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Besides their antiviral and immunomodulatory functions, type I (αβ) and II (γ) interferons (IFNs) exhibit either beneficial or detrimental effects on tumor progression. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of abnormal CD5+ B lymphocytes that escape death. Drug resistance and disease relapse still occur in CLL. Th...
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... of 17p13, 11q22, 13q14 and trisomy 12 were detected using fluorescence in situ hybridization (FISH) with the Metasystems XL DLEU/LAMP/12cen and XL ATM/TP53 Multi-Color Probe Kits (MetaSystems, Compiègne, France). The biological and clinical characteristics of CLL patients are listed in Table 1. Peripheral blood mononuclear cells (PBMCs) were isolated from blood using Ficoll-Hypaque density gradient (1.077 g/mL) centrifugation. ...Citations
... Notably, several pathways involved in cancer and hematopoietic malignancies development were identified by Reactome analysis of the top ten genes analyzed in this study, including Interferon alpha/ beta signaling (73)(74)(75), caspases and Rho GTPase activity (76), GHR signaling pathway (77)(78)(79), Integrin signaling (80), non-receptor Tyrosine Kinases activity (81), and FGF/FGFR pathways (82). Moreover, among the top ten genes, FIBP was found to be overexpressed in a specific group of CLL patients affected by a large loss at the 13q14 locus (83); as previously noted also, IGF1R was identified as overexpressed in various CLL subsets, suggesting a contribution to CLL pathology (63,81,84,85). ...
Analyzing gene expression profiles (GEP) through artificial intelligence provides meaningful insight into cancer disease. This study introduces DeepSHAP Autoencoder Filter for Genes Selection (DSAF-GS), a novel deep learning and explainable artificial intelligence-based approach for feature selection in genomics-scale data. DSAF-GS exploits the autoencoder’s reconstruction capabilities without changing the original feature space, enhancing the interpretation of the results. Explainable artificial intelligence is then used to select the informative genes for chronic lymphocytic leukemia prognosis of 217 cases from a GEP database comprising roughly 20,000 genes. The model for prognosis prediction achieved an accuracy of 86.4%, a sensitivity of 85.0%, and a specificity of 87.5%. According to the proposed approach, predictions were strongly influenced by CEACAM19 and PIGP, moderately influenced by MKL1 and GNE, and poorly influenced by other genes. The 10 most influential genes were selected for further analysis. Among them, FADD, FIBP, FIBP, GNE, IGF1R, MKL1, PIGP, and SLC39A6 were identified in the Reactome pathway database as involved in signal transduction, transcription, protein metabolism, immune system, cell cycle, and apoptosis. Moreover, according to the network model of the 3D protein-protein interaction (PPI) explored using the NetworkAnalyst tool, FADD, FIBP, IGF1R, QTRT1, GNE, SLC39A6, and MKL1 appear coupled into a complex network. Finally, all 10 selected genes showed a predictive power on time to first treatment (TTFT) in univariate analyses on a basic prognostic model including IGHV mutational status, del(11q) and del(17p), NOTCH1 mutations, β2-microglobulin, Rai stage, and B-lymphocytosis known to predict TTFT in CLL. However, only IGF1R [hazard ratio (HR) 1.41, 95% CI 1.08-1.84, P=0.013), COL28A1 (HR 0.32, 95% CI 0.10-0.97, P=0.045), and QTRT1 (HR 7.73, 95% CI 2.48-24.04, P<0.001) genes were significantly associated with TTFT in multivariable analyses when combined with the prognostic factors of the basic model, ultimately increasing the Harrell’s c-index and the explained variation to 78.6% (versus 76.5% of the basic prognostic model) and 52.6% (versus 42.2% of the basic prognostic model), respectively. Also, the goodness of model fit was enhanced (χ2 = 20.1, P=0.002), indicating its improved performance above the basic prognostic model. In conclusion, DSAF-GS identified a group of significant genes for CLL prognosis, suggesting future directions for bio-molecular research.
... 11 IFN-γ not only improved the ability of CLL cells to resist natural apoptosis in vitro but also significantly enhanced the resistance of CLL cells to drug-induced apoptosis. [12][13][14] These studies suggest that IFN-γ has the potential to enhance the survival and anti-apoptotic abilities of CLL cells. The activation of Janus kinases1/2 (JAK1/2)-signal transducer and activator of transcription (STAT) signaling pathway is required for IFN-γ exerting biological functions. ...
... Previous studies by us and others have demonstrated that IFN-γ promotes CLL cell survival and drug resistance, 12,13,17 but the mechanisms involved in this effect have not yet been characterized. In this study, we report that IFN-γ activated STAT3, AKT, and ERK signaling pathways and altered the expression of more than 500 genes related to anti-apoptosis, cell migration, and proliferation pathways. ...
... Given the potential role of the JAK1/2-STAT3 pathway in IFN-γ exerting its biological function, 13 the effect of this pathway on IFN-γinducible gene expression was also determined, we then found that the blockage of this pathway by JAK1/2 inhibitor Ruxolitinib, or STAT3 inhibitors Stattic or C188-9 significantly reduced the expression of a large number of IFN-γ-inducible genes ( Figure 5A). In contrast, Idelalisib and Selumetinib, inhibitors of PI3K/AKT and RAF/MEK/ERK signaling pathways, respectively, had no inhibitory effect on the expression of most genes, but instead promoted their expression ( Figure 5B). ...
Background
It is known that the microenvironmental cytokine interferon gamma (IFN‐γ) provides a survival advantage for chronic lymphocytic leukemia (CLL) cells. However, the mechanisms involved in this effect have not been properly investigated.
Methods
Herein, we conducted a comprehensive screening of the effects of IFN‐γ on signaling pathways and gene expression profiles in CLL cells by using western blotting, real‐time quantitative reverse transcription (RT‐qPCR) and high‐throughput RNA sequencing (RNA‐seq).
Results
We found that IFN‐γ not only activated the pro‐survival signal transducer and activator of transcription 3 (STAT3), but also activated the protein kinase B and extracellular signal‐regulated kinase signaling pathways. RNA‐seq analysis showed that IFN‐γ stimulation changed the expression profiles of more than 500 genes, with 391 being up‐regulated and 123 down‐regulated. These genes are involved in numerous biological processes, including anti‐apoptosis, cell migration, and proliferation. IFN‐γ significantly up‐regulated the expression of CD38, BCL6, CXCL9, BCL2A1, SCOS3, IL‐10, HGF, EGFR, THBS‐1, FN1, and MUC1, which encode proteins potentially associated with disease progression, worse prognosis or poor response to treatment. Blocking janus kinases1/2 (JAK1/2) or STAT3 signal by specific inhibitors affected the expression of most genes, suggesting a pivotal role of the JAK1/2‐STAT3 pathway in IFN‐γ pro‐survival effects in CLL.
Conclusions
Our data demonstrate that IFN‐γ regulates a complex pro‐survival signal network in CLL through JAK1/2‐STAT3, which provides a rational explanation for IFN‐γ promoting CLL cells survival and drug resistance.
... Bauvois B. and colleagues [8] discovered that the triggering of interferon (IFN) receptors had a positive effect on the survival of chronic lymphocytic leukemia (CLL) patients and studied the interaction between IFN and CLL cells. These authors confirmed that one of the survival processes, the STAT3 signaling pathway, was affected when CLL cells were treated with type I and II IFNs. ...
This Biomedicines Special Issue was designed to attract articles that focused on the pleiotropic role of the signal transducer and activator of transcription 3 (STAT3) transcription factor in different facets of tumorigenesis. STAT3 belongs to the signal transducer and activator of transcription (STAT) family [...]
... Insulin Growth Factor-1 (IGF-1) (113), CXCL12 (52, 62, 107) and CXCL13 (62), CCL19 and CCL21 (62), Vascular Endothelial Growth Factor (VEGF) (85, 114, 115), type I and II InterFeroN (IFN) (116,117), and TNFa (118) are also implicated in CLL cell survival, as well as CLL (97, 119) and HCL (120) cell proliferation for the lastly mentioned actor. ...
Mature B cell malignancies constitute a wide range of biologically and clinically heterogeneous hematological diseases. Despite an increasingly thorough understanding of the pathophysiology of these pathologies and significant improvements in therapies, a dismal outcome still affects a large number of patients. Therefore, further investigations into new treatment perspectives are highly needed and they depend entirely on the ex vivo culture of patient cells. Primary cells usually demand superior culture models, as they are notoriously difficult to cultivate. The literature is not devoid of approaches ranging from two- to three-dimensional systems for culturing mature malignant primary B cells. However, they display substantial protocol inter-variation. This imposes a high risk of failures, repeats, and inconsistent results, which are neither compatible with the rare value of primary cells nor the efficiency of the drug discovery process. In this review, we provide a thorough overview of the different approaches that have been implemented in the literature for the culture of mature malignant primary B cells, and we discuss associated considerations and limitations to assist researchers in determining a fit-for-purpose culture system, thereby attempting to reduce the number of trials and errors as well as associated biomaterial expenditure.
... The serum concentrations of IFNγ are higher in patients with CLL compared to healthy controls [10,11], which might be due, at least in part, to the production of IFNγ by CLL cells [11]. IFNγ protects CLL cells from spontaneous apoptosis and promotes CLL cell survival [11][12][13][14], and it can also induce proliferation and differentiation of CLL cells [15]. More importantly, IFNγ can rescue CLL cells from apoptosis triggered by targeted therapies, such as ibrutinib [16], and it is likely implicated in resistance to venetoclax through an Mcl-1-dependent mechanism [14,17,18]. ...
... IFNγ protects CLL cells from spontaneous apoptosis and promotes CLL cell survival [11][12][13][14], and it can also induce proliferation and differentiation of CLL cells [15]. More importantly, IFNγ can rescue CLL cells from apoptosis triggered by targeted therapies, such as ibrutinib [16], and it is likely implicated in resistance to venetoclax through an Mcl-1-dependent mechanism [14,17,18]. IFNγ is a type II IFN and it binds to the IFNγ receptor (IFNγR), a heterodimer of IFNγRI and IFNγRII. ...
... We thus initially demonstrated that IFNγ can activate CLL cells and rescue them from spontaneous and venetoclax-induced apoptosis. This is in line with previously published studies, that have reported the stimulating and anti-cell death properties of IFNγ on CLL cells [11][12][13][14]. ...
Chronic lymphocytic leukemia (CLL) is a hematological neoplasm of CD19-positive mature-appearing B lymphocytes. Despite the clinical success of targeted therapies in CLL, the development of resistance diminishes their therapeutic activity. This is also true for the Bcl-2 antagonist venetoclax. We investigated the molecular mechanisms that drive venetoclax resistance in CLL, with a clear focus to provide new strategies to successfully combat it. Activation of CLL cells with IFNγ, PMA/ionomycin, and sCD40L diminished the cytotoxicity of venetoclax. We demonstrated that the metabolic activity of cells treated with 1 nM venetoclax alone was 48% of untreated cells, and was higher for cells co-treated with IFNγ (110%), PMA/ionomycin (78%), and sCD40L (62%). As of molecular mechanism, we showed that PMA/ionomycin and sCD40L triggered translocation of NFκB in primary CLL cells, while IFNγ activated p38 MAPK, suppressed spontaneous and venetoclax-induced apoptosis and induced formation of the immunoproteasome. Inhibition of immunoproteasome with ONX-0914 suppressed activity of immunoproteasome and synergized with venetoclax against primary CLL cells. On the other hand, inhibition of p38 MAPK abolished cytoprotective effects of IFNγ. We demonstrated that venetoclax-resistant (MEC-1 VER) cells overexpressed p38 MAPK and p-Bcl-2 (Ser70), and underexpressed Mcl-1, Bax, and Bak. Inhibition of p38 MAPK or immunoproteasome triggered apoptosis in CLL cells and overcame the resistance to venetoclax of MEC-1 VER cells and venetoclax-insensitive primary CLL cells. In conclusion, the p38 MAPK pathway and immunoproteasome represent novel targets to combat venetoclax resistance in CLL.
... Ibrutinib, however, has some limitations, such as resistance development (mainly due to C481 BTK mutations), and toxicity (mainly due to off-target activity) 12,13 . It is suggested that MCL-1 protein levels are essential to CLL survival, and increased in CLL patients with ibrutinib resistance 14 . Through the introduction of more precise targeted therapies and novel combination treatments, CLL patients will bene t from more individualized and effective treatment strategies. ...
APG115 is a highly selective small-molecule inhibitor of MDM2-p53 interaction with oral activity, which restores p53 activation in patients with solid tumors in clinical trials. The Bruton tyrosine kinase inhibitor (BTKi) ibrutinib exhibits significant efficacy in chronic lymphocytic leukemia (CLL) patients including high-risk patients. However, the chemoresistance of ibrutinib still needs to be addressed urgently. Herein, we first demonstrated that the APG115 exerted apoptogenic and antiproliferative effects, and induced G0/G1 cell cycle arrest in CLL. As an agent used either alone or in combination with ibrutinib together, APG115 provided remarkable antitumor activity and overall survival extension in vivo . Mechanistically, the activation of p53 positively regulates the p53/p21 pathway, prompting MCL-1 degradation via inducing its ubiquitination. On basis of the upregulation of MCL-1 in CLL cells with ibrutinib resistance, these evidences explain how APG115 reduces the resistance of ibrutinib in CLL. This study offers promising prospects to constitute effective regimens of APG115 combined with ibrutinib for the CLL treatment.
... For example, CLL-cell treatment with another T-cell-produced factor, namely interferon γ (IFNγ), decreases spontaneous apoptosis [71]. Cultures with the interferons IFNβ or IFNγ also support the survival of CLL cells exposed to ibrutinib [72], and this is probably related to the activation of STAT3 signaling and the induction of MCL-1 levels [73]. Anti-apoptotic effects have also been described for IL13 and IL6, produced by Th2 cells [74,75]. ...
... IL4 has been shown to induce JAK3-dependent resistance against chemotherapeutics [108] and to mitigate the impact of ibrutinib and idelalisib on BCR signaling [55,109]. IFNγ was found to increase CLL survival via MCL-1 upregulation, which might support drug resistance [73]. On the other hand, the pro-apoptotic effect of IL21 is synergistic with the treatment of malignant B cells with fludarabine or rituximab [110]. ...
T cells are key components in environments that support chronic lymphocytic leukemia (CLL), activating CLL-cell proliferation and survival. Here, we review in vitro and in vivo model systems that mimic CLL–T-cell interactions, since these are critical for CLL-cell division and resistance to some types of therapy (such as DNA-damaging drugs or BH3-mimetic venetoclax). We discuss approaches for direct CLL-cell co-culture with autologous T cells, models utilizing supportive cell lines engineered to express T-cell factors (such as CD40L) or stimulating CLL cells with combinations of recombinant factors (CD40L, interleukins IL4 or IL21, INFγ) and additional B-cell receptor (BCR) activation with anti-IgM antibody. We also summarize strategies for CLL co-transplantation with autologous T cells into immunodeficient mice (NOD/SCID, NSG, NOG) to generate patient-derived xenografts (PDX) and the role of T cells in transgenic CLL mouse models based on TCL1 overexpression (Eµ-TCL1). We further discuss how these in vitro and in vivo models could be used to test drugs to uncover the effects of targeted therapies (such as inhibitors of BTK, PI3K, SYK, AKT, MEK, CDKs, BCL2, and proteasome) or chemotherapy (fludarabine and bendamustine) on CLL–T-cell interactions and CLL proliferation.
... Their study reported the increased expression of major histocompatibility complex (MHC) class I and II molecules, PD-L1 and programmed cell death ligand 2 (PD-L2) under inflammatory conditions [44], with interferon gamma (IFN-gamma) possibly responsible for upregulation of these molecules [44]. IFN-gamma has been reported to promote the survival of primary chronic lymphocytic leukemia (CLL) cells via JAK-Src/STAT3/Mcl-1 signaling pathway, with elevated IFN-gamma levels characteristic for advanced Rai stage disease [45]. ...
(1) Background: Ciliary body uveal melanoma is a rare subtype of uveal melanoma which comprises 3–5% of melanomas, an immunogenic cancer, and can present multifaceted initial clinical manifestations, masquerading as various ocular pathologies. Chronic lymphocytic leukemia (CLL) presents immunodeficiency and risk for the development of a secondary malignancy, with Bruton’s tyrosine kinase inhibitor treatment having a mutagenic effect and a secondary anti-platelet aggregation effect. We present the case of a 65-year-old patient undergoing treatment for CLL with ibrutinib who presented with recurrent hyphema that masked an underlying, inferiorly situated, ciliary body uveal melanoma; (2) Methods: Retrospective case review; (3) Results: An ophthalmological examination together with imaging via mode B ultrasound and contrast-enhanced magnetic resonance imaging resulted in the clinical and imagistic diagnosis of a ciliary body uveal melanoma. A pathological examination of the enucleated eye confirmed the diagnosis. Postoperative tumoral reoccurrence was not detected for 1½ years, however, CLL immunosuppression worsened with admission for severe COVID-19 disease. (4) Conclusions: CLL patient screening for melanoma should also include detailed ophthalmological examinations, which could also include ultrasound ophthalmological imaging. The avoidance of uveal melanoma metastatic disease is paramount for patient survival. CLL manifests additional profound immunosuppression.
The spectrum of myeloid disorders ranges from aplastic bone marrow failure characterized by an empty bone marrow completely lacking in hematopoiesis to acute myeloid leukemia where the marrow space is replaced by undifferentiated leukemic blasts. Recent advances in the capacity to sequence bulk tumor population as well as at a single cell level has provided significant insight into the stepwise process of transformation to acute myeloid leukemia. Using models of progression in the context of germline predisposition (trisomy 21, GATA2 deficiency, SAMD9/9L syndrome), premalignant states (clonal hematopoiesis and clonal cytopenia of unknown significance) and myelodysplastic syndrome, we review the mechanisms of progression focusing on the hierarchy of clonal mutation and potential roles of transcription factor alterations, splicing factor mutations and the bone marrow environment in progression to acute myeloid leukemia. Despite major advances in our understanding, preventing progression of these disorders or treating them at the acute leukemia phase remains a major area of unmet medical need.
Chronic lymphocytic leukemia (CLL) is characterized by an expansion of mature B cells in the bone marrow, peripheral lymphoid organs and blood. CD4 T helper (Th) lymphocytes significantly contribute to the physiopathology of CLL, but the subset(s) of Th cell involved in CLL pathogenesis is (are) still under debate. In this study, we performed flow cytometry analysis of the circulatory T cells of untreated CLL patients and observed an increase in follicular helper T cells (Tfh), which is a subset of T cells specialized in B cell help. Elevated numbers of Tfh cells correlated with disease severity as measured by the Binet staging system. Tfh from CLL patients were activated and skewed toward a Th1 profile as evidenced by their PD-1 + IL-21 + IFNγ+ phenotype and their CXCR3 + CCR6- chemokine receptor profile. Tfh efficiently enhanced B-CLL survival and proliferation through IL-21 but independently of IFNγ. Finally, we observed an inverse correlation between the Tfh1 and IgA and IgG serum levels in patients, suggesting a role for this Tfh subset in the immune dysfunction associated with CLL. Altogether, our data highlight an impairment in circulatory Tfh subsets in CLL patients and their critical role in CLL physiopathology.
