Therapeutic Targets in Chronic Lymphocytic Leukemia

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

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 21317

Special Issue Editors

Institute of Hematology, Università Cattolica del Sacro Cuore, Rome, Italy
Interests: chronic lymphocytic leukemia; targeted therapy; leukemia
Special Issues, Collections and Topics in MDPI journals
International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
Interests: chronic lymphocytic leukemia; B cell lymphoma; B cell receptor; toll-like receptor; apoptosis regulation, targeted therapy

Special Issue Information

Dear Colleagues,

In recent years, major progress has been made in understanding the cellular and molecular mechanisms that drive chronic lymphocytic leukemia. This knowledge has resulted in the development of novel drugs that have revolutionized treatment of this disease. Among these, drugs that target the B cell receptor pathway and the antiapoptotic protein BCL2 have already been successfully exploited in the clinic and have become available for routine clinical use. However, although most patients initially respond to treatment with these drugs, the vast majority achieve only a partial remission, and a substantial proportion of these subsequently suffer a relapse or undergo Richter transformation, for which no effective treatment currently exists. To further improve treatment responses, combinations of drugs that target patient-specific genetic lesions and common microenvironmental signals will most likely be required. 

In this Special Issue, we will focus on established and emerging therapeutic targets in chronic lymphocytic leukemia and Richter syndrome. We also welcome contributions that provide novel insights into mechanisms of resistance to targeted treatments as well as preclinical and clinical studies describing novel approaches to overcome this resistance.

Prof. Luca Laurenti
Prof. Dimitar Efremov
Guest Editors

Manuscript Submission Information

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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 leukemia
  • Targeted therapy
  • B cell receptor
  • BCL2
  • Apoptosis resistance
  • Allogeneic stem cell transplantation
  • CAR-T

Published Papers (8 papers)

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Editorial

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4 pages, 190 KiB  
Editorial
Therapeutic Targets in Chronic Lymphocytic Leukemia
by Luca Laurenti and Dimitar G. Efremov
Cancers 2020, 12(11), 3259; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113259 - 04 Nov 2020
Cited by 3 | Viewed by 1738
Abstract
Chronic lymphocytic leukemia (CLL) is a common B cell malignancy and is the most common type of adult leukemia in western countries [...] Full article
(This article belongs to the Special Issue Therapeutic Targets in Chronic Lymphocytic Leukemia)

Research

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16 pages, 2027 KiB  
Article
Elucidation of Focal Adhesion Kinase as a Modulator of Migration and Invasion and as a Potential Therapeutic Target in Chronic Lymphocytic Leukemia
by Thomas A. Burley, Andrew Hesketh, Giselda Bucca, Emma Kennedy, Eleni E. Ladikou, Benjamin P. Towler, Simon Mitchell, Colin P. Smith, Christopher Fegan, Rosalynd Johnston, Andrea Pepper and Chris Pepper
Cancers 2022, 14(7), 1600; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14071600 - 22 Mar 2022
Cited by 6 | Viewed by 2339
Abstract
The retention and re-migration of Chronic Lymphocytic Leukemia cells into cytoprotective and proliferative lymphoid niches is thought to contribute to the development of resistance, leading to subsequent disease relapse. The aim of this study was to elucidate the molecular processes that govern CLL [...] Read more.
The retention and re-migration of Chronic Lymphocytic Leukemia cells into cytoprotective and proliferative lymphoid niches is thought to contribute to the development of resistance, leading to subsequent disease relapse. The aim of this study was to elucidate the molecular processes that govern CLL cell migration to elicit a more complete inhibition of tumor cell migration. We compared the phenotypic and transcriptional changes induced in CLL cells using two distinct models designed to recapitulate the peripheral circulation, CLL cell migration across an endothelial barrier, and the lymph node interaction between CLL cells and activated T cells. Initially, CLL cells were co-cultured with CD40L-expressing fibroblasts and exhibited an activated B-cell phenotype, and their transcriptional signatures demonstrated the upregulation of pro-survival and anti-apoptotic genes and overrepresentation of the NF-κB signaling pathway. Using our dynamic circulating model, we were able to study the transcriptomics and miRNomics associated with CLL migration. More than 3000 genes were altered when CLL cells underwent transendothelial migration, with an overrepresentation of adhesion and cell migration gene sets. From this analysis, an upregulation of the FAK signaling pathway was observed. Importantly, PTK2 (FAK) gene expression was significantly upregulated in migrating CLL cells (PTK2 Fold-change = 4.9). Here we demonstrate that TLR9 agonism increased levels of p-FAK (p ≤ 0.05), which could be prevented by pharmacological inhibition of FAK with defactinib (p ≤ 0.01). Furthermore, a reduction in CLL cell migration and invasion was observed when FAK was inhibited (p ≤ 0.0001), supporting a role for FAK in both CLL migration and tissue invasion. When taken together, our data highlights the potential for combining FAK inhibition with current targeted therapies as a more effective treatment regime for CLL. Full article
(This article belongs to the Special Issue Therapeutic Targets in Chronic Lymphocytic Leukemia)
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17 pages, 2345 KiB  
Article
Targeting the Non-Canonical NF-κB Pathway in Chronic Lymphocytic Leukemia and Multiple Myeloma
by Thomas A. Burley, Emma Kennedy, Georgia Broad, Melanie Boyd, David Li, Timothy Woo, Christopher West, Eleni E. Ladikou, Iona Ashworth, Christopher Fegan, Rosalynd Johnston, Simon Mitchell, Simon P. Mackay, Andrea G. S. Pepper and Chris Pepper
Cancers 2022, 14(6), 1489; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061489 - 15 Mar 2022
Cited by 6 | Viewed by 2846
Abstract
In this study, we evaluated an NF-κB inducing kinase (NIK) inhibitor, CW15337, in primary chronic lymphocytic leukemia (CLL) cells, CLL and multiple myeloma (MM) cell lines and normal B- and T-lymphocytes. Basal NF-κB subunit activity was characterized using an enzyme linked immunosorbent assay [...] Read more.
In this study, we evaluated an NF-κB inducing kinase (NIK) inhibitor, CW15337, in primary chronic lymphocytic leukemia (CLL) cells, CLL and multiple myeloma (MM) cell lines and normal B- and T-lymphocytes. Basal NF-κB subunit activity was characterized using an enzyme linked immunosorbent assay (ELISA), and the effects of NIK inhibition were then assessed in terms of cytotoxicity and the expression of nuclear NF-κB subunits following monoculture and co-culture with CD40L-expressing fibroblasts, as a model of the lymphoid niche. CW15337 induced a dose-dependent increase in apoptosis, and nuclear expression of the non-canonical NF-κB subunit, p52, was correlated with sensitivity to CW15337 (p = 0.01; r2 = 0.39). Co-culture on CD40L-expressing cells induced both canonical and non-canonical subunit expression in nuclear extracts, which promoted in vitro resistance against fludarabine and ABT-199 (venetoclax) but not CW15337. Furthermore, the combination of CW15337 with fludarabine or ABT-199 showed cytotoxic synergy. Mechanistically, CW15337 caused the selective inhibition of non-canonical NF-κB subunits and the transcriptional repression of BCL2L1, BCL2A1 and MCL1 gene transcription. Taken together, these data suggest that the NIK inhibitor, CW15337, exerts its effects via suppression of the non-canonical NF-κB signaling pathway, which reverses BCL2 family-mediated resistance in the context of CD40L stimulation. Full article
(This article belongs to the Special Issue Therapeutic Targets in Chronic Lymphocytic Leukemia)
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10 pages, 821 KiB  
Article
CD200 Baseline Serum Levels Predict Prognosis of Chronic Lymphocytic Leukemia
by Giovanni D’Arena, Candida Vitale, Marta Coscia, Daniela Lamorte, Giuseppe Pietrantuono, Francesca Perutelli, Fiorella D’Auria, Teodora Statuto, Luciana Valvano, Annamaria Tomasso, Valentina Griggio, Rebecca Jones, Giovanna Mansueto, Oreste Villani, Simona D’Agostino, Vito Viglioglia, Vincenzo De Feo, Fabrizio Calapai, Carmen Mannucci, Alessandro Sgambato, Dimitar G. Efremov and Luca Laurentiadd Show full author list remove Hide full author list
Cancers 2021, 13(16), 4239; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13164239 - 23 Aug 2021
Cited by 2 | Viewed by 2272
Abstract
Membrane-bound CD200 is overexpressed in chronic lymphocytic leukemia (CLL), and there is some evidence that its soluble ectodomain (sCD200) could also be involved in the pathophysiology and the disease. However, very little is known about sCD200’s prognostic significance. sCD200 was tested at diagnosis [...] Read more.
Membrane-bound CD200 is overexpressed in chronic lymphocytic leukemia (CLL), and there is some evidence that its soluble ectodomain (sCD200) could also be involved in the pathophysiology and the disease. However, very little is known about sCD200’s prognostic significance. sCD200 was tested at diagnosis in 272 patients with CLL and in 78 age- and sex-matched healthy subjects using a specific human CD200 (OX-2 membrane glycoprotein) ELISA kit. A significantly higher concentration of sCD200 was found in CLL patients compared to controls. In our cohort, sCD200 was significantly higher in patients who were older than 66 years, with Binet stage C, unmutated IgVH and unfavorable (del11q or del17p) FISH. Time-to-first treatment and overall survival were significantly shorter in patients with higher sCD200 concentration, using as a cut-off 1281 pg/mL, the median value for sCD200 concentration in the whole CLL cohort. However, the prognostic impact of sCD200 was not confirmed in multivariate analysis. Baseline sCD200 values appeared to have an impact on the response to chemotherapy or chemo-immunotherapy, but not to targeted agents. Collectively, our data show that sCD200 serum levels correlate with more aggressive clinical and biological features and are able to predict a worse prognosis. This work supports the relevant role of CD200 not only as a diagnostic tool but also as a prognostic indicator and a potential therapeutic target in CLL. Full article
(This article belongs to the Special Issue Therapeutic Targets in Chronic Lymphocytic Leukemia)
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Review

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27 pages, 3292 KiB  
Review
Multiple Mechanisms of NOTCH1 Activation in Chronic Lymphocytic Leukemia: NOTCH1 Mutations and Beyond
by Federico Pozzo, Tamara Bittolo, Erika Tissino, Antonella Zucchetto, Riccardo Bomben, Laura Polcik, Svenja Dannewitz Prosseda, Tanja Nicole Hartmann and Valter Gattei
Cancers 2022, 14(12), 2997; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14122997 - 17 Jun 2022
Cited by 5 | Viewed by 2766
Abstract
The Notch signaling pathway plays a fundamental role for the terminal differentiation of multiple cell types, including B and T lymphocytes. The Notch receptors are transmembrane proteins that, upon ligand engagement, undergo multiple processing steps that ultimately release their intracytoplasmic portion. The activated [...] Read more.
The Notch signaling pathway plays a fundamental role for the terminal differentiation of multiple cell types, including B and T lymphocytes. The Notch receptors are transmembrane proteins that, upon ligand engagement, undergo multiple processing steps that ultimately release their intracytoplasmic portion. The activated protein ultimately operates as a nuclear transcriptional co-factor, whose stability is finely regulated. The Notch pathway has gained growing attention in chronic lymphocytic leukemia (CLL) because of the high rate of somatic mutations of the NOTCH1 gene. In CLL, NOTCH1 mutations represent a validated prognostic marker and a potential predictive marker for anti-CD20-based therapies, as pathological alterations of the Notch pathway can provide significant growth and survival advantage to neoplastic clone. However, beside NOTCH1 mutation, other events have been demonstrated to perturb the Notch pathway, namely somatic mutations of upstream, or even apparently unrelated, proteins such as FBXW7, MED12, SPEN, SF3B1, as well as physiological signals from other pathways such as the B-cell receptor. Here we review these mechanisms of activation of the NOTCH1 pathway in the context of CLL; the resulting picture highlights how multiple different mechanisms, that might occur under specific genomic, phenotypic and microenvironmental contexts, ultimately result in the same search for proliferative and survival advantages (through activation of MYC), as well as immune escape and therapy evasion (from anti-CD20 biological therapies). Understanding the preferential strategies through which CLL cells hijack NOTCH1 signaling may present important clues for designing targeted treatment strategies for the management of CLL. Full article
(This article belongs to the Special Issue Therapeutic Targets in Chronic Lymphocytic Leukemia)
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25 pages, 790 KiB  
Review
PI3K Inhibitors for the Treatment of Chronic Lymphocytic Leukemia: Current Status and Future Perspectives
by Iwona Hus, Bartosz Puła and Tadeusz Robak
Cancers 2022, 14(6), 1571; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061571 - 18 Mar 2022
Cited by 17 | Viewed by 3816
Abstract
Phosphoinositide 3-kinases (PI3Ks) signaling regulates key cellular processes, such as growth, survival and apoptosis. Among the three classes of PI3K, class I is the most important for the development, differentiation and activation of B and T cells. Four isoforms are distinguished within class [...] Read more.
Phosphoinositide 3-kinases (PI3Ks) signaling regulates key cellular processes, such as growth, survival and apoptosis. Among the three classes of PI3K, class I is the most important for the development, differentiation and activation of B and T cells. Four isoforms are distinguished within class I (PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ). PI3Kδ expression is limited mainly to the B cells and their precursors, and blocking PI3K has been found to promote apoptosis of chronic lymphocytic leukemia (CLL) cells. Idelalisib, a selective PI3Kδ inhibitor, was the first-in-class PI3Ki introduced into CLL treatment. It showed efficacy in patients with del(17p)/TP53 mutation, unmutated IGHV status and refractory/relapsed disease. However, its side effects, such as autoimmune-mediated pneumonitis and colitis, infections and skin changes, limited its widespread use. The dual PI3Kδ/γ inhibitor duvelisib is approved for use in CLL patients but with similar toxicities to idelalisib. Umbralisib, a highly selective inhibitor of PI3Kδ and casein kinase-1ε (CK1ε), was found to be efficient and safe in monotherapy and in combination regimens in phase 3 trials in patients with CLL. Novel PI3Kis are under evaluation in early phase clinical trials. In this paper we present the mechanism of action, efficacy and toxicities of PI3Ki approved in the treatment of CLL and developed in clinical trials. Full article
(This article belongs to the Special Issue Therapeutic Targets in Chronic Lymphocytic Leukemia)
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24 pages, 1148 KiB  
Review
Targeting the p53 Pathway in CLL: State of the Art and Future Perspectives
by Marwan Kwok, Angelo Agathanggelou, Nicholas Davies and Tatjana Stankovic
Cancers 2021, 13(18), 4681; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13184681 - 18 Sep 2021
Cited by 9 | Viewed by 3641 | Correction
Abstract
The p53 pathway is a desirable therapeutic target, owing to its critical role in the maintenance of genome integrity. This is exemplified in chronic lymphocytic leukemia (CLL), one of the most common adult hematologic malignancies, in which functional loss of p53 arising from [...] Read more.
The p53 pathway is a desirable therapeutic target, owing to its critical role in the maintenance of genome integrity. This is exemplified in chronic lymphocytic leukemia (CLL), one of the most common adult hematologic malignancies, in which functional loss of p53 arising from genomic aberrations are frequently associated with clonal evolution, disease progression, and therapeutic resistance, even in the contemporary era of CLL targeted therapy and immunotherapy. Targeting the ‘undruggable’ p53 pathway therefore arguably represents the holy grail of cancer research. In recent years, several strategies have been proposed to exploit p53 pathway defects for cancer treatment. Such strategies include upregulating wild-type p53, restoring tumor suppressive function in mutant p53, inducing synthetic lethality by targeting collateral genome maintenance pathways, and harnessing the immunogenicity of p53 pathway aberrations. In this review, we will examine the biological and clinical implications of p53 pathway defects, as well as our progress towards development of therapeutic approaches targeting the p53 pathway, specifically within the context of CLL. We will appraise the opportunities and pitfalls associated with these therapeutic strategies, and evaluate their place amongst the array of new biological therapies for CLL. Full article
(This article belongs to the Special Issue Therapeutic Targets in Chronic Lymphocytic Leukemia)
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1 pages, 160 KiB  
Correction
Correction: Kwok et al. Targeting the p53 Pathway in CLL: State of the Art and Future Perspectives. Cancers 2021, 13, 4681
by Marwan Kwok, Angelo Agathanggelou, Nicholas Davies and Tatjana Stankovic
Cancers 2022, 14(2), 321; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14020321 - 10 Jan 2022
Cited by 3 | Viewed by 915
Abstract
The authors wish to make the following corrections to their paper [1] [...] Full article
(This article belongs to the Special Issue Therapeutic Targets in Chronic Lymphocytic Leukemia)
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