scholarly journals Nurse-Like Cells and Chronic Lymphocytic Leukemia B Cells: A Mutualistic Crosstalk inside Tissue Microenvironments

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 217
Author(s):  
Stefania Fiorcari ◽  
Rossana Maffei ◽  
Claudio Giacinto Atene ◽  
Leonardo Potenza ◽  
Mario Luppi ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Hematological Disease ◽  
Drug Induced ◽  
Comprehensive Overview ◽  
Leukemic Clone ◽  
Immunosuppressive Microenvironment ◽  
Induced Apoptosis ◽  
Adult Leukemia

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries and is an example of hematological disease where cooperation between genetic defects and tumor microenvironmental interaction is involved in pathogenesis. CLL is a disease that is considered as “addicted to the host”; indeed, the crosstalk between leukemic cells and the tumor microenvironment is essential for leukemic clone maintenance supporting CLL cells’ survival, proliferation, and protection from drug-induced apoptosis. CLL cells are not innocent bystanders but actively model and manipulate the surrounding microenvironment to their own advantage. Besides the different players involved in this crosstalk, nurse-like cells (NLC) resemble features related to leukemia-associated macrophages with an important function in preserving CLL cell survival and supporting an immunosuppressive microenvironment. This review provides a comprehensive overview of the role played by NLC in creating a nurturing and permissive milieu for CLL cells, illustrating the therapeutic possibilities in order to specifically target and re-educate them.

scholarly journals Notch2 Increases the Resistance to Venetoclax-Induced Apoptosis in Chronic Lymphocytic Leukemia B Cells by Inducing Mcl-1

2022 ◽  
Vol 11 ◽  
Author(s):  
Stefania Fiorcari ◽  
Rossana Maffei ◽  
Claudio Giacinto Atene ◽  
Nicolò Mesini ◽  
Monica Maccaferri ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Acquired Resistance ◽  
Lymphocytic Leukemia ◽  
Drug Induced ◽  
Effective Response ◽  
Incurable Disease ◽  
Trisomy 12 ◽  
Leukemic Clone ◽  
Induced Apoptosis ◽  
Interferon Regulatory Factor 4

Chronic lymphocytic leukemia (CLL) has experienced a clinical revolution—thanks to the discovery of crucial pathogenic mechanisms. CLL is still an incurable disease due to intrinsic or acquired resistance of the leukemic clone. Venetoclax is a Bcl-2 inhibitor with a marked activity in CLL, but emerging patterns of resistance are being described. We hypothesize that intrinsic features of CLL cells may contribute to drive mechanisms of resistance to venetoclax. We analyzed the expression of Interferon Regulatory Factor 4 (IRF4), Notch2, and Mcl-1 in a cohort of CLL patients. We evaluated CLL cell viability after genetic and pharmaceutical modulation of Notch2 expression in patients harboring trisomy 12. We tested venetoclax in trisomy 12 CLL cells either silenced or not for Notch2 expression or in combination with an inhibitor of Mcl-1, AMG-176. Trisomy 12 CLL cells were characterized by low expression of IRF4 associated with high levels of Notch2 and Mcl-1. Notch2 and Mcl-1 expression determined protection of CLL cells from spontaneous and drug-induced apoptosis. Considering the involvement of Mcl-1 in venetoclax resistance, our data demonstrated a contribution of high levels of Notch2 and Mcl-1 in a reduced response to venetoclax in CLL cells carrying trisomy 12. Furthermore, reduction of Mcl-1 expression by silencing Notch2 or by treatment with AMG-176 was able to restore the response of CLL cells to venetoclax. The expression of Notch2 identifies a subset of CLL patients, mainly harboring trisomy 12, characterized by high levels of Mcl-1. This biological mechanism may compromise an effective response to venetoclax.

scholarly journals Induction of apoptotic cell death in chronic lymphocytic leukemia by 2- chloro-2'-deoxyadenosine and 9-beta-D-arabinosyl-2-fluoroadenine

Blood ◽  
1993 ◽  
Vol 81 (1) ◽  
pp. 143-150 ◽  
Author(s):  
LE Robertson ◽  
S Chubb ◽  
RE Meyn ◽  
M Story ◽  
R Ford ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Dna Fragmentation ◽  
Dna Cleavage ◽  
Light And Electron Microscopy ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Dna Integrity ◽  
Drug Induced ◽  
Prolonged Incubation

Abstract 2-Chloro-2′-deoxyadenosine (CldAdo) and 9-beta-D-arabinosyl-2- fluoroadenine (F-ara-A) have shown marked activity in the treatment of indolent lymphoid malignancies. Based on the susceptibility of various lymphocyte populations to apoptosis, we investigated whether CldAdo or F-ara-A would induce this process in lymphocytes from patients with chronic lymphocytic leukemia (CLL). In vitro exposure of leukemic lymphocytes to CldAdo or F-ara-A for 24 to 72 hours elicited features of apoptosis visible by light and electron microscopy. Analysis of DNA integrity showed DNA cleavage into nucleosomal-sized multimers. Using a quantitative assay, drug-induced DNA fragmentation was both time and dose dependent. Inhibition of active macromolecular synthesis did not prevent drug-induced fragmentation; however, both drug-induced and spontaneous DNA fragmentation were prevented by intracellular calcium chelation. In vitro culture with phorbol ester generally decreased drug- induced DNA cleavage. After prolonged incubation, CLL cells exhibited spontaneous cleavage; albeit, at significantly lower rates than drug- treated cells. Heterogeneity was observed for spontaneous and drug- induced DNA fragmentation and was significantly lower in B-leukemic cells obtained from patients with high-risk and refractory disease. We conclude that CldAdo and F-ara-A are potent inducers of apoptotic death in CLL and that this feature correlates with the disease status.

BMS-936564 (MDX1338): A Fully Human Anti-CXCR4 Antibody Induces Apoptosis in an in Vitro Model of Stromal – Leukemia Cell Interaction for Chronic Lymphocytic Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2887-2887
Author(s):  
Manoj Kumar Kashyap ◽  
Deepak Kumar ◽  
Harrison Jones Jones ◽  
Michael Y. Choi ◽  
Johanna Melo-Cardenas ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Stromal Cells ◽  
Leukemia Cell ◽  
Cell Interaction ◽  
Lymphocytic Leukemia ◽  
Leukemia Cells ◽  
Drug Induced ◽  
Induced Apoptosis ◽  
Cells Cultured

Abstract Abstract 2887 Chronic lymphocytic leukemia (CLL) remains incurable despite advances in the biology and treatment of this disease. Current data support the notion that resistance to therapy is promoted by a “protective” tumor microenvironment in which non-leukemia cells produce factors that enhance the resistance of CLL cells to spontaneous or drug-induced apoptosis. One such factor is the chemokine CXCL12, which interacts with its receptor CXCR4 on CLL cells to promote cancer cell survival. To examine the therapeutic potential of blocking CXCL12-CXCR4 interactions, we studied the effect of BMS-936564, a fully human IgG4 anti-CXCR4 antibody, using an in vitro co-culture model of human bone marrow derived stomal-NKter cells – leukemia cell interaction. Such stromal-NKter cells secrete CXCL12 and enhance the resistance of CLL cells to apoptosis in vitro. We observed that primary CLL cells co-cultured with stromal-NKter cells had significantly greater viability than CLL cells cultured alone (20–60% above baseline at 48 hours). Moreover, CLL cells co-cultured with stromal cells had enhanced resistance to drug-induced apoptosis. We found that BMS-936564 antibody at concentrations of 2–200nM could enhance the rate of apoptosis of CLL cells cultured alone or in the presence of stromal cells. CLL cells that expressed unmutated IgVH genes or ZAP-70 appeared equally susceptible to treatment with BMS-936564 as did CLL cells that lack these adverse prognostic markers, as did CLL cells that harbored deletions in 17p13.2 and that were resistant to chemotherapeutic agents, such a fludarabine monophosphate. BMS-936564 antibody inhibited CXCL12 mediated F-Actin polymerization in CLL cells at lower concentrations (20–200nM) compared to AMD-3100 (Mozobil), a small molecule CXCR4 inhibitor (50–150μM). In addition, AMD-3100 did not induce apoptosis in CLL cells (10–300μM). In summary, we observed that the anti-CXCR4 antibody BMS-936564 inhibited CXCL12 mediated activation of the CXCR4 receptor in CLL cells and induced apoptosis in leukemia cells. The pro-apoptotic activity of BMS-936564 was observed in cells cultured alone or together with stromal cells suggesting that this antibody had direct cytotoxic effect on leukemia cells and that it can overcome the protective tumor microenvironment. More over, the activity of BMS-936564 was independent of the presence of poor prognostic factors such as del(17p) suggesting that its mechanism of action is P53 independent. These findings show evidence that the CXCR4-CXCL12 pathway is a valid therapeutic target in CLL and provide additional biological rationale for ongoing clinical trials in CLL and other hematological malignancies using BMS-936564. Disclosures: Kuhne: Bristol-Myers Squibb: Employment. Sabbatini:Bristol-Myers Squibb: Employment. Cohen:Bristol-Myers Squibb: Employment. Shelat:Bristol-Myers Squibb: Employment. Cardarelli:Bristol-Myers Squibb: Employment. Kipps:Abbott: Consultancy, Research Funding.

Valproic Acid Induces Apoptosis in Chronic Lymphocytic Leukemia Cells through Activation of the Death Receptor Pathway and Potentiates TRAIL Response.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4949-4949
Author(s):  
Laurence Lagneaux ◽  
Nicolas Gillet ◽  
Alain Delforge ◽  
Marielle Dejeneffe ◽  
Basile Stamatopoulos ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Chronic Lymphocytic Leukemia ◽  
Mononuclear Cells ◽  
Single Agent ◽  
Death Receptor ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Potent Inducer ◽  
Mutational Status ◽  
Induced Apoptosis

Abstract Background: The anti-leukemic in vitro activity of valproic acid (VPA), a commonly used antiepileptic agent, was tested on lymphocytes derived from 40 patients with chronic lymphocytic leukemia (CLL) (Binet stage A=34, B=3, C=3). These patients had not been previously treated or remained untreated for the previous 6 months. Combined analysis of ZAP-70, CD38 and IgVH mutational status was performed for each patient. Methods: Mononuclear cells were incubated with VPA at 1, 5 and 10 mM for 24 hours. Cell viability was assessed by trypan blue exclusion assay, apoptosis by annexin V/propidium iodide(PI) labelling and PI staining after cell permeabilisation. Caspase activation was studied by flow cytometry analysis after cell treatment with selective caspase inhibitors. Results: Exposure of CLL cells to VPA resulted in dose-dependent cytotoxicity and apoptosis in all CLL patients tested. VPA-treatment induced apoptotic changes in CLL cells including phosphatidylserine (PS) externalisation and DNA fragmentation. The mean apoptotic rate was similar between IgVH mutated and unmutated patients or ZAP-70+/ZAP-70- cases. VPA induced apoptosis by the extrinsic pathway involving engagement of the caspase-8 dependent cascade. Although CLL cells are commonly resistant to death receptor-induced apoptosis, VPA increased significantly the sensitivity of leukemic cells to TRAIL (tumor necrosis factor α-related apoptosis-inducing ligand). In addition, VPA overcomed the prosurvival effects of bone marrow stromal cells. Conclusions: These data indicate that VPA, at the pharmacological concentration of 1 mM, is a potent inducer of apoptosis in CLL and should be further explored as a single agent. Also the combination of VPA and TRAIL may be a promising approach in the treatment of CLL.

The Non-Death Domain Containing TNFR Member HVEM Induces Apoptosis and Chemokine Production on B-Chronic Lymphocytic Leukemia Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4720-4720
Author(s):  
Daniel R. Olive ◽  
Christine Pasero ◽  
Bernadette Barbarat ◽  
Alem Truneh ◽  
Sylvaine Just ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Activation ◽  
Lymphocytic Leukemia ◽  
Death Domain ◽  
B Cell Activation ◽  
Chemokine Production ◽  
Cytokines And Chemokines ◽  
Induced Apoptosis ◽  
Adult Leukemia

Abstract B-cell chronic lymphocytic leukemia (B-CLL) is the most common adult leukemia and it still remains incurable. New therapies are required for this disease characterized by failure of mature lymphocytes to undergo apoptosis. Members of tumor necrosis factor receptors (TNFR) family play important roles in cell activation, proliferation, differentiation and apoptosis. We focused our study on HVEM (Herpes virus entry mediator), devoid of intracytoplasmic death domain, which is known to costimulate T- and B-cell activation, and its ligand LIGHT. Surprisingly, we found that LIGHT, as well as some anti-HVEM antibodies, induced apoptosis of B-CLL cells. This apoptosis was associated with activation of caspase-3, -8 and -9, decrease in mitochondrial membrane potential, and upregulation of the pro-apoptotic protein Bax. Importantly, the efficiency of HVEM-cell killing compared favorably with that of the pan-B cell therapeutic monoclonal antibody Rituximab. In addition, HVEM induced upregulation of various cytokines and chemokines, and a major increase in IL-8 secretion. Thus, HVEM stimulation induces apoptosis of B-CLL cells and could potentially also participate in the recruitment of immune effectors, and may therefore be useful for clinical treatment of this malignancy.

Involvement of BAFF and APRIL in the resistance to apoptosis of B-CLL through an autocrine pathway

Blood ◽  
2004 ◽  
Vol 103 (2) ◽  
pp. 679-688 ◽  
Author(s):  
Catherine Kern ◽  
Jean-François Cornuel ◽  
Christian Billard ◽  
Ruoping Tang ◽  
Danielle Rouillard ◽  
...  
Keyword(s):  
B Cell ◽  
B Lymphocytes ◽  
Cell Activation ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Soluble Form ◽  
B Cell Activation ◽  
Drug Induced ◽  
Flight Mass Spectrometry ◽  
Induced Apoptosis

Abstract Tumor necrosis factor (TNF) superfamily members BAFF, or B-cell activation factor of the TNF family, and APRIL, a proliferation-inducing ligand, are involved in normal B-cell survival and differentiation. They interact with 3 receptors: BAFF-R, specific to BAFF; and TACI and BCMA, which are shared by BAFF and APRIL. We tested the potential role of these proteins in B-cell chronic lymphocytic leukemia (B-CLL) resistance to apoptosis. TACI and BAFF-R mRNAs were found in leukemic B cells. BAFF and APRIL mRNAs and proteins were detected in B-CLL leukemic cells and normal blood or tonsil-derived B lymphocytes. Yet, in contrast to normal B lymphocytes, BAFF and APRIL were expressed at the membranes of leukemic cells. Adding soluble BAFF or APRIL protected B-CLL cells against spontaneous and drug-induced apoptosis and stimulated NF-κB activation. Conversely, adding soluble BCMA-Fc or anti-BAFF and anti-APRIL antibodies enhanced B-CLL apoptosis. Moreover, a soluble form of BAFF was detected using surface-enhanced laser desorption/ionization–time-of-flight mass spectrometry (SELDI-TOF MS) in the sera of B-CLL patients but not of healthy donors. Taken together, our results indicate that B-CLL cells can be rescued from apoptosis through an autocrine process involving BAFF, APRIL, and their receptors. Inhibiting BAFF and APRIL pathways may be of therapeutic value for B-CLL treatment.

Sildenafil and vardenafil, types 5 and 6 phosphodiesterase inhibitors, induce caspase-dependent apoptosis of B-chronic lymphocytic leukemia cells

Blood ◽  
2003 ◽  
Vol 101 (1) ◽  
pp. 265-269 ◽  
Author(s):  
Marika Sarfati ◽  
Véronique Mateo ◽  
Sylvie Baudet ◽  
Manuel Rubio ◽  
Christine Fernandez ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phosphodiesterase Inhibitors ◽  
Inhibitory Effect ◽  
Lymphocytic Leukemia ◽  
Interleukin 4 ◽  
Drug Induced ◽  
Pde Inhibitors ◽  
Induced Apoptosis

Abstract Type 4 phosphodiesterase (PDE4) inhibitors reportedly induce apoptosis in chronic lymphocytic leukemia (CLL) cells. Following clinical improvement of one previously untreated CLL patient with sildenafil therapy, we evaluated the in vitro induction of apoptosis in CLL cells by 4 PDE5/6 inhibitors, including sildenafil, vardenafil, zaprinast, and methoxyquinazoline (MQZ). After 24 hours of culture, the various PDE inhibitors differed in their ability to induce apoptosis, with zaprinast displaying no killing effect. Normal B cells isolated from control donors were totally resistant to PDE-induced apoptosis. Vardenafil was 3 and 30 times more potent an inducer of apoptosis than sildenafil and MQZ, respectively. Both vardenafil and sildenafil failed to elevate adenosine 3′5′ cyclic monophosphate (cAMP) levels, largely excluding an inhibitory effect on cAMP-PDE3, -PDE4, and -PDE7. Vardenafil- or sildenafil-treated B-CLL cells displayed up to 30% intracellular active caspase 3. Drug-induced apoptosis was inhibited by the caspase inhibitor z-VAD.fmk, prevented by interleukin-4 (IL-4), and significantly reduced by stromal-derived factor1-α (SDF-1α). We conclude that vardenafil and sildenafil induce caspase-dependent apoptosis of B-CLL cells in vitro and thus might be considered in the treatment of CLL patients. However, further in vivo investigations should be warranted.

Spontaneous and drug-induced apoptosis is mediated by conformational changes of Bax and Bak in B-cell chronic lymphocytic leukemia

Blood ◽  
2002 ◽  
Vol 100 (5) ◽  
pp. 1810-1816 ◽  
Author(s):  
Beatriz Bellosillo ◽  
Neus Villamor ◽  
Armando López-Guillermo ◽  
Silvia Marcé ◽  
Francesc Bosch ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Conformational Changes ◽  
Intracellular Localization ◽  
Reactive Oxygen Species Generation ◽  
Lymphocytic Leukemia ◽  
Drug Induced ◽  
Mitochondrial Potential ◽  
Induced Apoptosis ◽  
Cell Chronic Lymphocytic Leukemia

The role of Bax and Bak, 2 proapoptotic proteins of the Bcl-2 family, was analyzed in primary B-cell chronic lymphocytic leukemia (CLL) cells following in vitro treatment with fludarabine, dexamethasone, or the combination of fludarabine with cyclophosphamide and mitoxantrone (FCM). A strong correlation was found between the number of apoptotic cells and the percentage of cells stained with antibodies recognizing conformational changes of Bax (n = 33;r = 0.836; P < .001) or Bak (n = 10;r = 0.948; P < .001). Preincubation of CLL cells with Z-VAD.fmk (N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone), a broad caspase inhibitor, abolished caspase-3 activation, exposure of phosphatidylserine residues, and reactive oxygen species generation; partially reversed the loss of transmembrane mitochondrial potential (ΔΨm); but did not affect Bax or Bak conformational changes. These results indicate that the conformational changes of Bax and Bak occur upstream of caspase activation or are caspase independent. Following drug-induced apoptosis, Bax integrates into mitochondria, as demonstrated by fluorescence microscopy and Western blot, without changes in the total amount of Bax or Bak protein. Fludarabine and FCM induce p53 stabilization, but do not seem to be essential in inducing Bax and Bak conformational changes, as they are also observed in dexamethasone-treated CLL cells. These results demonstrate that, in CLL cells, the change in the intracellular localization of Bax from cytosol to mitochondria and the conformational changes of Bax and Bak are among the early steps in the induction of cell death.

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