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.

Inhibition of Bortezomib-Induced Apoptosis in Chronic Lymphocytic Leukemia by Red Blood Cell Uptake.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5027-5027
Author(s):  
Luise M.C. Wheat ◽  
Susan L. Kohlhaas ◽  
Johan Monbaliu ◽  
Roland De Coster ◽  
Aneela Majid ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Whole Blood ◽  
Mononuclear Cells ◽  
Lymphocytic Leukemia ◽  
Cell Uptake ◽  
Reversible Inhibitor ◽  
Apoptotic Pathway ◽  
Mutational Status ◽  
Induced Apoptosis

Abstract Bortezomib (PS-341/Velcade™) is a reversible inhibitor of the proteasome that has shown promising activity in clinical trials in several malignancies including multiple myeloma, mantle cell lymphoma and follicular lymphoma, including those with refractory disease. However, results have been less encouraging in chronic lymphocytic leukemia (CLL) and we have, therefore, sought to determine the barriers to effective therapy with bortezomib in this disease. Patients with CLL were eligible but were required to have received no therapy in the six months prior to the study. In a panel of 26 patients with CLL, both purified mononuclear cells and whole blood were tested for their apoptotic response to bortezomib (1–100 nM) up to 24 h by flow cytometry and western blotting. In all cases, purified CLL cells were sensitive to bortezomib-induced apoptosis in a concentration and time-dependent fashion, irrespective of stage of disease, resistance to prior therapy, IGHV mutational status or the presence of TP53 mutations. Apoptosis was induced at low (>10 nM) nanomolar concentrations of bortezomib by activation of the intrinsic apoptotic pathway. Bortezomib-induced apoptosis correlated with levels of ubiquitination, Bax activation, and caspase cleavage. Apoptosis of CLL cells was obtained at drug levels readily obtained in vivo using currently-used dosing protocols. However, in vitro, it was necessary to maintain these concentrations for 16–24 hours to obtain maximal apoptosis. Apoptosis measured in a whole blood apoptosis assay was markedly less than in isolated lymphocytes at comparable time points and concentrations. Activity of bortezomib in purified cells was not diminished by addition of exogenous plasma but was abrogated by addition of autologous red blood cells (RBC), suggesting preferential active uptake of the drug by these cells. These data were confirmed in animal models showing preferential distribution of bortezomib to the RBC fraction. RBC uptake may therefore account for the low serum levels of bortezomib attained in vivo during terminal half-life and thus the lack of activity against cells in the peripheral blood. Together with pharmacokinetic and in vivo data, these studies suggest that different dosing schedules of bortezomib other than bolus injections may be more effective in patients with CLL.

scholarly journals Association of Bax Expression and Bcl2/Bax Ratio with Clinical and Molecular Prognostic Markers in Chronic Lymphocytic Leukemia

2016 ◽  
Vol 35 (2) ◽  
pp. 150-157 ◽  
Author(s):  
Ksenija Vucicevic ◽  
Vladimir Jakovljevic ◽  
Natasa Colovic ◽  
Natasa Tosic ◽  
Tatjana Kostic ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
Mononuclear Cells ◽  
Prognostic Markers ◽  
Statistical Significance ◽  
Genetic Alterations ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Aberrant Expression ◽  
Mutational Status

Summary Background: In chronic lymphocytic leukemia (CLL), in vivo apoptotic resistance of malignant B lymphocytes results, in part, from the intrinsic defects of their apoptotic machinery. These include genetic alterations and aberrant expression of many apoptosis regulators, among which the Bcl2 family members play a central role. Aim: The aim of this study was to investigate the association of pro-apoptotic Bax gene expression and Bcl2/Bax ratio with the clinical features of CLL patients as well as with molecular prognostic markers, namely the mutational status of rearranged immunoglobulin heavy variable (IGHV) genes and lipoprotein lipase (LPL) gene expression. Methods: We analyzed the expression of Bax mRNA and Bcl2/Bax mRNA ratio in the peripheral blood mononuclear cells of 58 unselected CLL patients and 10 healthy controls by the quantitative reverse-transcriptase polymerase chain reaction. Results: We detected significant Bax gene overexpression in CLL samples compared to non-leukemic samples (p=0.003), as well as an elevated Bcl2/Bax ratio (p=<0.001). Regarding the association with prognostic markers, the Bcl2/Bax ratio showed a negative correlation to lymphocyte doubling time (r=−0.307; p=0.0451), while high-level Bax expression was associated with LPL-positive status (p=0.035). Both the expression of Bax and Bcl2/Bax ratio were higher in patients with unmutated vs. mutated IGHV rearrangements, but this difference did not reach statistical significance. Conclusions: Our results suggest that dysregulated expression of Bcl2 and Bax, which leads to a high Bcl2/Bax ratio in leukemic cells, contributes to the pathogenesis and clinical course of CLL.

The natural product honokiol induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells

Blood ◽  
2005 ◽  
Vol 106 (2) ◽  
pp. 690-697 ◽  
Author(s):  
Traci E. Battle ◽  
Jack Arbiser ◽  
David A. Frank
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Natural Product ◽  
Mononuclear Cells ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Interleukin 4 ◽  
Response To Treatment ◽  
Potent Inducer ◽  
Cell Chronic Lymphocytic Leukemia

Abstract B-cell chronic lymphocytic leukemia (B-CLL) remains an incurable disease that requires innovative new approaches to improve therapeutic outcome. Honokiol is a natural product known to possess potent antineoplastic and antiangiogenic properties. We examined whether honokiol can overcome apoptotic resistance in primary tumor cells derived from B-CLL patients. Honokiol induced caspase-dependent cell death in all of the B-CLL cells examined and was more toxic toward B-CLL cells than to normal mononuclear cells, suggesting greater susceptibility of the malignant cells. Honokiol-induced apoptosis was characterized by the activation of caspase-3, -8, and -9 and cleavage of poly(adenosine diphosphate-ribose) polymerase (PARP). Exposure of B-CLL cells to honokiol resulted in up-regulation of Bcl2-associated protein (Bax) and down-regulation of the expression of the key survival protein myeloid-cell leukemia sequence 1 (Mcl-1), which is associated with response to treatment in B-CLL patients. In addition, B-CLL cells pretreated with interleukin-4 (IL-4), a cytokine known to support B-CLL survival, underwent apoptosis when subsequently incubated with honokiol, indicating that honokiol could also overcome the prosurvival effects of IL-4. Furthermore, honokiol enhanced cytotoxicity induced by fludarabine, cladribine, or chlorambucil. These data indicate that honokiol is a potent inducer of apoptosis in B-CLL cells and should be examined for further clinical application either as a single agent or in combination with other anticancer agents. (Blood. 2005;106:690-697)

scholarly journals High CXCR3 on Leukemic Cells Distinguishes IgHVmut from IgHVunmut in Chronic Lymphocytic Leukemia: Evidence from CD5high and CD5low Clones

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Gayane Manukyan ◽  
Tomas Papajik ◽  
Zuzana Mikulkova ◽  
Renata Urbanova ◽  
Veronika Smotkova Kraiczova ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Chemokine Receptors ◽  
Prognostic Value ◽  
Surface Antigens ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Neoplastic Cells ◽  
Cxcr3 Expression ◽  
Mutational Status ◽  
Proliferative Pool

Despite the shared pattern of surface antigens, neoplastic cells in chronic lymphocytic leukemia (CLL) are highly heterogeneous in CD5 expression, a marker linked to a proliferative pool of neoplastic cells. To further characterize CD5high and CD5low neoplastic cells, we assessed the chemokine receptors (CCR5, CCR7, CCR10, CXCR3, CXCR4, CXCR5) and adhesion molecules (CD54, CD62L, CD49d) on the CD5high and CD5low subpopulations, defined by CD5/CD19 coexpression, in peripheral blood of CLL patients (n=60) subgrouped according to the IgHV mutational status (IgHVmut, n=24; IgHVunmut, n=36). CD5high subpopulation showed a high percentage of CXCR3 (P<0.001), CCR10 (P=0.001), and CD62L (P=0.031) and high levels of CXCR5 (P=0.005), CCR7 (P=0.013) compared to CD5low cells expressing high CXCR4 (P<0.001). Comparing IgHVmut and IgHVunmut patients, high levels of CXCR3 on CD5high and CD5low subpopulations were detected in the IgHVmut patients, with better discrimination in CD5low subpopulation. Levels of CXCR3 on CD5low subpopulation were associated with time to the next treatment, thus further confirming its prognostic value. Taken together, our analysis revealed higher CXCR3 expression on both CD5high and CD5low neoplastic cells in IgHVmut with a better prognosis compared to IgHVunmut patients. Contribution of CXCR3 to CLL pathophysiology and its suitability for prognostication and therapeutic exploitation deserves future investigations.

The Receptor for Hyaluronic Acid Mediated Motility (RHAMM/CD168) Is a Potential Target for Immunotherapy of Patients with B-Cell Chronic Lymphocytic Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 53-53 ◽  
Author(s):  
Krzysztof Giannopoulos ◽  
Iwona Hus ◽  
Li Li ◽  
Agnieszka Bojarska-Junak ◽  
Jochen Greiner ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Mononuclear Cells ◽  
Tissue Expression ◽  
T Cell Response ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Peripheral Blood Mononuclear ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Definition of appropriate target antigens might open new avenues to antigen targeted immunotherapies for patients with B-cell chronic lymphocytic leukemia (B-CLL). We screened the mRNA expression of tumor associated antigens (TAAs), from the literature (fibromodulin, survivin, OFA-iLRP, BAGE, G250, MAGE1, PRAME, proteinase, Syntaxin, hTERT, WT-1), and TAAs defined earlier by serological analysis of cDNA expression libraries from leukemic cells (PINCH, HSJ2, MAZ, MPP11, RHAMM/CD168, NY-Ren60). Peripheral blood mononuclear cells from 43 B-CLL patients and 20 healthy volunteers (HVs) were examined by conventional and quantitative RT-PCR. mRNA of RHAMM/CD168, fibromodulin, syntaxin and NY-Ren60 was expressed in 55–90%, mRNA of HSJ2, MAZ and OFA-iLRP in 90–100% of the patients. No expression of WT-1, h-TERT, BAGE, G250, MAGE1 and survivin was observed. Low (2–20%) expression frequencies of MPP11, PINCH, PRAME and proteinase were detected. RHAMM/CD168, fibromodulin, PRAME and MPP11 showed expression in B-CLL patients, but not in HVs. Because of the exquisite tissue expression of RHAMM/CD168 and its high expression frequency in B-CLL patients even in early stages of disease, mixed lymphocyte peptide culture (MLPC), enzyme-linked immunosorbent spot (ELISPOT) and flow cytometry were performed for antigen specific T cells. In MLPC, RHAMM specific responses by CD8+HLA-A2/R3tetramer+CCR7-CD45RAhigh effector T cells were detected. Moreover, we observed an enhanced RHAMM/CD168 specific CD8+ T cell response after vaccination in one from four HLA-A2 positive B-CLL patients vaccinated with tumor cell lysate pulsed dendritic cells. Therefore, RHAMM/CD168 is an interesting candidate antigen for future immunotherapies in both ZAP-70 (+) and ZAP-70 (−) B-CLL patients.

RHAMM/CD168 Is a Novel Leukemia Associated Antigen with Prognostic Value for Patients with B-Cell Chronic Lymphocytic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2773-2773
Author(s):  
Krzysztof Giannopoulos ◽  
Alexander Krober ◽  
Anna Dmoszynska ◽  
Jacek Rolinski ◽  
Hartmut Dohner ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Surrogate Marker ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Free Survival ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Background and Aims: Differential expression of molecules in patients with B-cell chronic lymphocytic leukemia (B-CLL) might define suitable targets for T cell based vaccines and/or antibody approaches. Methods: We assessed the mRNA expression of the tumor associated antigen (TAA) RHAMM/CD168 defined earlier by serological analysis of cDNA expression libraries (SEREX) from leukemic cells. Results: Peripheral blood mononuclear cells from 40 B-CLL patients and 20 healthy volunteers (HVs) were examined by quantitative RT-PCR. A leukemia-restricted expression of the antigen RHAMM/CD168 was observed in 39/40 B-CLL patients in contrast to the absence of its expression in HVs. To evaluate the immunogenicity of this novel LAA, mixed lymphocyte peptide cultures (MLPCs), followed by enzyme-linked immunosorbent spot (ELISPOT) and flow cytometry assays were performed to detect antigen-specific CD8+ T cells. RHAMM/CD168 specific responses by CD8+ HLA-A2/R3tetramer+CCR7-CD45RAhigh effector T cells were detected. As these CD8+ T cells contribute to the elimination of RHAMM+ CLL cells, we questioned whether expression of the antigen would be associated with a better survival. RHAMM/CD168 expression revealed to be higher in patients with unmutated IgVH status. RHAMM normalized against the housekeeping gene TATA binding protein (TBP), i.e. the RHAMM/TBP ratio was defined as a prognostic surrogate marker for B-CLL. B-CLL patients with a RHAMM/TBP ratio > 1.67 showed a significantly shorter treatment free survival (TFS) (Fig. 1). A tendency towards higher RHAMM/TBP expression ratios was observed in B-CLL cases with del11q. Conclusion: RHAMM/CD168 is a novel LAA in B-CLL patients, an antigen correlating with the clinical course of the disease. Therefore, we consider RHAMM/CD168 an interesting target for immunotherapy in early stage B-CLL patients, especially with worse prognosis (IgVH unmutated). Figure 1. Treatment-free-survival (TFS) according to RHAMM/TBP ratio Figure 1. Treatment-free-survival (TFS) according to RHAMM/TBP ratio

Identification of Therapeutic Targets for Chronic Lymphocytic Leukemia in the Relapsed and Refractory Setting.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2068-2068
Author(s):  
Daphne Friedman ◽  
J. Brice Weinberg ◽  
Karen M Bond ◽  
Alicia D Volkheimer ◽  
Youwei Chen ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Alkylating Agents ◽  
Single Agent ◽  
Response To Therapy ◽  
Lymphocytic Leukemia ◽  
Gene Set Enrichment Analysis ◽  
Leukemic Cells ◽  
Nucleic Acid Metabolism ◽  
Beta Catenin ◽  
Gene Probes

Abstract Cancer patients with relapsed or refractory disease often require repeated sequential therapies. This approach may induce resistance to conventional chemotherapy and may drive selection for cancer cells that rely on pro-survival signals. Such changes in the molecular constitution of the cancer at the time of each treatment have implications in the drive to personalize cancer therapy. We investigated this phenomenon in Chronic Lymphocytic Leukemia (CLL), a common incurable leukemia that often requires multiple therapeutic regimens over time. Using stored purified CLL cells and serum from a cohort of patients followed at the Duke University and Durham VA Medical Centers, we identified twenty pairs of samples collected from patients prior to and after therapy, and eight pairs of samples collected from patients where no therapy was administered. There were no significant differences in time between paired sample collection or prognostic factors such as Rai stage, cytogenetic aberrations, or IgVH mutational, CD38 or ZAP70 status between these two groups of patients. In the group of sample pairs collected before therapy and upon progression, there was a lower white blood cell count in the second sample (p = 0.04, Wilcoxon signed rank), but no significant change in percentage of cells expressing CD38 or ZAP70 by flow cytometry. The therapies given to patients included alkylating agents alone (14/20), R-CHOP (1/20), Fludarabine-containing regimens (4/20), and single agent-Rituximab (1/20). We profiled gene expression of malignant lymphocytes using Affymetrix U133 Plus 2.0 GeneChips and measured serum levels of circulating cytokines and cytokine receptors from these paired samples in order to identify consistent changes that occurred with therapy. Using supervised analyses of the genomic data, we identified 207 gene probes that were differentially expressed in the twenty pairs of samples where treatment was given. Importantly, these gene probes were not altered in the pairs of samples where no therapy was administered. We next analyzed genomic pathways using gene ontology, Gene Set Enrichment Analysis, and genomic signatures of oncogenic deregulation. We found that after therapy, there is upregulation of genes involved in cellular and nucleic acid metabolism, cell interaction, and signal transduction, with the phosphoinositol 3-kinase and beta-catenin pathways specifically affected. In addition, upregulation of the myc pathway prior to therapy was associated with a shorter duration of response to therapy. Upon studying serum cytokine and cytokine receptor levels in these patients, we found significantly different levels of EGF, EGFR, G-CSF, and RAGE before therapy compared to those on progression of disease. Higher levels of pre-treatment serum cytokines such as GM-CSF and IL-6 were associated with shorter durations of response to therapy. The results of these experiments demonstrate that there are consistent intra- and extra-cellular signals in CLL that are altered after heterogeneous therapies. These signals could be responsible for maintaining leukemic cells despite therapy, and thus are potential targets for future therapies, specifically in the relapsed and refractory patient.

scholarly journals Homoharringtonine reduced Mcl-1 expression and induced apoptosis in chronic lymphocytic leukemia

Blood ◽  
2011 ◽  
Vol 117 (1) ◽  
pp. 156-164 ◽  
Author(s):  
Rong Chen ◽  
Lei Guo ◽  
Yuling Chen ◽  
Yingjun Jiang ◽  
William G. Wierda ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Stromal Cells ◽  
Single Agent ◽  
Myeloid Cell ◽  
Lymphocytic Leukemia ◽  
Caspase Cleavage ◽  
Translation Inhibition ◽  
Transcription Inhibitor ◽  
Induced Apoptosis ◽  
Elongation Phase

Abstract Homoharringtonine (HHT) is a plant alkaloid that inhibits the elongation phase of translation that is currently in clinical trials. Because the intrinsically short-lived antiapoptotic protein myeloid cell leukemia-1 (Mcl-1) has been reported to support the survival of chronic lymphocytic leukemia (CLL) cells, we hypothesized that inhibition of protein synthesis by HHT would decrease Mcl-1 expression and induce apoptosis in CLL. In primary CLL cells, HHT induced significant apoptosis independent of the prognostic characteristics of the patients. This was associated with inhibition of translation and decreased Mcl-1 levels in CLL cells. Mcl-1 reduction was evident as early as 2 hours and continued to decrease in the next 6-8 hours, whereas cell death started in 2 hours and continued to increase for 24 hours. Reduction of the Mcl-1 level was due to translation inhibition and proteasome degradation rather than to transcription inhibition or caspase cleavage. HHT and the transcription inhibitor SNS-032 induced synergistic cell killing. Although stromal cells induced Mcl-1 expression and protected CLL cells from the toxicity of fludarabine, this induction was reversed by HHT, which overcame stromal cell–mediated protection. Thus, these results provide a rationale for clinical development of HHT in CLL as single agent or in combinations.

Dexamethasone Induces Apoptosis “Ex Vivo” in Chronic Lymphocytic Leukemia Cells with Either Unmutated IgVH Genes or High ZAP-70 Expression.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2945-2945
Author(s):  
Ana Muntanola ◽  
Marta Crespo ◽  
Eva Gine ◽  
Neus Villamor ◽  
Emili Montserrat ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Cell Viability ◽  
Ex Vivo ◽  
Lymphocytic Leukemia ◽  
Dependent Manner ◽  
Prognostic Features ◽  
Mutational Status ◽  
Cell Mortality ◽  
Igvh Mutational Status ◽  
Induced Apoptosis

Abstract Patients with chronic lymphocytic leukemia (CLL) and unmutated IgVH genes or high ZAP-70 expression have poorer prognosis than those with mutated IgVH genes or low ZAP-70 levels. This is in part related to the resistance of unmutated and ZAP-70 positive cases to treatment agents that induce apoptosis in a p53-dependent manner. It has been suggested that corticosteroids are active in CLL through p53-independent pathways. The aim of this study was to analyze the “ex vivo” response to dexamethasone in CLL cells according to the IgVH mutational status and ZAP-70 expression. Frozen lymphocytes from 60 patients with CLL were analyzed for ZAP-70 expression and IgVH mutational status (n=44). Cells were cultured and treated using fludarabine (5μgr/ml), mitoxantrone (0.5μgr/ml), FCM (fludarabine 1μgr/ml, maphosphamide 1μgr/ml and mitoxantrone 0.5 μgr/ml), and dexamethasone (5.2 μg/mL). Cell viability and apoptosis were determined by annexinV/PI staining and FACscan analysis at three different time points and conditions (0h and 24h without treatment, and 24h with treatment). The expression of glucocorticoid receptor (GR) isoforms alpha, beta and gamma was analyzed by Quantitative RT-PCR in 20 cases. Dexamethasone-induced apoptosis was significantly higher in patients with unmutated IgVH and/or high ZAP-70 expression (≥20%) than in those with mutated IgVH and/or low ZAP-70 expression (median cell viability 65% vs. 81%, respectively; p&lt;0.001). In contrast, mitoxantrone induced higher cell toxicity in patients with IgVH mutations or low ZAP-70 expression (p=0.009). No differences in cell viability were found according to ZAP-70 expression or IgVH mutational status after “ex vivo” treatment with fludarabine or FCM (p=0.649 and p=0.055, respectively). Expression of different GR isoforms was similar in corticosteroid-responders and non-responders. In conclusion, in this study CLL cells with unmutated IgVH genes or high ZAP-70 expression showed a higher cell mortality after “ex vivo” exposure to dexamethasone than those with mutated IgVH genes or low ZAP-70 expression, with no relationship with the expression of the different GR isoforms. These data give conceptual support to trials aimed at determining the role of dexamethasone in the treatment of patients with CLL and poor prognostic features or resistant to fludarabine. Figure Figure

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