Aim of this review is to analyze and outline the clinical and pathological features of the most frequent PP-BCLs, and to critically analyze the major issues in their diagnosis and management. Full article

(This article belongs to the Special Issue B Cell Malignancies (including B Cell Lymphoma, Multiple Myeloma and B-CLL))

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36 pages, 1837 KiB

Open AccessReview

Metabolic Effects of Recurrent Genetic Aberrations in Multiple Myeloma

by Timon A. Bloedjes, Guus de Wilde and Jeroen E. J. Guikema

Cancers 2021, 13(3), 396; https://doi.org/10.3390/cancers13030396 - 21 Jan 2021

Cited by 20 | Viewed by 4234

Abstract

Oncogene activation and malignant transformation exerts energetic, biosynthetic and redox demands on cancer cells due to increased proliferation, cell growth and tumor microenvironment adaptation. As such, altered metabolism is a hallmark of cancer, which is characterized by the reprogramming of multiple metabolic pathways. [...] Read more.

Oncogene activation and malignant transformation exerts energetic, biosynthetic and redox demands on cancer cells due to increased proliferation, cell growth and tumor microenvironment adaptation. As such, altered metabolism is a hallmark of cancer, which is characterized by the reprogramming of multiple metabolic pathways. Multiple myeloma (MM) is a genetically heterogeneous disease that arises from terminally differentiated B cells. MM is characterized by reciprocal chromosomal translocations that often involve the immunoglobulin loci and a restricted set of partner loci, and complex chromosomal rearrangements that are associated with disease progression. Recurrent chromosomal aberrations in MM result in the aberrant expression of MYC, cyclin D1, FGFR3/MMSET and MAF/MAFB. In recent years, the intricate mechanisms that drive cancer cell metabolism and the many metabolic functions of the aforementioned MM-associated oncogenes have been investigated. Here, we discuss the metabolic consequences of recurrent chromosomal translocations in MM and provide a framework for the identification of metabolic changes that characterize MM cells. Full article

(This article belongs to the Special Issue B Cell Malignancies (including B Cell Lymphoma, Multiple Myeloma and B-CLL))

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20 pages, 1364 KiB

Open AccessReview

Hematopoietic versus Solid Cancers and T Cell Dysfunction: Looking for Similarities and Distinctions

by Chiara Montironi, Cristina Muñoz-Pinedo and Eric Eldering

Cancers 2021, 13(2), 284; https://doi.org/10.3390/cancers13020284 - 14 Jan 2021

Cited by 17 | Viewed by 4154

Abstract

Cancer cells escape, suppress and exploit the host immune system to sustain themselves, and the tumor microenvironment (TME) actively dampens T cell function by various mechanisms. Over the last years, new immunotherapeutic approaches, such as adoptive chimeric antigen receptor (CAR) T cell therapy [...] Read more.

Cancer cells escape, suppress and exploit the host immune system to sustain themselves, and the tumor microenvironment (TME) actively dampens T cell function by various mechanisms. Over the last years, new immunotherapeutic approaches, such as adoptive chimeric antigen receptor (CAR) T cell therapy and immune checkpoint inhibitors, have been successfully applied for refractory malignancies that could only be treated in a palliative manner previously. Engaging the anti-tumor activity of the immune system, including CAR T cell therapy to target the CD19 B cell antigen, proved to be effective in acute lymphocytic leukemia. In low-grade hematopoietic B cell malignancies, such as chronic lymphocytic leukemia, clinical outcomes have been tempered by cancer-induced T cell dysfunction characterized in part by a state of metabolic lethargy. In multiple myeloma, novel antigens such as BCMA and CD38 are being explored for CAR T cells. In solid cancers, T cell-based immunotherapies have been applied successfully to melanoma and lung cancers, whereas application in e.g., breast cancer lags behind and is modestly effective as yet. The main hurdles for CAR T cell immunotherapy in solid tumors are the lack of suitable antigens, anatomical inaccessibility, and T cell anergy due to immunosuppressive TME. Given the wide range of success and failure of immunotherapies in various cancer types, it is crucial to comprehend the underlying similarities and distinctions in T cell dysfunction. Hence, this review aims at comparing selected, distinct B cell-derived versus solid cancer types and at describing means by which malignant cells and TME might dampen T cell anti-tumor activity, with special focus on immunometabolism. Drawing a meaningful parallel between the efficacy of immunotherapy and the extent of T cell dysfunction will shed light on areas where we can improve immune function to battle cancer. Full article

(This article belongs to the Special Issue B Cell Malignancies (including B Cell Lymphoma, Multiple Myeloma and B-CLL))

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41 pages, 2237 KiB

Open AccessReview

Immune-Checkpoint Inhibitors in B-Cell Lymphoma

by Marc Armengol, Juliana Carvalho Santos, Miranda Fernández-Serrano, Núria Profitós-Pelejà, Marcelo Lima Ribeiro and Gaël Roué

Cancers 2021, 13(2), 214; https://doi.org/10.3390/cancers13020214 - 8 Jan 2021

Cited by 27 | Viewed by 6939

Abstract

For years, immunotherapy has been considered a viable and attractive treatment option for patients with cancer. Among the immunotherapy arsenal, the targeting of intratumoral immune cells by immune-checkpoint inhibitory agents has recently revolutionised the treatment of several subtypes of tumours. These approaches, aimed [...] Read more.

For years, immunotherapy has been considered a viable and attractive treatment option for patients with cancer. Among the immunotherapy arsenal, the targeting of intratumoral immune cells by immune-checkpoint inhibitory agents has recently revolutionised the treatment of several subtypes of tumours. These approaches, aimed at restoring an effective antitumour immunity, rapidly reached the market thanks to the simultaneous identification of inhibitory signals that dampen an effective antitumor response in a large variety of neoplastic cells and the clinical development of monoclonal antibodies targeting checkpoint receptors. Leading therapies in solid tumours are mainly focused on the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) pathways. These approaches have found a promising testing ground in both Hodgkin lymphoma and non-Hodgkin lymphoma, mainly because, in these diseases, the malignant cells interact with the immune system and commonly provide signals that regulate immune function. Although several trials have already demonstrated evidence of therapeutic activity with some checkpoint inhibitors in lymphoma, many of the immunologic lessons learned from solid tumours may not directly translate to lymphoid malignancies. In this sense, the mechanisms of effective antitumor responses are different between the different lymphoma subtypes, while the reasons for this substantial difference remain partially unknown. This review will discuss the current advances of immune-checkpoint blockade therapies in B-cell lymphoma and build a projection of how the field may evolve in the near future. In particular, we will analyse the current strategies being evaluated both preclinically and clinically, with the aim of fostering the use of immune-checkpoint inhibitors in lymphoma, including combination approaches with chemotherapeutics, biological agents and/or different immunologic therapies. Full article

(This article belongs to the Special Issue B Cell Malignancies (including B Cell Lymphoma, Multiple Myeloma and B-CLL))

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30 pages, 477 KiB

Open AccessReview

Overcoming the Hurdles of Autologous T-Cell-Based Therapies in B-Cell Non-Hodgkin Lymphoma

by Jaco A. C. van Bruggen, Anne W. J. Martens, Sanne H. Tonino and Arnon P. Kater

Cancers 2020, 12(12), 3837; https://doi.org/10.3390/cancers12123837 - 18 Dec 2020

Cited by 10 | Viewed by 4218 | Correction

Abstract

The next frontier towards a cure for B-cell non-Hodgkin lymphomas (B-NHL) is autologous cellular immunotherapy such as immune checkpoint blockade (ICB), bispecific antibodies (BsAbs) and chimeric antigen receptor (CAR) T-cells. While highly successful in various solid malignancies and in aggressive B-cell leukemia, this [...] Read more.

The next frontier towards a cure for B-cell non-Hodgkin lymphomas (B-NHL) is autologous cellular immunotherapy such as immune checkpoint blockade (ICB), bispecific antibodies (BsAbs) and chimeric antigen receptor (CAR) T-cells. While highly successful in various solid malignancies and in aggressive B-cell leukemia, this clinical success is often not matched in B-NHL. T-cell subset skewing, exhaustion, expansion of regulatory T-cell subsets, or other yet to be defined mechanisms may underlie the lack of efficacy of these treatment modalities. In this review, a systematic overview of results from clinical trials is given and is accompanied by reported data on T-cell dysfunction. From these results, we distill the underlying pathways that might be responsible for the observed differences in clinical responses towards autologous T-cell-based cellular immunotherapy modalities between diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). By integration of the clinical and biological findings, we postulate strategies that might enhance the efficacy of autologous-based cellular immunotherapy for the treatment of B-NHL. Full article

(This article belongs to the Special Issue B Cell Malignancies (including B Cell Lymphoma, Multiple Myeloma and B-CLL))

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19 pages, 1332 KiB

Open AccessReview

Ubiquitination and Ubiquitin-Like Modifications in Multiple Myeloma: Biology and Therapy

by Matthias Wirth, Markus Schick, Ulrich Keller and Jan Krönke

Cancers 2020, 12(12), 3764; https://doi.org/10.3390/cancers12123764 - 14 Dec 2020

Cited by 17 | Viewed by 4744

Abstract

Multiple myeloma is a genetically heterogeneous plasma cell malignancy characterized by organ damage and a massive production of (in-)complete monoclonal antibodies. Coping with protein homeostasis and post-translational regulation is therefore essential for multiple myeloma cells to survive. Furthermore, post-translational modifications such as ubiquitination [...] Read more.

Multiple myeloma is a genetically heterogeneous plasma cell malignancy characterized by organ damage and a massive production of (in-)complete monoclonal antibodies. Coping with protein homeostasis and post-translational regulation is therefore essential for multiple myeloma cells to survive. Furthermore, post-translational modifications such as ubiquitination and SUMOylation play key roles in essential pathways in multiple myeloma, including NFκB signaling, epigenetic regulation, as well as DNA damage repair. Drugs modulating the ubiquitin–proteasome system, such as proteasome inhibitors and thalidomide analogs, are approved and highly effective drugs in multiple myeloma. In this review, we focus on ubiquitin and ubiquitin-like modifications in the biology and current developments of new treatments for multiple myeloma. Full article

(This article belongs to the Special Issue B Cell Malignancies (including B Cell Lymphoma, Multiple Myeloma and B-CLL))

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26 pages, 1525 KiB

Open AccessReview

Molecular Genetics of Relapsed Diffuse Large B-Cell Lymphoma: Insight into Mechanisms of Therapy Resistance

by Madeleine R. Berendsen, Wendy B. C. Stevens, Michiel van den Brand, J. Han van Krieken and Blanca Scheijen

Cancers 2020, 12(12), 3553; https://doi.org/10.3390/cancers12123553 - 28 Nov 2020

Cited by 25 | Viewed by 4698

Abstract

The majority of patients with diffuse large B-cell lymphoma (DLBCL) can be treated successfully with a combination of chemotherapy and the monoclonal anti-CD20 antibody rituximab. Nonetheless, approximately one-third of the patients with DLBCL still experience relapse or refractory (R/R) disease after first-line immunochemotherapy. [...] Read more.

The majority of patients with diffuse large B-cell lymphoma (DLBCL) can be treated successfully with a combination of chemotherapy and the monoclonal anti-CD20 antibody rituximab. Nonetheless, approximately one-third of the patients with DLBCL still experience relapse or refractory (R/R) disease after first-line immunochemotherapy. Whole-exome sequencing on large cohorts of primary DLBCL has revealed the mutational landscape of DLBCL, which has provided a framework to define novel prognostic subtypes in DLBCL. Several studies have investigated the genetic alterations specifically associated with R/R DLBCL, thereby uncovering molecular pathways linked to therapy resistance. Here, we summarize the current state of knowledge regarding the genetic alterations that are enriched in R/R DLBCL, and the corresponding pathways affected by these gene mutations. Furthermore, we elaborate on their potential role in mediating therapy resistance, also in connection with findings in other B-cell malignancies, and discuss alternative treatment options. Hence, this review provides a comprehensive overview on the gene lesions and molecular mechanisms underlying R/R DLBCL, which are considered valuable parameters to guide treatment. Full article

(This article belongs to the Special Issue B Cell Malignancies (including B Cell Lymphoma, Multiple Myeloma and B-CLL))

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16 pages, 1986 KiB

Open AccessReview

Risk and Response-Adapted Treatment in Multiple Myeloma

by Titouan Cazaubiel, Olga Mulas, Lydia Montes, Anaïs Schavgoulidze, Hervé Avet-Loiseau, Jill Corre and Aurore Perrot

Cancers 2020, 12(12), 3497; https://doi.org/10.3390/cancers12123497 - 24 Nov 2020

Cited by 12 | Viewed by 3689

Abstract

Myeloma therapeutic strategies have been adapted to patients’ age and comorbidities for a long time. However, although cytogenetics and clinical presentations (plasmablastic cytology; extramedullary disease) are major prognostic factors, until recently, all patients received the same treatment whatever their initial risk. No strong [...] Read more.

Myeloma therapeutic strategies have been adapted to patients’ age and comorbidities for a long time. However, although cytogenetics and clinical presentations (plasmablastic cytology; extramedullary disease) are major prognostic factors, until recently, all patients received the same treatment whatever their initial risk. No strong evidence allows us to use a personalized treatment according to one cytogenetic abnormality in newly diagnosed myeloma. Retrospective studies showed a benefit of a double autologous transplant in high-risk cytogenetics according to the International Myeloma Working Group definition (t(4;14), t(14;16) or del(17p)). Moreover, this definition has to be updated since other independent abnormalities, namely gain 1q, del(1p32), and trisomies 5 or 21, as well as TP53 mutations, are also prognostic. Another very strong predictive tool is the response to treatment assessed by the evaluation of minimal residual disease (MRD). We are convinced that the time has come to use it to adapt the strategy to a dynamic risk. Many trials are ongoing to answer many questions: when and how should we adapt the therapy, its intensity and duration. Nevertheless, we also have to take into account the clinical outcome for one patient, especially adverse events affecting his or her quality of life and his or her preferences for continuous/fixed duration treatment. Full article

(This article belongs to the Special Issue B Cell Malignancies (including B Cell Lymphoma, Multiple Myeloma and B-CLL))

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24 pages, 1552 KiB

Open AccessReview

BH3 Mimetics for the Treatment of B-Cell Malignancies—Insights and Lessons from the Clinic

by Victor S. Lin, Zhuo-Fan Xu, David C. S. Huang and Rachel Thijssen

Cancers 2020, 12(11), 3353; https://doi.org/10.3390/cancers12113353 - 12 Nov 2020

Cited by 11 | Viewed by 5578

Abstract

The discovery of the link between defective apoptotic regulation and cancer cell survival engendered the idea of targeting aberrant components of the apoptotic machinery for cancer therapy. The intrinsic pathway of apoptosis is tightly controlled by interactions amongst members of three distinct subgroups [...] Read more.

The discovery of the link between defective apoptotic regulation and cancer cell survival engendered the idea of targeting aberrant components of the apoptotic machinery for cancer therapy. The intrinsic pathway of apoptosis is tightly controlled by interactions amongst members of three distinct subgroups of the B-cell lymphoma 2 (BCL2) family of proteins. The pro-survival BCL2 proteins prevent apoptosis by keeping the pro-apoptotic effector proteins BCL2-associated X protein (BAX) and BCL2 homologous antagonist/killer (BAK) in check, while the BH3-only proteins initiate apoptosis by either neutralizing the pro-survival BCL2 proteins or directly activating the pro-apoptotic effector proteins. This tripartite regulatory mechanism is commonly perturbed in B-cell malignancies facilitating cell death evasion. Over the past two decades, structure-based drug discovery has resulted in the development of a series of small molecules that mimic the function of BH3-only proteins called the BH3 mimetics. The most clinically advanced of these is venetoclax, which is a highly selective inhibitor of BCL2 that has transformed the treatment landscape for chronic lymphocytic leukemia (CLL). Other BH3 mimetics, which selectively target myeloid cell leukemia 1 (MCL1) and B-cell lymphoma extra large (BCLxL), are currently under investigation for use in diverse malignancies. Here, we review the current role of BH3 mimetics in the treatment of CLL and other B-cell malignancies and address open questions in this rapidly evolving field. Full article

(This article belongs to the Special Issue B Cell Malignancies (including B Cell Lymphoma, Multiple Myeloma and B-CLL))

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21 pages, 1387 KiB

Open AccessReview

Impact of MYC on Anti-Tumor Immune Responses in Aggressive B Cell Non-Hodgkin Lymphomas: Consequences for Cancer Immunotherapy

by A. Vera de Jonge, Tuna Mutis, Margaretha G. M. Roemer, Blanca Scheijen and Martine E. D. Chamuleau

Cancers 2020, 12(10), 3052; https://doi.org/10.3390/cancers12103052 - 20 Oct 2020

Cited by 13 | Viewed by 4565

Abstract

Patients with MYC overexpressing high grade B cell lymphoma (HGBL) face significant dismal prognosis after treatment with standard immunochemotherapy regimens. Recent preclinical studies indicate that MYC not only contributes to tumorigenesis by its effects on cell proliferation and differentiation, but also plays an [...] Read more.

Patients with MYC overexpressing high grade B cell lymphoma (HGBL) face significant dismal prognosis after treatment with standard immunochemotherapy regimens. Recent preclinical studies indicate that MYC not only contributes to tumorigenesis by its effects on cell proliferation and differentiation, but also plays an important role in promoting escape from anti-tumor immune responses. This is of specific interest, since reversing tumor immune inhibition with immunotherapy has shown promising results in the treatment of both solid tumors and hematological malignancies. In this review, we outline the current understanding of impaired immune responses in B cell lymphoid malignancies with MYC overexpression, with a particular emphasis on diffuse large B cell lymphoma. We also discuss clinical consequences of MYC overexpression in the treatment of HGBL with novel immunotherapeutic agents and potential future treatment strategies. Full article

(This article belongs to the Special Issue B Cell Malignancies (including B Cell Lymphoma, Multiple Myeloma and B-CLL))

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24 pages, 1008 KiB

Open AccessReview

Fc-Engineered Antibodies with Enhanced Fc-Effector Function for the Treatment of B-Cell Malignancies

by Hilma J. van der Horst, Inger S. Nijhof, Tuna Mutis and Martine E. D. Chamuleau

Cancers 2020, 12(10), 3041; https://doi.org/10.3390/cancers12103041 - 19 Oct 2020

Cited by 46 | Viewed by 11040

Abstract

Monoclonal antibody (mAb) therapy has rapidly changed the field of cancer therapy. In 1997, the CD20-targeting mAb rituximab was the first mAb to be approved by the U.S. Food and Drug Administration (FDA) for treatment of cancer. Within two decades, dozens of mAbs [...] Read more.

Monoclonal antibody (mAb) therapy has rapidly changed the field of cancer therapy. In 1997, the CD20-targeting mAb rituximab was the first mAb to be approved by the U.S. Food and Drug Administration (FDA) for treatment of cancer. Within two decades, dozens of mAbs entered the clinic for treatment of several hematological cancers and solid tumors, and numerous more are under clinical investigation. The success of mAbs as cancer therapeutics lies in their ability to induce various cytotoxic machineries against specific targets. These cytotoxic machineries include antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC), which are all mediated via the fragment crystallizable (Fc) domain of mAbs. In this review article, we will outline the novel approaches of engineering these Fc domains of mAbs to enhance their Fc-effector function and thereby their anti-tumor potency, with specific focus to summarize their (pre-) clinical status for the treatment of B-cell malignancies, including chronic lymphocytic leukemia (CLL), B-cell non-Hodgkin lymphoma (B-NHL), and multiple myeloma (MM). Full article

(This article belongs to the Special Issue B Cell Malignancies (including B Cell Lymphoma, Multiple Myeloma and B-CLL))

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21 pages, 1072 KiB

Open AccessReview

Diagnosis and Treatment of Primary Cutaneous B-Cell Lymphomas: State of the Art and Perspectives

by Maëlle Dumont, Maxime Battistella, Caroline Ram-Wolff, Martine Bagot and Adèle de Masson

Cancers 2020, 12(6), 1497; https://doi.org/10.3390/cancers12061497 - 8 Jun 2020

Cited by 15 | Viewed by 8626

Abstract

Primary cutaneous B-cell lymphomas are rare entities that develop primarily in the skin. They constitute a heterogeneous group that represents around a quarter of primary cutaneous lymphomas. The 2018 update of the World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) [...] Read more.

Primary cutaneous B-cell lymphomas are rare entities that develop primarily in the skin. They constitute a heterogeneous group that represents around a quarter of primary cutaneous lymphomas. The 2018 update of the World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification differentiates primary cutaneous marginal zone lymphoma and primary cutaneous follicle center lymphoma with an indolent course from primary cutaneous diffuse large B-cell lymphoma, leg type with an aggressive behavior. The broad spectrum of clinical presentations and the disease course marked by frequent relapses are diagnostic and therapeutic challenges. The classification of these diseases has been refined in recent years, which allows to better define their immunopathogenesis and specific management. In the present article, we review the main clinico-biological characteristics and the current therapeutic options of these three main subsets. Based on the recent therapeutic advances in nodal B-cell lymphomas, we focus on the development of novel treatment options applicable to primary cutaneous B-cell lymphomas, including targeted therapies, combination treatments and immunotherapeutic approaches, and cover basic, translational and clinical aspects aiming to improve the treatment of cutaneous B-cell lymphomas. Full article

(This article belongs to the Special Issue B Cell Malignancies (including B Cell Lymphoma, Multiple Myeloma and B-CLL))

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31 pages, 2219 KiB

Open AccessReview

Ibrutinib Resistance Mechanisms and Treatment Strategies for B-Cell Lymphomas

by Bhawana George, Sayan Mullick Chowdhury, Amber Hart, Anuvrat Sircar, Satish Kumar Singh, Uttam Kumar Nath, Mukesh Mamgain, Naveen Kumar Singhal, Lalit Sehgal and Neeraj Jain

Cancers 2020, 12(5), 1328; https://doi.org/10.3390/cancers12051328 - 22 May 2020

Cited by 70 | Viewed by 11192

Abstract

Chronic activation of B-cell receptor (BCR) signaling via Bruton tyrosine kinase (BTK) is largely considered to be one of the primary mechanisms driving disease progression in B–Cell lymphomas. Although the BTK-targeting agent ibrutinib has shown promising clinical responses, the presence of primary or [...] Read more.

Chronic activation of B-cell receptor (BCR) signaling via Bruton tyrosine kinase (BTK) is largely considered to be one of the primary mechanisms driving disease progression in B–Cell lymphomas. Although the BTK-targeting agent ibrutinib has shown promising clinical responses, the presence of primary or acquired resistance is common and often leads to dismal clinical outcomes. Resistance to ibrutinib therapy can be mediated through genetic mutations, up-regulation of alternative survival pathways, or other unknown factors that are not targeted by ibrutinib therapy. Understanding the key determinants, including tumor heterogeneity and rewiring of the molecular networks during disease progression and therapy, will assist exploration of alternative therapeutic strategies. Towards the goal of overcoming ibrutinib resistance, multiple alternative therapeutic agents, including second- and third-generation BTK inhibitors and immunomodulatory drugs, have been discovered and tested in both pre-clinical and clinical settings. Although these agents have shown high response rates alone or in combination with ibrutinib in ibrutinib-treated relapsed/refractory(R/R) lymphoma patients, overall clinical outcomes have not been satisfactory due to drug-associated toxicities and incomplete remission. In this review, we discuss the mechanisms of ibrutinib resistance development in B-cell lymphoma including complexities associated with genomic alterations, non-genetic acquired resistance, cancer stem cells, and the tumor microenvironment. Furthermore, we focus our discussion on more comprehensive views of recent developments in therapeutic strategies to overcome ibrutinib resistance, including novel BTK inhibitors, clinical therapeutic agents, proteolysis-targeting chimeras and immunotherapy regimens. Full article

(This article belongs to the Special Issue B Cell Malignancies (including B Cell Lymphoma, Multiple Myeloma and B-CLL))

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1 pages, 164 KiB

Open AccessCorrection

Correction: van Bruggen et al. Overcoming the Hurdles of Autologous T-Cell-Based Therapies in B-Cell Non-Hodgkin Lymphoma. Cancers 2020, 12, 3837

by Jaco A. C. van Bruggen, Anne W. J. Martens, Sanne H. Tonino and Arnon P. Kater

Cancers 2021, 13(19), 4738; https://doi.org/10.3390/cancers13194738 - 22 Sep 2021

Cited by 1 | Viewed by 1586

Abstract

In the original article [...] Full article

(This article belongs to the Special Issue B Cell Malignancies (including B Cell Lymphoma, Multiple Myeloma and B-CLL))

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