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16 pages, 2907 KiB

Open AccessArticle

Low BACH2 Expression Predicts Adverse Outcome in Chronic Lymphocytic Leukaemia

by Carmela Ciardullo, Katarzyna Szoltysek, Peixun Zhou, Monika Pietrowska, Lukasz Marczak, Elaine Willmore, Amir Enshaei, Anna Walaszczyk, Jia Yee Ho, Vikki Rand, Scott Marshall, Andrew G. Hall, Christine J. Harrison, Meera Soundararajan and Jeyanthy Eswaran

Cancers 2022, 14(1), 23; https://doi.org/10.3390/cancers14010023 - 21 Dec 2021

Cited by 9 | Viewed by 4274

Abstract

Chronic lymphocytic leukaemia (CLL) is a heterogeneous disease with a highly variable clinical outcome. There are well-established CLL prognostic biomarkers that have transformed treatment and improved the understanding of CLL biology. Here, we have studied the clinical significance of two crucial B cell [...] Read more.

Chronic lymphocytic leukaemia (CLL) is a heterogeneous disease with a highly variable clinical outcome. There are well-established CLL prognostic biomarkers that have transformed treatment and improved the understanding of CLL biology. Here, we have studied the clinical significance of two crucial B cell regulators, BACH2 (BTB and CNC homology 1, basic leucine zipper transcription factor 2) and BCL6 (B-cell CLL/lymphoma 6), in a cohort of 102 CLL patients and determined the protein interaction networks that they participate in using MEC-1 CLL cells. We observed that CLL patients expressing low levels of BCL6 and BACH2 RNA had significantly shorter overall survival (OS) than high BCL6- and BACH2-expressing cases. Notably, their low expression specifically decreased the OS of immunoglobulin heavy chain variable region-mutated (IGHV-M) CLL patients, as well as those with 11q and 13q deletions. Similar to the RNA data, a low BACH2 protein expression was associated with a significantly shorter OS than a high expression. There was no direct interaction observed between BACH2 and BCL6 in MEC-1 CLL cells, but they shared protein networks that included fifty different proteins. Interestingly, a prognostic index (PI) model that we generated, using integrative risk score values of BACH2 RNA expression, age, and 17p deletion status, predicted patient outcomes in our cohort. Taken together, these data have shown for the first time a possible prognostic role for BACH2 in CLL and have revealed protein interaction networks shared by BCL6 and BACH2, indicating a significant role for BACH2 and BCL6 in key cellular processes, including ubiquitination mediated B-cell receptor functions, nucleic acid metabolism, protein degradation, and homeostasis in CLL biology. Full article

(This article belongs to the Special Issue Chronic Lymphocytic Leukaemia (CLL))

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16 pages, 2109 KiB

Open AccessArticle

Targeting of HSP70/HSF1 Axis Abrogates In Vitro Ibrutinib-Resistance in Chronic Lymphocytic Leukemia

by Federica Frezzato, Andrea Visentin, Filippo Severin, Serena Pizzo, Edoardo Ruggeri, Nayla Mouawad, Leonardo Martinello, Elisa Pagnin, Valentina Trimarco, Alessia Tonini, Samuela Carraro, Stefano Pravato, Silvia Imbergamo, Sabrina Manni, Francesco Piazza, Anna Maria Brunati, Monica Facco and Livio Trentin

Cancers 2021, 13(21), 5453; https://doi.org/10.3390/cancers13215453 - 29 Oct 2021

Cited by 7 | Viewed by 2691

Abstract

The Btk inhibitor ibrutinib has significantly changed the management of chronic lymphocytic leukemia (CLL) patients. Despite its clinical efficacy, relapses occur, and outcomes after ibrutinib failure are poor. Although BTK and PLCγ2 mutations have been found to be associated with ibrutinib resistance in [...] Read more.

The Btk inhibitor ibrutinib has significantly changed the management of chronic lymphocytic leukemia (CLL) patients. Despite its clinical efficacy, relapses occur, and outcomes after ibrutinib failure are poor. Although BTK and PLCγ2 mutations have been found to be associated with ibrutinib resistance in a fair percentage of CLL patients, no information on resistance mechanisms is available in patients lacking these mutations. The heat shock protein of 70 kDa (HSP70) and its transcription factor heat shock factor 1 (HSF1) play a role in mediating the survival and progression of CLL, as well as taking part in drug resistance in various cancers. We demonstrated that resveratrol and related phenols were able to induce apoptosis in vitro in leukemic cells from CLL untreated patients by acting on the HSP70/HSF1 axis. The same was achieved in cells recovered from 13 CLL patients failing in vivo ibrutinib treatment. HSP70 and HSF1 levels decreased following in vitro treatment, correlating to apoptosis induction. We suggest an involvement of HSP70/HSF1 axis in controlling resistance to ibrutinib in CLL cells, since their inhibition is effective in inducing in vitro apoptosis in cells from ibrutinib refractory patients. The targeting of HSP70/HSF1 axis could represent a novel rational therapeutic strategy for CLL, also for relapsing patients. Full article

(This article belongs to the Special Issue Chronic Lymphocytic Leukaemia (CLL))

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20 pages, 5631 KiB

Open AccessArticle

Targeting Autophagy Triggers Apoptosis and Complements the Action of Venetoclax in Chronic Lymphocytic Leukemia Cells

by Damjan Avsec, Alma Tana Jakoš Djordjevič, Maša Kandušer, Helena Podgornik, Matevž Škerget and Irena Mlinarič-Raščan

Cancers 2021, 13(18), 4557; https://doi.org/10.3390/cancers13184557 - 10 Sep 2021

Cited by 16 | Viewed by 4593

Abstract

Continuous treatment of patients with chronic lymphocytic leukemia (CLL) with venetoclax, an antagonist of the anti-apoptotic protein Bcl-2, can result in resistance, which highlights the need for novel targets to trigger cell death in CLL. Venetoclax also induces autophagy by perturbing the Bcl-2/Beclin-1 [...] Read more.

Continuous treatment of patients with chronic lymphocytic leukemia (CLL) with venetoclax, an antagonist of the anti-apoptotic protein Bcl-2, can result in resistance, which highlights the need for novel targets to trigger cell death in CLL. Venetoclax also induces autophagy by perturbing the Bcl-2/Beclin-1 complex, so autophagy might represent a target in CLL. Diverse autophagy inhibitors were assessed for cytotoxic activities against patient-derived CLL cells. The AMPK inhibitor dorsomorphin, the ULK1/2 inhibitor MRT68921, and the autophagosome–lysosome fusion inhibitor chloroquine demonstrated concentration-dependent and time-dependent cytotoxicity against CLL cells, even in those from hard-to-treat patients who carried del(11q) and del(17p). Dorsomorphin and MRT68921 but not chloroquine triggered caspase-dependent cell death. According to the metabolic activities of CLL cells and PBMCs following treatments with 10 µM dorsomorphin (13% vs. 84%), 10 µM MRT68921 (7% vs. 78%), and 25 µM chloroquine (41% vs. 107%), these autophagy inhibitors are selective toward CLL cells. In these CLL cells, venetoclax induced autophagy, and addition of dorsomorphin, MRT68921, or chloroquine showed potent synergistic cytotoxicities. Additionally, MRT68921 alone induced G2 arrest, but when combined with venetoclax, it triggered caspase-dependent cytotoxicity. These data provide the rationale to target autophagy and for autophagy inhibitors as potential treatments for patients with CLL. Full article

(This article belongs to the Special Issue Chronic Lymphocytic Leukaemia (CLL))

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17 pages, 1940 KiB

Open AccessArticle

The Calcitriol/Vitamin D Receptor System Regulates Key Immune Signaling Pathways in Chronic Lymphocytic Leukemia

by Marina Gerousi, Fotis Psomopoulos, Konstantia Kotta, Maria Tsagiopoulou, Niki Stavroyianni, Achilles Anagnostopoulos, Athanasios Anastasiadis, Maria Gkanidou, Ioannis Kotsianidis, Stavroula Ntoufa and Kostas Stamatopoulos

Cancers 2021, 13(2), 285; https://doi.org/10.3390/cancers13020285 - 14 Jan 2021

Cited by 7 | Viewed by 3742

Abstract

It has been proposed that vitamin D may play a role in prevention and treatment of cancer while epidemiological studies have linked vitamin D insufficiency to adverse disease outcomes in various B cell malignancies, including chronic lymphocytic leukemia (CLL). In this study, we [...] Read more.

It has been proposed that vitamin D may play a role in prevention and treatment of cancer while epidemiological studies have linked vitamin D insufficiency to adverse disease outcomes in various B cell malignancies, including chronic lymphocytic leukemia (CLL). In this study, we sought to obtain deeper biological insight into the role of vitamin D and its receptor (VDR) in the pathophysiology of CLL. To this end, we performed expression analysis of the vitamin D pathway molecules; complemented by RNA-Sequencing analysis in primary CLL cells that were treated in vitro with calcitriol, the biologically active form of vitamin D. In addition, we examined calcitriol effects ex vivo in CLL cells cultured in the presence of microenvironmental signals, namely anti-IgM/CD40L, or co-cultured with the supportive HS-5 cells; and, CLL cells from patients under ibrutinib treatment. Our study reports that the calcitriol/VDR system is functional in CLL regulating signaling pathways critical for cell survival and proliferation, including the TLR and PI3K/AKT pathways. Moreover, calcitriol action is likely independent of the microenvironmental signals in CLL, since it was not significantly affected when combined with anti-IgM/CD40L or in the context of the co-culture system. This finding was also supported by our finding of preserved calcitriol signaling capacity in CLL patients under ibrutinib treatment. Overall, our results indicate a relevant biological role for vitamin D in CLL pathophysiology and allude to the potential clinical utility of vitamin D supplementation in patients with CLL. Full article

(This article belongs to the Special Issue Chronic Lymphocytic Leukaemia (CLL))

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20 pages, 4102 KiB

Open AccessArticle

Enhanced Expression of miR-181b in B Cells of CLL Improves the Anti-Tumor Cytotoxic T Cell Response

by Mirco Di Marco, Serena Veschi, Paola Lanuti, Alice Ramassone, Stefania Pacillo, Sara Pagotto, Felice Pepe, Jonahunnatha Nesson George-William, Claudia Curcio, Marco Marchisio, Sebastiano Miscia, Idanna Innocenti, Francesco Autore, Barbara Vannata, Patrizia Di Gregorio, Mario Di Gioacchino, Silvia Valentinuzzi, Manuela Iezzi, Renato Mariani-Costantini, Luigi Maria Larocca, Luca Laurenti, Angelo Veronese and Rosa Visone Show full author list Hide full author list

Cancers 2021, 13(2), 257; https://doi.org/10.3390/cancers13020257 - 12 Jan 2021

Cited by 12 | Viewed by 3220

Abstract

The clinical progression of B cell chronic lymphocytic leukemia (CLL) is associated with immune cell dysfunction and a strong decrease of miR-181b-5p (miR-181b), promoting the death of CLL cells. Here we investigated whether the reduction of miR-181b impairs the immune response [...] Read more.

The clinical progression of B cell chronic lymphocytic leukemia (CLL) is associated with immune cell dysfunction and a strong decrease of miR-181b-5p (miR-181b), promoting the death of CLL cells. Here we investigated whether the reduction of miR-181b impairs the immune response in CLL. We demonstrate that activated CD4+ T cells increase miR-181b expression in CLL through CD40–CD40L signaling, which enhances the maturation and activity of cytotoxic T cells and, consequently, the apoptotic response of CLL cells. The cytotoxic response is facilitated by a depletion of the anti-inflammatory cytokine interleukin 10, targeted by miR-181b. In vivo experiments in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice confirmed that miR-181b promotes the apoptotic death of CLL cells only when functional T cells are restored. Overall, our findings suggest that the reinstatement of miR-181b in CLL cells could be an exploitable adjuvant therapeutic option for the treatment of CLL. Full article

(This article belongs to the Special Issue Chronic Lymphocytic Leukaemia (CLL))

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Review

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18 pages, 939 KiB

Open AccessReview

Protein Phosphorylation and Redox Status: An as Yet Elusive Dyad in Chronic Lymphocytic Leukemia

by Mario Angelo Pagano, Federica Frezzato, Andrea Visentin, Livio Trentin and Anna Maria Brunati

Cancers 2022, 14(19), 4881; https://doi.org/10.3390/cancers14194881 - 6 Oct 2022

Cited by 4 | Viewed by 2198

Abstract

Malignant cells in chronic lymphocytic leukemia (CLL) are characterized by oxidative stress that is related to abundant generation of reactive oxygen species (ROS) by increased mitochondrial oxidative phosphorylation (OXPHOS). Lymphoid tissues have been shown to provide a protective microenvironment that antagonizes the effects [...] Read more.

Malignant cells in chronic lymphocytic leukemia (CLL) are characterized by oxidative stress that is related to abundant generation of reactive oxygen species (ROS) by increased mitochondrial oxidative phosphorylation (OXPHOS). Lymphoid tissues have been shown to provide a protective microenvironment that antagonizes the effects of ROS, contributing to establishing redox homeostasis that supports the vitality of CLL cells. In the last few decades, a complex antioxidant machinery has been demonstrated to be activated in CLL cells, including the different superoxide dismutase (SOD) isoforms, the thioredoxin (Trx) system, and the enzyme cascade inducing glutathione (GSH) biosynthesis and recycling, to name a few. Their expression is known to be upregulated by the activation of specific transcription factors, which can be regulated by either oxidative stress or phosphorylation. These two latter aspects have mostly been explored separately, and only recently an increasing body of evidence has been providing reasonable inference that ROS and phosphorylation may cooperate in an interplay that contributes to the survival mechanisms of CLL cells. Here, we present an overview of how oxidative stress and phosphorylation-dependent signals are intertwined in CLL, focusing on transcription factors that regulate the balance between ROS production and scavenging. Full article

(This article belongs to the Special Issue Chronic Lymphocytic Leukaemia (CLL))

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17 pages, 1424 KiB

Open AccessReview

Biological and Clinical Insight from Analysis of the Tumor B-Cell Receptor Structure and Function in Chronic Lymphocytic Leukemia

by Francesco Forconi, Stuart A. Lanham and Giorgia Chiodin

Cancers 2022, 14(3), 663; https://doi.org/10.3390/cancers14030663 - 28 Jan 2022

Cited by 7 | Viewed by 3598

Abstract

The B-cell receptor (BCR) is essential to the behavior of the majority of normal and neoplastic mature B cells. The identification in 1999 of the two major CLL subsets expressing unmutated immunoglobulin (Ig) variable region genes (U-IGHV, U-CLL) of pre-germinal center origin and [...] Read more.

The B-cell receptor (BCR) is essential to the behavior of the majority of normal and neoplastic mature B cells. The identification in 1999 of the two major CLL subsets expressing unmutated immunoglobulin (Ig) variable region genes (U-IGHV, U-CLL) of pre-germinal center origin and poor prognosis, and mutated IGHV (M-CLL) of post-germinal center origin and good prognosis, ignited intensive investigations on structure and function of the tumor BCR. These investigations have provided fundamental insight into CLL biology and eventually the mechanistic rationale for the development of successful therapies targeting BCR signaling. U-CLL and M-CLL are characterized by variable low surface IgM (sIgM) expression and signaling capacity. Variability of sIgM can in part be explained by chronic engagement with (auto)antigen at tissue sites. However, other environmental elements, genetic changes, and epigenetic signatures also contribute to the sIgM variability. The variable levels have consequences on the behavior of CLL, which is in a state of anergy with an indolent clinical course when sIgM expression is low, or pushed towards proliferation and a more aggressive clinical course when sIgM expression is high. Efficacy of therapies that target BTK may also be affected by the variable sIgM levels and signaling and, in part, explain the development of resistance. Full article

(This article belongs to the Special Issue Chronic Lymphocytic Leukaemia (CLL))

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14 pages, 1236 KiB

Open AccessReview

Interleukin (IL)-9 Supports the Tumor-Promoting Environment of Chronic Lymphocytic Leukemia

by Laura Patrussi, Nagaja Capitani and Cosima T. Baldari

Cancers 2021, 13(24), 6301; https://doi.org/10.3390/cancers13246301 - 15 Dec 2021

Cited by 11 | Viewed by 3405

Abstract

Interleukin (IL)-9 is a soluble factor secreted by immune cells into the microenvironment. Originally identified as a mediator of allergic responses, IL-9 has been detected in recent years in several tumor niches. In solid tumors, it mainly promotes anti-tumor immune responses, while in [...] Read more.

Interleukin (IL)-9 is a soluble factor secreted by immune cells into the microenvironment. Originally identified as a mediator of allergic responses, IL-9 has been detected in recent years in several tumor niches. In solid tumors, it mainly promotes anti-tumor immune responses, while in hematologic malignancies, it sustains the growth and survival of neoplastic cells. IL-9 has been recently implicated in the pathogenesis of chronic lymphocytic leukemia; however, the molecular mechanisms underlying its contribution to this complex neoplasia are still unclear. Here, we summarize the current knowledge of IL-9 in the tumor microenvironment, with a focus on its role in the pathogenesis of chronic lymphocytic leukemia. Full article

(This article belongs to the Special Issue Chronic Lymphocytic Leukaemia (CLL))

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16 pages, 329 KiB

Open AccessReview

Autoimmune Hemolytic Anemia in Chronic Lymphocytic Leukemia: A Comprehensive Review

by Francesco Autore, Raffaella Pasquale, Idanna Innocenti, Alberto Fresa, Federica Sora’ and Luca Laurenti

Cancers 2021, 13(22), 5804; https://doi.org/10.3390/cancers13225804 - 19 Nov 2021

Cited by 12 | Viewed by 5327

Abstract

Chronic lymphocytic leukemia (CLL) patients have a greater predisposition to develop autoimmune complications. The most common of them is autoimmune hemolytic anemia (AIHA) with a frequency of 7–10% of cases. Pathogenesis is multifactorial involving humoral, cellular, and innate immunity. CLL B-cells have damaged [...] Read more.

Chronic lymphocytic leukemia (CLL) patients have a greater predisposition to develop autoimmune complications. The most common of them is autoimmune hemolytic anemia (AIHA) with a frequency of 7–10% of cases. Pathogenesis is multifactorial involving humoral, cellular, and innate immunity. CLL B-cells have damaged apoptosis, produce less immunoglobulins, and could be responsible for antigen presentation and releasing inflammatory cytokines. CLL B-cells can act similar to antigen-presenting cells activating self-reactive T helper cells and may induce T-cell subsets imbalance, favoring autoreactive B-cells which produce anti-red blood cells autoantibodies. Treatment is individualized and it depends on the presence and severity of clinical symptoms, disease status, and comorbidities. Corticosteroids are the standardized first-line treatment; second-line treatment comprises rituximab. Patients not responding to corticosteroids and rituximab should be treated with CLL-specific drugs as per current guidelines according to age and comorbidities. New targeted drugs (BTK inhibitors and anti BCL2) are recently used after or together with steroids to manage AIHA. In the case of cold agglutinin disease, rituximab is preferred, because steroids are ineffective. Management must combine supportive therapies, including vitamins; antibiotics and heparin prophylaxis are indicated in order to minimize infectious and thrombotic risk. Full article

(This article belongs to the Special Issue Chronic Lymphocytic Leukaemia (CLL))

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