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Advances in Chronic Lymphocytic Leukemia Microenvironment: The Disruption of the...
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Advances in Chronic Lymphocytic Leukemia Microenvironment: The Disruption of the Supportive Leukemic/Accessory Cells Interactions to Improve Therapy Response

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

Deadline for manuscript submissions: 15 September 2024 | Viewed by 8079

Special Issue Editors

Dr. Daniela De Totero

E-Mail Website
Guest Editor
Molecular Pathology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy
Interests: lymphoproliferative disorders; tumor microenvironment; cytokines; myeloid suppressor cells
Dr. Paolo Giannoni

E-Mail Website
Guest Editor
Department of Experimental Medicine, University of Genoa, Genoa, Italy
Interests: tumor microenvironment; mesenchymal stem cells; growth factors; microenvironment in vitro models

Special Issue Information

Dear Colleagues,

Chronic Lymphocytic leukemia (CLL) is a lymphoproliferative disorder characterized by the relentless accumulation of leukemic B cells in the blood, secondary lymphoid tissue and bone marrow. It has become increasingly clear that the stimuli derived by the cross-talk between the neoplastic cells and the microenvironment have a critical role in CLL-pathogenesis: this finding suggests the importance of disrupting survival advantages conferred by growth-favorable niches to improve the response to therapy. Indeed, several cytokines released within the microenvironment and specific cell–cell contacts favor clonal B cells expansion and resistance to drug treatments. It is further worth noting that leukemic B cells shape their microenvironment and polarize M1 vs. M2 or Th1 vs. Th2 cells, causing, therefore, suppression of the immune response.

Novel therapeutic agents targeting the BCR signaling pathways can also be effective in modulating these interactions, but we still need to better understand cell-intrinsic and -extrinsic causes of therapy failure, further taking into account the opportunity of combined therapies usage.

Today, the exploitation of CLL–tumor-microenvironment (TME) interactions by innovative 3D models, mimicking a more reliable and physiological neoplastic/accessory cells in vivo setting, will further shed new lights and be of interest for both research and clinical purposes.

This Special Issue encompasses new research articles and reviews to advance our knowledge in CLL–TME cross-talk and to highlight novel treatments optimized to reshape the protumor microenvironment and to potentiate current therapies.

Dr. Daniela De Totero
Dr. Paolo Giannoni
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

  • chronic lymphocytic leukemia
  • tumor microenvironment
  • cytokines
  • targeted therapy
  • combination therapy
  • 2D/3D models of CLL–tumor microenviroment

Published Papers (6 papers)

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Research

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9 pages, 242 KiB  
Article
Second Neoplasms in Italian Patients with Hairy Cell Leukemia after Treatment with Cladribine: A Multicenter Investigation and Literature Review
by Marianna Criscuolo, Maria Elena Tosti, Alessandro Broccoli, Marzia Varettoni, Alessio Maria Edoardo Maraglino, Antonella Anastasia, Maria Cantonetti, Livio Trentin, Sofia Kovalchuk, Lorella Orsucci, Marina Deodato, Angelica Spolzino, Stefano Volpetti, Ombretta Annibali, Sergio Storti, Caterina Stelitano, Francesco Marchesi, Sonia Morè, Luana Fianchi, Brunangelo Falini, Alessandro Pulsoni, Enrico Tiacci, Pier Luigi Zinzani and Livio Paganoadd Show full author list remove Hide full author list
Cancers 2024, 16(8), 1475; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers16081475 - 11 Apr 2024
Viewed by 553
Abstract
Concern has emerged about the prevalence of second cancers among patients with hairy cell leukemia (HCL) treated with purine analogs. We investigated 513 patients with HCL treated with cladribine over the last 30 years at 18 Italian centers and calculated their standardized incidence [...] Read more.
Concern has emerged about the prevalence of second cancers among patients with hairy cell leukemia (HCL) treated with purine analogs. We investigated 513 patients with HCL treated with cladribine over the last 30 years at 18 Italian centers and calculated their standardized incidence ratios (SIRs). We identified 24 patients with a second cancer diagnosed at a median time from treatment with cladribine of 59.9 months (range: 9.2–169.7 months). All patients with solid neoplasms presented with a limited-stage disease, except four cases of locally advanced cancer; multiple myeloma patients had a smoldering disease, while lymphoma patients had stage Ie and stage IV diseases. Response to therapy was complete in 19 cases; 1 patient is still receiving treatment for a relapsing bladder disease, while 2 patients progressed during treatment and died. These two patients died from unrelated causes: one from infection and one due to surgery complications. The median OS from HCL was 98.5 months (range: 38.4–409.2 months), while the median OS from second cancer was 27.6 months (range: 1–117.8 months). The SIR was 0.86 (95% CI: 0.54–1.30) for males and 1.13 (95% CI: 0.36–2.73) for females: no statistically significant differences were highlighted. We were not able to demonstrate an excess of second cancer or a significant association with the specific studied neoplasm. Full article
(This article belongs to the Special Issue Advances in Chronic Lymphocytic Leukemia Microenvironment: The Disruption of the Supportive Leukemic/Accessory Cells Interactions to Improve Therapy Response)
16 pages, 1115 KiB  
Article
Real-World Outcome of Treatment with Single-Agent Ibrutinib in Italian Patients with Chronic Lymphocytic Leukemia: Final Results of the EVIdeNCE Study
by Francesca Romana Mauro, Potito Rosario Scalzulli, Lydia Scarfò, Carla Minoia, Roberta Murru, Paolo Sportoletti, Ferdinando Frigeri, Francesco Albano, Nicola Di Renzo, Alessandro Sanna, Luca Laurenti, Massimo Massaia, Ramona Cassin, Marta Coscia, Caterina Patti, Elsa Pennese, Agostino Tafuri, Annalisa Chiarenza, Piero Galieni, Omar Perbellini, Carmine Selleri, Catello Califano, Felicetto Ferrara, Antonio Cuneo, Marco Murineddu, Gaetano Palumbo, Ilaria Scortechini, Alessandra Tedeschi, Livio Trentin, Marzia Varettoni, Fabrizio Pane, Anna Marina Liberati, Francesco Merli, Lucia Morello, Gerardo Musuraca, Monica Tani, Adalberto Ibatici, Giulia Regazzoni, Michele Di Candia, Maria Palma, Danilo Arienti and Stefano Molicaadd Show full author list remove Hide full author list
Cancers 2024, 16(6), 1228; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers16061228 - 20 Mar 2024
Viewed by 1056
Abstract
Real-world data in clinical practice are needed to confirm the efficacy and safety that ibrutinib has demonstrated in clinical trials of patients with chronic lymphocytic leukemia (CLL). We described the real-world persistence rate, patterns of use, and clinical outcomes in 309 patients with [...] Read more.
Real-world data in clinical practice are needed to confirm the efficacy and safety that ibrutinib has demonstrated in clinical trials of patients with chronic lymphocytic leukemia (CLL). We described the real-world persistence rate, patterns of use, and clinical outcomes in 309 patients with CLL receiving single-agent ibrutinib in first line (1L, n = 118), 2L (n = 127) and ≥3L (n = 64) in the prospective, real-world, Italian EVIdeNCE study. After a median follow-up of 23.9 months, 29.8% of patients discontinued ibrutinib (1L: 24.6%, 2L: 29.9%, ≥3L: 39.1%), mainly owing to adverse events (AEs)/toxicity (14.2%). The most common AEs leading to discontinuation were infections (1L, ≥3L) and cardiac events (2L). The 2-year retention rate was 70.2% in the whole cohort (1L: 75.4%, 2L: 70.1%, ≥3L: 60.9%). The 2-year PFS and OS were, respectively, 85.4% and 91.7% in 1L, 80.0% and 86.2% in 2L, and 70.1% and 80.0% in ≥3L. Cardiovascular conditions did not impact patients’ clinical outcomes. The most common AEs were infections (30.7%), bleeding (12.9%), fatigue (10.0%), and neutropenia (9.7%), while grade 3–4 atrial fibrillation occurred in 3.9% of patients. No new safety signals were detected. These results strongly support ibrutinib as a valuable treatment option for CLL. Full article
(This article belongs to the Special Issue Advances in Chronic Lymphocytic Leukemia Microenvironment: The Disruption of the Supportive Leukemic/Accessory Cells Interactions to Improve Therapy Response)
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17 pages, 2112 KiB  
Article
Prognostic Potential of Galectin-9 mRNA Expression in Chronic Lymphocytic Leukemia
by Agnieszka Bojarska-Junak, Wioleta Kowalska, Sylwia Chocholska, Agata Szymańska, Waldemar Tomczak, Michał Konrad Zarobkiewicz and Jacek Roliński
Cancers 2023, 15(22), 5370; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15225370 - 11 Nov 2023
Viewed by 916
Abstract
Galectin-9 (Gal-9), very poorly characterized in chronic lymphocytic leukemia (CLL), was chosen in our study to examine its potential role as a CLL biomarker. The relation of Gal-9 expression in malignant B-cells and other routinely measured CLL markers, as well as its clinical [...] Read more.
Galectin-9 (Gal-9), very poorly characterized in chronic lymphocytic leukemia (CLL), was chosen in our study to examine its potential role as a CLL biomarker. The relation of Gal-9 expression in malignant B-cells and other routinely measured CLL markers, as well as its clinical relevance are poorly understood. Gal-9 mRNA expression was quantified with RT-qPCR in purified CD19+ B-cells of 100 CLL patients and analyzed in the context of existing clinical data. Our results revealed the upregulation of Gal-9 mRNA in CLL cells. High Gal-9 mRNA expression was closely associated with unfavorable prognostic markers. In addition, Gal-9 expression in leukemic cells was significantly elevated in CLL patients who did not respond to the first-line therapy compared to those who did respond. This suggests its potential predictive value. Importantly, Gal-9 was an independent predictor for the time to treatment parameters. Thus, we can suggest an adverse role of Gal-9 expression in CLL. Interestingly, it is possible that Gal-9 expression is induced in B-cells by EBV infection, so we determined the patients’ EBV status. Our suggestion is that EBV coinfection could worsen prognosis in CLL, partly due to Gal-9 expression upregulation caused by EBV. Full article
(This article belongs to the Special Issue Advances in Chronic Lymphocytic Leukemia Microenvironment: The Disruption of the Supportive Leukemic/Accessory Cells Interactions to Improve Therapy Response)
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16 pages, 3993 KiB  
Article
Characterization of the Intraclonal Complexity of Chronic Lymphocytic Leukemia B Cells: Potential Influences of B-Cell Receptor Crosstalk with Other Stimuli
by Andrea N. Mazzarello, Mark Fitch, Martina Cardillo, Anita Ng, Sabreen Bhuiya, Esha Sharma, Davide Bagnara, Jonathan E. Kolitz, Jacqueline C. Barrientos, Steven L. Allen, Kanti R. Rai, Joanna Rhodes, Marc K. Hellerstein and Nicholas Chiorazzi
Cancers 2023, 15(19), 4706; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15194706 - 25 Sep 2023
Cited by 1 | Viewed by 1565
Abstract
Chronic lymphocytic leukemia (CLL) clones contain subpopulations differing in time since the last cell division (“age”): recently born, proliferative (PF; CXCR4DimCD5Bright), intermediate (IF; CXCR4IntCD5Int), and resting (RF; CXCR4BrightCD5Dim) fractions. Herein, we [...] Read more.
Chronic lymphocytic leukemia (CLL) clones contain subpopulations differing in time since the last cell division (“age”): recently born, proliferative (PF; CXCR4DimCD5Bright), intermediate (IF; CXCR4IntCD5Int), and resting (RF; CXCR4BrightCD5Dim) fractions. Herein, we used deuterium (2H) incorporation into newly synthesized DNA in patients to refine the kinetics of CLL subpopulations by characterizing two additional CXCR4/CD5 fractions, i.e., double dim (DDF; CXCR4DimCD5Dim) and double bright (DBF; CXCR4BrightCD5Bright); and intraclonal fractions differing in surface membrane (sm) IgM and IgD densities. Although DDF was enriched in recently divided cells and DBF in older cells, PF and RF remained the most enriched in youngest and oldest cells, respectively. Similarly, smIgMHigh and smIgDHigh cells were the youngest, and smIgMLow and smIgDLow were the oldest, when using smIG levels as discriminator. Surprisingly, the cells closest to the last stimulatory event bore high levels of smIG, and stimulating via TLR9 and smIG yielded a phenotype more consistent with the in vivo setting. Finally, older cells were less sensitive to in vivo inhibition by ibrutinib. Collectively, these data define additional intraclonal subpopulations with divergent ages and phenotypes and suggest that BCR engagement alone is not responsible for the smIG levels found in vivo, and the differential sensitivity of distinct fractions to ibrutinib might account, in part, for therapeutic relapse. Full article
(This article belongs to the Special Issue Advances in Chronic Lymphocytic Leukemia Microenvironment: The Disruption of the Supportive Leukemic/Accessory Cells Interactions to Improve Therapy Response)
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Review

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24 pages, 1729 KiB  
Review
The Role of the Microenvironment and Cell Adhesion Molecules in Chronic Lymphocytic Leukemia
by Marina Cerreto, Robin Foà and Alessandro Natoni
Cancers 2023, 15(21), 5160; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15215160 - 26 Oct 2023
Cited by 2 | Viewed by 1679
Abstract
Chronic lymphocytic leukemia (CLL) is a B-cell malignancy whose progression largely depends on the lymph node and bone marrow microenvironment. Indeed, CLL cells actively proliferate in specific regions of these anatomical compartments, known as proliferation centers, while being quiescent in the blood stream. [...] Read more.
Chronic lymphocytic leukemia (CLL) is a B-cell malignancy whose progression largely depends on the lymph node and bone marrow microenvironment. Indeed, CLL cells actively proliferate in specific regions of these anatomical compartments, known as proliferation centers, while being quiescent in the blood stream. Hence, CLL cell adhesion and migration into these protective niches are critical for CLL pathophysiology. CLL cells are lodged in their microenvironment through a series of molecular interactions that are mediated by cellular adhesion molecules and their counter receptors. The importance of these adhesion molecules in the clinic is demonstrated by the correlation between the expression levels of some of them, in particular CD49d, and the prognostic likelihood. Furthermore, novel therapeutic agents, such as ibrutinib, impair the functions of these adhesion molecules, leading to an egress of CLL cells from the lymph nodes and bone marrow into the circulation together with an inhibition of homing into these survival niches, thereby preventing disease progression. Several adhesion molecules have been shown to participate in CLL adhesion and migration. Their importance also stems from the observation that they are involved in promoting, directly or indirectly, survival signals that sustain CLL proliferation and limit the efficacy of standard and novel chemotherapeutic drugs, a process known as cell adhesion-mediated drug resistance. In this respect, many studies have elucidated the molecular mechanisms underlying cell adhesion-mediated drug resistance, which have highlighted different signaling pathways that may represent potential therapeutic targets. Here, we review the role of the microenvironment and the adhesion molecules that have been shown to be important in CLL and their impact on transendothelial migration and cell-mediated drug resistance. We also discuss how novel therapeutic compounds modulate the function of this important class of molecules. Full article
(This article belongs to the Special Issue Advances in Chronic Lymphocytic Leukemia Microenvironment: The Disruption of the Supportive Leukemic/Accessory Cells Interactions to Improve Therapy Response)
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15 pages, 1279 KiB  
Review
Unraveling the Bone Tissue Microenvironment in Chronic Lymphocytic Leukemia
by Paolo Giannoni, Cecilia Marini, Giovanna Cutrona, Gian Mario Sambuceti, Franco Fais and Daniela de Totero
Cancers 2023, 15(20), 5058; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15205058 - 19 Oct 2023
Viewed by 1396
Abstract
Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in Western countries. Although characterized by the progressive expansion and accumulation of leukemic B cells in peripheral blood, CLL cells develop in protective niches mainly located within lymph nodes and bone marrow. Multiple interactions [...] Read more.
Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in Western countries. Although characterized by the progressive expansion and accumulation of leukemic B cells in peripheral blood, CLL cells develop in protective niches mainly located within lymph nodes and bone marrow. Multiple interactions between CLL and microenvironmental cells may favor the expansion of a B cell clone, further driving immune cells toward an immunosuppressive phenotype. Here, we summarize the current understanding of bone tissue alterations in CLL patients, further addressing and suggesting how the multiple interactions between CLL cells and osteoblasts/osteoclasts can be involved in these processes. Recent findings proposing the disruption of the endosteal niche by the expansion of a leukemic B cell clone appear to be a novel field of research to be deeply investigated and potentially relevant to provide new therapeutic approaches. Full article
(This article belongs to the Special Issue Advances in Chronic Lymphocytic Leukemia Microenvironment: The Disruption of the Supportive Leukemic/Accessory Cells Interactions to Improve Therapy Response)
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