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Advances in Chronic Lymphocytic Leukaemia (CLL) Research
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Advances in Chronic Lymphocytic Leukaemia (CLL) Research

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: 31 December 2024 | Viewed by 9215

Special Issue Editor

Prof. Dr. H. Denis Alexander

E-Mail Website
Guest Editor
Personalised Medicine Centre, School of Medicine, Ulster University, C-TRIC Building, Altnagelvin Hospital, Derry/Londonderry BT47 6SB, Northern Ireland, UK
Interests: B-CLPD; B-CLL; plasma cell dyscrasias; cellular, proteomic and molecular investigations; precision medicine; NGS; GEP
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Nearly a quarter of a century has elapsed since the seminal publications in Blood in 1999 by Hamblin, Oscier, and Stevenson group in Southampton/Bournemouth, and the Chiorazzi group in New York, where they demonstrated the importance of somatic hypermutation of the IGHV genes in survival in chronic lymphocytic leukaemia (CLL). These papers accelerated research activity in various aspects of CLL, including aetiology, the biology of the malignant cells, IGHV mutational status and gene usage, chromosomal and molecular aberrations, roles of flow cytometry and molecular investigations in defining complete remissions, and treatment strategies, including use of more targeted therapies and novel agents.

This has also translated into widespread research in post-bone marrow B cell malignancies overall, including the B cell lymphomas, but CLL remains at the forefront of understanding of this, the largest group of haematological malignancies. It seems timely to review progress towards answering questions raised by the original papers and whether these have provided a better understanding of the aetiology of CLL, whether pathogenic- or auto-antibodies are pivotal in initiation of the oncogenic transformation of normal B cells, and, most importantly, progress towards improved survival and a potential cure.

To mark the approaching 25th anniversary in 2024, Cancers (IF 6.575) has decided to publish a Special Issue on CLL and invited me to act as Guest Editor. The plan will be to publish a mix of Invited Review papers, covering aspects highlighted above, and original research papers. We invite you and your group to submit your relevant CLL original research manuscripts. These will be subject to rigorous peer review, with decisions on acceptance anticipated within a few weeks. We trust you will give serious consideration to participation in this project, with the opportunity to have your work published in a Special Issue of this preeminent open access oncology journal.

Prof. Dr. H. Denis Alexander
Guest Editor

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 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

  • chronic lymphocytic leukaemia
  • CLL
  • aetiology
  • oncogenic transformation
  • survival
  • cure

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Published Papers (4 papers)

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Research

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18 pages, 2352 KiB  
Article
Mice Overexpressing Wild-Type RRAS2 Are a Novel Model for Preclinical Testing of Anti-Chronic Lymphocytic Leukemia Therapies
by Alejandro M. Hortal, Ana Villanueva, Irene Arellano, Cristina Prieto, Pilar Mendoza, Xosé R. Bustelo and Balbino Alarcón
Cancers 2023, 15(24), 5817; https://doi.org/10.3390/cancers15245817 - 12 Dec 2023
Viewed by 1428
Abstract
B-cell chronic lymphocytic leukemia (B-CLL) is the most common type of leukemia in the Western world. Mutation in different genes, such as TP53 and ATM, and deletions at specific chromosomic regions, among which are 11q or 17p, have been described to be [...] Read more.
B-cell chronic lymphocytic leukemia (B-CLL) is the most common type of leukemia in the Western world. Mutation in different genes, such as TP53 and ATM, and deletions at specific chromosomic regions, among which are 11q or 17p, have been described to be associated to worse disease prognosis. Recent research from our group has demonstrated that, contrary to what is the usual cancer development process through missense mutations, B-CLL is driven by the overexpression of the small GTPase RRAS2 in its wild-type form without activating mutations. Some mouse models of this disease have been developed to date and are commonly used in B-CLL research, but they present different disadvantages such as the long waiting period until the leukemia fully develops, the need to do cell engraftment or, in some cases, the fact that the model does not recapitulate the alterations found in human patients. We have recently described Rosa26-RRAS2fl/flxmb1-Cre as a new mouse model of B-CLL with a full penetrance of the disease. In this work, we have validated this mouse model as a novel tool for the development of new therapies for B-CLL, by testing two of the most broadly applied targeted agents: ibrutinib and venetoclax. This also opens the door to new targeted agents against R-RAS2 itself, an approach not yet explored in the clinic. Full article
(This article belongs to the Special Issue Advances in Chronic Lymphocytic Leukaemia (CLL) Research)
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16 pages, 2040 KiB  
Article
Therapeutic Targeting Potential of Novel Silver Nanoparticles Coated with Anti-CD20 Antibody against Chronic Lymphocytic Leukemia
by Francesco Maria Adamo, Estevao Carlos Silva Barcelos, Filomena De Falco, Erica Dorillo, Chiara Rompietti, Daniele Sorcini, Arianna Stella, Beatrice Del Papa, Stefano Baldoni, Angela Esposito, Clelia Geraci, Roberta Arcaleni, Chiara Pennetta, Francesco Ragonese, Lorenzo Moretti, Mariagrazia Mameli, Mauro Di Ianni, Emanuela Rosati, Bernard Fioretti and Paolo Sportoletti
Cancers 2023, 15(14), 3618; https://doi.org/10.3390/cancers15143618 - 14 Jul 2023
Cited by 3 | Viewed by 2025
Abstract
Background: Chronic lymphocytic leukemia (CLL) is an incurable disorder associated with alterations in several pathways essential for survival and proliferation. Despite the advances made in CLL therapy with the new target agents, in some cases, relapses and resistance could occur, making the discovery [...] Read more.
Background: Chronic lymphocytic leukemia (CLL) is an incurable disorder associated with alterations in several pathways essential for survival and proliferation. Despite the advances made in CLL therapy with the new target agents, in some cases, relapses and resistance could occur, making the discovery of new alternatives to manage CLL refractoriness necessary. To provide new therapeutic strategies for CLL, we investigated the anti-leukemic activity of silver nanoparticles (AgNPs), whose impact on CLL cells has been poorly explored. Methods: We studied the action mechanisms of AgNPs in vitro through flow cytometry and molecular analyses. To improve the bioavailability of AgNPs, we generated AgNPs coated with the anti-CD20 antibody Rituximab (AgNPs@Rituximab) and carried out imaging-based approaches and in vivo experiments to evaluate specificity, drug uptake, and efficacy. Results: AgNPs reduced the viability of primary CLL cells and the HG-3 cell line by inducing an intrinsic apoptotic pathway characterized by Bax/Bcl-2 imbalance, caspase activation, and PARP degradation. Early apoptotic events triggered by AgNPs included enhanced Ca2+ influx and ROS overproduction. AgNPs synergistically potentiated the cytotoxicity of Venetoclax, Ibrutinib, and Bepridil. In vitro, the AgNPs@Rituximab conjugates were rapidly internalized within CLL cells and strongly prolonged the survival of CLL xenograft models compared to each unconjugated single agent. Conclusions: AgNPs showed strong anti-leukemic activity in CLL, with the potential for clinical translation in combination with agents used in CLL. The increased specificity of AgNPs@Rituximab toward CLL cells could be relevant for overcoming in vivo AgNPs’ non-specific distribution and increasing their efficacy. Full article
(This article belongs to the Special Issue Advances in Chronic Lymphocytic Leukaemia (CLL) Research)
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18 pages, 1786 KiB  
Article
PKCβ Facilitates Leukemogenesis in Chronic Lymphocytic Leukaemia by Promoting Constitutive BCR-Mediated Signalling
by Jodie Hay, Anuradha Tarafdar, Ailsa K. Holroyd, Hothri A. Moka, Karen M. Dunn, Alzahra Alshayeb, Bryony H. Lloyd, Jennifer Cassels, Natasha Malik, Ashfia F. Khan, IengFong Sou, Jamie Lees, Hassan N. B. Almuhanna, Nagesh Kalakonda, Joseph R. Slupsky and Alison M. Michie
Cancers 2022, 14(23), 6006; https://doi.org/10.3390/cancers14236006 - 6 Dec 2022
Cited by 3 | Viewed by 2710
Abstract
B cell antigen receptor (BCR) signalling competence is critical for the pathogenesis of chronic lymphocytic leukaemia (CLL). Defining key proteins that facilitate these networks aid in the identification of targets for therapeutic exploitation. We previously demonstrated that reduced PKCα function in mouse hematopoietic [...] Read more.
B cell antigen receptor (BCR) signalling competence is critical for the pathogenesis of chronic lymphocytic leukaemia (CLL). Defining key proteins that facilitate these networks aid in the identification of targets for therapeutic exploitation. We previously demonstrated that reduced PKCα function in mouse hematopoietic stem/progenitor cells (HPSCs) resulted in PKCβII upregulation and generation of a poor-prognostic CLL-like disease. Here, prkcb knockdown in HSPCs leads to reduced survival of PKCα-KR-expressing CLL-like cells, concurrent with reduced expression of the leukemic markers CD5 and CD23. SP1 promotes elevated expression of prkcb in PKCα-KR expressing cells enabling leukemogenesis. Global gene analysis revealed an upregulation of genes associated with B cell activation in PKCα-KR expressing cells, coincident with upregulation of PKCβII: supported by activation of key signalling hubs proximal to the BCR and elevated proliferation. Ibrutinib (BTK inhibitor) or enzastaurin (PKCβII inhibitor) treatment of PKCα-KR expressing cells and primary CLL cells showed similar patterns of Akt/mTOR pathway inhibition, supporting the role for PKCβII in maintaining proliferative signals in our CLL mouse model. Ibrutinib or enzastaurin treatment also reduced PKCα-KR-CLL cell migration towards CXCL12. Overall, we demonstrate that PKCβ expression facilitates leukemogenesis and identify that BCR-mediated signalling is a key driver of CLL development in the PKCα-KR model. Full article
(This article belongs to the Special Issue Advances in Chronic Lymphocytic Leukaemia (CLL) Research)
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Review

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20 pages, 2259 KiB  
Review
The Five “Ws” of Frailty Assessment and Chronic Lymphocytic Leukemia: Who, What, Where, Why, and When
by Isabel González-Gascón-y-Marín, Mónica Ballesteros-Andrés, Sara Martínez-Flores, Ana-E Rodríguez-Vicente, Claudia Pérez-Carretero, Miguel Quijada-Álamo, Alberto Rodríguez-Sánchez and José-Ángel Hernández-Rivas
Cancers 2023, 15(17), 4391; https://doi.org/10.3390/cancers15174391 - 2 Sep 2023
Cited by 1 | Viewed by 2237
Abstract
Chronic lymphocytic leukemia (CLL) is a disease of the elderly, but chronological age does not accurately discriminate frailty status at the inter-individual level. Frailty describes a person’s overall resilience. Since CLL is a stressful situation, it is relevant to assess the patient´s degree [...] Read more.
Chronic lymphocytic leukemia (CLL) is a disease of the elderly, but chronological age does not accurately discriminate frailty status at the inter-individual level. Frailty describes a person’s overall resilience. Since CLL is a stressful situation, it is relevant to assess the patient´s degree of frailty, especially before starting antineoplastic treatment. We are in the era of targeted therapies, which have helped to control the disease more effectively and avoid the toxicity of chemo (immuno) therapy. However, these drugs are not free of side effects and other aspects arise that should not be neglected, such as interactions, previous comorbidities, or adherence to treatment, since most of these medications are taken continuously. The challenge we face is to balance the risk of toxicity and efficacy in a personalized way and without forgetting that the most frequent cause of death in CLL is related to the disease. For this purpose, comprehensive geriatric assessment (GA) provides us with the opportunity to evaluate multiple domains that may affect tolerance to treatment and that could be improved with appropriate interventions. In this review, we will analyze the state of the art of GA in CLL through the five Ws. Full article
(This article belongs to the Special Issue Advances in Chronic Lymphocytic Leukaemia (CLL) Research)
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