Disruption of the eIF4F translation initiation complex as a determinant of diffuse large B-cell lymphoma responsiveness to enzastaurin (LY317615.HCl) and its primary metabolite (LY326020).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8082-8082
Author(s):  
Jeremy Richard Graff ◽  
Ann M McNulty ◽  
Chad A Dumstorf ◽  
Stephen H Parsons ◽  
Bruce W Konicek ◽  
...  
Keyword(s):  
B Cell ◽  
Intracellular Signaling ◽  
B Cell Lymphoma ◽  
Time Dependent ◽  
Dependent Manner ◽  
Primary Metabolite ◽  
Tor Pathway ◽  
Gene Expression Analyses ◽  
Apoptotic Effects ◽  
First Time

8082 Background: Enzastaurin (enza) is in ph 3 registration trials for DLBCL patients at high risk of relapse following R-CHOP therapy. In a phase 2 DLBCL study, 4 of 55 treated patients were progression- free after prolonged, continuous oral enza therapy with 3 of these 4 confirmed as complete responders (Robertson et al., JCO, 2007). The molecular mechanism for this differential response is unclear. Methods: In clinical trials, Enza yields 2-4 µM total circulating drug, comprised of ~50% enza, ~50% primary metabolite, LY326020. We therefore evaluated the sensitivity of a DLBCL cell panel representing both Activated B Cell (ABC) and Germinal Center (GC) subtypes to enza and LY326020. Gene expression analyses, western blotting to explore intracellular signaling and mRNA cap analogue co-capture assays were used to identify the critical effectors of drug sensitivity. Results: For the first time, we show the profound biological activity of LY326020, the primary metabolite that accounts for ~ 50% of circulating drug in patients. Like Enza, though more potently, LY326020 inhibits PKC and PI3K-AKT-TOR pathway signaling and robustly induces apoptosis in both ABC and GC DLBCL cells. In both sensitive and resistant cells, enza and LY326020 reduced phosphorylation of numerous proteins in the PI3K-AKT-TOR pathway (e.g. pGSK3βser9) in a dose and time-dependent manner. However, only sensitive DLBCL cells showed reduced 4EBP1ser65 phosphorylation. Accordingly, we show a dose and time-dependent increase in 4EBP1: eIF4E binding. This increase is most pronounced by LY326020. Moreover, cells selected for resistance to enza show reduced 4EBP1 expression and cells lacking 4EBP1 are insensitive to the pro-apoptotic effects of enza and LY326020. Conclusions: These data demonstrate that sensitivity of DLBCL to both enza and LY326020 is critically dependent upon 4EBP1 modulation and subsequent disruption of the eIF4F translation complex. Moreover, these data are the first to show the potent biologic activity of LY326020, the primary metabolite of enza that accounts for ~50% of total circulating drug in patients and in preclinical models.

Targeting Syk (spleen tyrosine kinase) Inhibits the Proliferation, Migration and Viability of Multiple Myeloma Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4071-4071
Author(s):  
Ruth-Miriam Körber ◽  
Stefanie AE Held ◽  
Solveig Daecke ◽  
Marie von Lilienfeld-Toal ◽  
Anita Bringmann ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Map Kinase ◽  
Cell Lines ◽  
Intracellular Signaling ◽  
Conflicts Of Interest ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Dependent Manner

Abstract Abstract 4071 Introduction: Multiple myeloma (MM) is a malignant plasma cell disorder characterized by clonal expansion of single plasma cells in the bone marrow. Despite high-dose melphalan therapy with autologous stem cell transplantation (ASCT) and the introduction of active drugs like bortezomib or lenalidomide that have been associated with improved survival MM is still incurable. Thus, the identification of novel molecular targets and additional treatment options are warranted. In B-cell malignancies such as chronic lymphocytic leukaemia (CLL) or diffuse large B cell lymphoma, the inhibition of the tyrosine kinase Syk gave promising preclinical and first clinical results.In our study, we analyzed the potential of Syk as a target in MM. Methods: The MM cell lines AMO-1, U266, MMS-1 and RPMI8226 and primary MM cells were treated with the Syk-inhibitors BAY61-3606 or piceatannol and proliferation, migration and apoptosis induction were analyzed. Effects on involved intracellular signaling cascades were determined by Western blotting. Results: Incubation of MM cell lines with Syk-inhibitors resulted in a reduced proliferation and and SDF-1 induced migration, that was accompanied by a concentration dependent inhibition of the MAP kinase signaling characterized by reduced phosphorylation of ERK an p38 molecules. Furthermore, the nuclear localized expression of the NF-kB members RelA and RelB was inhibited in treated cells. In addition, Syk inhibition induced apoptosis in MM cell lines and primary MM cells in a dose-dependent manner as demonstrated by flow cytometry, caspase-3 activity and PARP-1 cleavage. While there was no effect on the expression of xIAP, survivin or MCL-1, Syk inhibition reduced the expression of pro-apoptotic Bcl-2 and Bcl-xl molecules and increased the release of cytochrome c, indicating that the apoptotic cell death is mediated via the internal mitochondrial pathway. Combination of piceatannol with lenalidomide and orally bioavailable dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235but not with bortezomib or dexamethasone enhanced the cytotoxic effects of the compound. In line with the results from previous experiments the addition of MAPK inhibitors PD98059, SP600125, U0126, SB202190 and SB203580 to piceatannol further increased the efficacy of Syk inhibition. Conclusions: Our results show that Syk inhibition might represent a promissing new treatment option in MM with an increased efficacy when combined with lenalidomide or MAP kinase inhibitors. Disclosures: No relevant conflicts of interest to declare.

Intracellular nickel accumulation induces apoptosis and cell cycle arrest in human astrocytic cells

Metallomics ◽  
2020 ◽  
Author(s):  
Ruedeemars Yubolphan ◽  
Suttinee Phuagkhaopong ◽  
Kant Sangpairoj ◽  
Nathawut Sibmooh ◽  
Christopher Power ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Electronic Cigarettes ◽  
Neuronal Cell ◽  
B Cell Lymphoma ◽  
Cyclin B1 ◽  
Time Dependent ◽  
Dependent Manner ◽  
Astrocytoma Cells ◽  
Human Astrocytes ◽  
Nickel Exposure

Abstract Nickel, a heavy metal found in electronic wastes and fume from electronic cigarettes, induces neuronal cell death and is associated with neurocognitive impairment. Astrocytes are the first line of defense against nickel after entering the brain; however, the effects of nickel on astrocytes remain unknown. Herein, we investigated the effect of nickel exposure on cell survival and proliferation and the underlying mechanisms in U-87 MG human astrocytoma cells and primary human astrocytes. Intracellular nickel levels were elevated in U-87 MG cells in both a dose- and time-dependent manner after exposure to nickel chloride. The median toxic concentrations of nickel in astrocytoma cells and primary human astrocytes were 600.60 μM and > 1,000 μM at 48 h post-exposure, respectively. Nickel exposure triggered apoptosis in concomitant with the decreased expression of anti-apoptotic B-cell lymphoma protein (Bcl-2), and increased caspase-3/7 activity. Nickel induced reactive oxygen species formation. Additionally, nickel suppressed astrocyte proliferation in a dose- and time-dependent manner by delaying G2 to M phase transition through the upregulation of cyclin B1 and p27 protein expression. These results indicate that nickel-induced cytotoxicity of astrocytes is mediated by the activation of apoptotic pathway and disruption of cell cycle regulation.

scholarly journals MiR-28-5p mediates the anti-proliferative and pro-apoptotic effects of curcumin on human diffuse large B-cell lymphoma cells

2020 ◽  
Vol 48 (7) ◽  
pp. 030006052094379
Author(s):  
Tian Kang ◽  
Wei-Li Sun ◽  
Xiao-Fei Lu ◽  
Xin-Liang Wang ◽  
Lian Jiang
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Luciferase Reporter Assay ◽  
Luciferase Reporter ◽  
Reporter Assay ◽  
Large B Cell Lymphoma ◽  
Apoptotic Effects ◽  
Large B Cell ◽  
Dual Luciferase Reporter Assay

Objective To investigate the anti-proliferative and pro-apoptotic effects of curcumin on diffuse large B-cell lymphoma (DLBCL) cells and explore the mechanism. Methods OCI-LY7 cells were treated with curcumin (2.5, 5, 10, 20, and 40 μM) for 24, 48, or 72 hours. Cell viability and apoptosis were determined using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyl tetrazolium bromide assay and TdT-mediated dUTP nick-end labeling staining, respectively. MiR-28-5p expression was detected via qRT-PCR. The binding site of miR-28-5p was predicted using online databases and verified using the dual-luciferase reporter assay. MiR-28-5p overexpression and inhibition were achieved via transfection with an miR-28-5p mimic and inhibitor, respectively. Results Curcumin decreased the viability of OCI-LY7 cells in a concentration- and time-dependent manner, and these effects were attenuated by miR-28-5p inhibition. MiR-28-5p expression was upregulated by curcumin. Curcumin increased the numbers of apoptotic cells and upregulated cleaved caspase-3 expression, and these effects were attenuated by miR-28-5p inhibition. The dual-luciferase reporter assay confirmed that miR-28-5p directly targets the 3′-untranslated region of BECN1. Curcumin downregulated BECN1 and microtubule-associated protein 1 light chain 3 beta-II/I expression and upregulated p62 expression. Conclusions Our results described the curcumin exerted anti-proliferative and pro-apoptotic effects on OCI-LY7 cells through a mechanism potentially involving miR-28-5p.

scholarly journals IVIg modulates BCR signaling through CD22 and promotes apoptosis in mature human B lymphocytes

Blood ◽  
2010 ◽  
Vol 116 (10) ◽  
pp. 1698-1704 ◽  
Author(s):  
Jean-François Séïté ◽  
Divi Cornec ◽  
Yves Renaudineau ◽  
Pierre Youinou ◽  
Rizgar A. Mageed ◽  
...  
Keyword(s):  
B Cell ◽  
B Lymphocytes ◽  
B Lymphocyte ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Time Dependent ◽  
G1 Phase ◽  
Dependent Manner ◽  
Bcr Signaling ◽  
Sustained Activation

Abstract Among various mechanisms for interactions with B cells, intravenous immunoglobulin (IVIg) may operate through the insertion of its Fc part into the Fc-γ receptor, or the binding of its sialic acid (SA)–bearing glycans to the negatively regulating CD22 lectin. It appeared that IVIg reduces B lymphocyte viability in a dose- and time-dependent manner. Furthermore, we show by confocal microscopy that SA-positive IgG, but not SA-negative IgG bind to CD22. This interaction reduces the strength of B-cell receptor–mediated signaling trough down-regulating tyrosine phosphorylation of Lyn and the B-cell linker proteins, and up-regulating phospholipase Cγ2 activation. This cascade resulted in a sustained activation of Erk 1/2 and arrest of the cell cycle at the G1 phase. These changes may be accounted for the efficacy of IVIg in autoimmune diseases.

Acquirement of Rituximab Resistance Is Associated with the Development of Chemotherapy Resistance in B-Cell Lymphoma Cells: Evidence of Shared Pathways of Resistance between Chemotherapeutic Agents and Biological Therapies.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2297-2297
Author(s):  
Scott H. Olejniczak ◽  
Francisco J. Hernandez ◽  
Myron S. Czuczman
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Caspase 3 ◽  
Cell Lymphoma ◽  
Chemotherapy Resistance ◽  
B Cell Lymphoma ◽  
Parental Cell ◽  
Chemotherapeutic Agents ◽  
Lymphoma Cells ◽  
Apoptotic Effects

Abstract Pre-clinical studies have demonstrated that rituximab triggers apoptotic signals in B-cell lymphoma cells upon biding to CD20 antigen. Downstream signaling events observed in lymphoma cells following in vitro exposure of rituximab or chemotherapy include: 1) activation of the intrinsic apoptotic pathway and 2) increased mitogen activated protein kinase (MAPK) activity. In addition, pre-clinical and clinical studies strongly suggest that rituximab may sensitize lymphoma cells to apoptotic effects of various drugs used to treat NHL. Despite its anti-tumor activity, many patients relapse after initial response to rituximab-based therapy and demonstrate variable degrees of rituximab resistance. To further study the impact of rituximab resistance in cellular responses to chemotherapy we developed several rituximab resistant cell lines (RRCL) derived from Raji, SU-DHL-4 and RL cells by exposing cells to escalating doses of rituximab with (4RH cells) or without (2R cells) human serum. The rituximab resistance of each RRCL was confirmed by immunological assays. Subsequently, lymphoma cells (parental and RRCL) were exposed to various chemotherapeutic agents (cisplatin, doxorubicin, paclitaxel, or vincristine) for up to 48 hours. Detection of cell death was determined by trypan blue and/or propidium iodine staining. Caspase-3 activity was measured by PhiPhi Lux G1D2 enzymatic cleavage. Bcl-2 expression was determined by Western blotting. Chemotherapy resistance to all agents tested was observed in RRCL when compared to parental Raji, SU-DHL-4 and RL cell lines. In addition, caspase-3 activity was lower in RRCL following chemotherapy exposure than in parental cell lines. A significantly lower percent of RRCL cells within sub-G0/G1 peaks in cell cycle histograms confirmed that RRCL were less sensitive to chemotherapy-induced apoptosis. Additionally, an increase in Bcl-2 expression was observed in RRCL when compared parental cell lines. Our data strongly suggest that chemotherapy resistance emerges concomitantly with the acquirement of rituximab resistance in lymphoma cells. Chronic exposure to rituximab appears to cause overexpression of Bcl-2, which likely renders RRCL less susceptible to the apoptotic effects of chemotherapy agents. Ongoing studies are aimed at identifying and overcoming rituximab/chemotherapy shared cellular pathways of resistance.

Extracellular Nucleotide UTP Regulate Lipopolisaccharide-Induced Cytokine Production in Human Neutrophils.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3791-3791
Author(s):  
Analia E. Garcia ◽  
Florin Tuluc ◽  
John Meshki ◽  
Ovidiu Bredetean ◽  
Satya P. Kunapuli
Keyword(s):  
Intracellular Signaling ◽  
Interleukin 8 ◽  
Time Dependent ◽  
Extracellular Nucleotides ◽  
Mitogen Activated Protein Kinase ◽  
Human Neutrophils ◽  
Dependent Manner ◽  
Extracellular Nucleotide ◽  
Extracellular Medium ◽  
Present Evidence

Abstract Extracellular nucleotides can function as paracrine and autocrine mediators that signal through P2Y nucleotide receptors. Human polymorphonuclear (PMN) cells express P2Y receptors on the cell surface but the role of these G protein-coupled receptors in human neutrophils is not well established. Interleukin-8 (IL-8), which is a CXC-chemokine that induces adherence of neutrophils to vascular endothelium and extravasation into tissue, is produced by macrophages and endothelium. Additionally, neutrophils can synthesize and release interleukin-8 upon stimulation with lipopolisacharides (LPS) but the intracellular signaling pathways involved in this process are not clearly understood. LPS is a potent activator of macrophages and is responsible for the initiation the septic shock, increasing the secretion of various cytokines. Here we present evidence that LPS (1 ng/ml to 100 ng/ml) causes IL-8 production in a dose- and time- dependent manner and demonstrate that LPS itself is responsible for mitogen-activated protein kinase (MAPK) ERK1/2 phosphorylation. We used an enzyme immunosorbent-linked assay (ELISA) to determinate the amount of IL-8 released by isolated human neutrophils and present evidence that extracellular nucleotide uridine triphosphate (UTP) (1 μM/ml to 100 μM/ml) can inhibit IL-8 production in human neutrophils in a dose- and time- dependent manner. The addition of ATP had a similar inhibitory effect suggesting that nucleotides act on neutrophils via the P2Y2 receptor, which is equally activated by UTP and ATP. A cytokine array was used to detect the release of 42 different cytokines in the extracellular medium. IL-8 and IL-6 ere the major cytokines detected in the medium, though other cytokines were detected in lower concentrations. In the current study, we demonstrated that extracellular nucleotides may have an important role in regulating IL-8 production in neutrophils and potentially modulating the inflammatory response.

A Fully Human Anti-CD40 Antagonistic Antibody, CHIR-12.12, Inhibit the Proliferation of Human B Cell Non-Hodgkin’s Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3279-3279 ◽  
Author(s):  
Wen-Kai Weng ◽  
Xia Tong ◽  
Mohammad Luqman ◽  
Ronald Levy
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Expression Level ◽  
Primary Lymphoma ◽  
Immunoglobulin Gene ◽  
Dependent Manner ◽  
Lymphoma Cells

Abstract Immunotherapy using anti-tumor antibodies has become a feasible alternative for treating patients with lymphoma. These anti-tumor antibodies may target a specific receptor to disrupt proliferative signaling or mediate their anti-tumor effect by antibody-dependent cellular cytotoxicity (ADCC) or complement-mediated killing. The CD40 antigen is a good target for such anti-tumor antibodies for several reasons: CD40 is expressed on the vast majority of the non-Hodgkin’s B cell lymphomas and it has been proposed that the CD40/CD40L interaction provides a critical survival or proliferative signal for B cell lymphoma, especially the low-grade follicular lymphoma. In addition, B lymphoma cell lines become less sensitive to chemotherapy-induced apoptosis after CD40 cross-linking in an in vitro study. Therefore, an anti-CD40 antagonist that disrupts the CD40/CD40L interaction and mediates effector mechanism could have a therapeutic advantage. In this report, we describe a fully human anti-CD40 antagonistic IgG1 monoclonal antibody, CHIR-12.12 that was generated from mice with a human immunoglobulin gene loci (XenoMouse®mice, Abgenix Inc.). We first compared the antigen expression level of CD40 to the level of CD20, the target for rituximab, on primary lymphoma cells. While the expression level of CD40 was similar between different samples of primary follicular lymphoma cells, it was 10 fold less than the level of CD20. The expression of CD40 and CD20 on chronic lymphocytic leukemia/small lymphocytic lymphoma cells (CLL/SLL) was more variable. However, the level of CD20 was still significantly higher than the level of CD40 in all samples tested (2.4 to 13 fold). While CHIR-12.12 binds to primary lymphoma cells similarly to several other anti-CD40 antibodies, CHIR-12.12 did not induce proliferation of these primary tumore cells. By contrast, an agonist anti-CD40 antibody induced proliferation of these lymphoma cells up to 6-fold over baseline. To study the ability of CHIR-12.12 to interrupt the CD40-CD40L interaction, we cultured lymphoma cells with CD40L-transfected feeder cells in the presence of control IgG1, CHIR-12.12 or rituximab. In this system, the lymphoma cells proliferate in response to CD40-CD40L interaction. The addition of rituximab did not influence the proliferation. However, CHIR-12.12 inhibited the proliferation of follicular lymphoma and of CLL/SLL cells in a dose-dependent manner. The inhibition was observed with antibody concentration at 1 μg/ml and reached maximum of 90% inhibition at 10 μg/ml. We then evaluated the ability of CHIR-12.12 to elicit complement-mediated killing or ADCC. In vitro, rituximab induced complement-mediated cytotoxicity, while CHIR-12.12 did not. However, both CHIR-12.12 and rituximab induced effective ADCC of primary follicular lymphoma cells using purified NK cells from a healthy donor. Even though the level of CD40 is 10-fold less than the level of CD20 on the cell surface of these tumor cells, CHIR-12.12 induced the same degree of ADCC killing as did rituximab. Thus, this novel antagonist CHIR-12.12 antibody both blocks tumor-stimulatory CD40/CD40L interaction and mediates ADCC in the presence of a low number of target antigen. Our results support further development of this antibody to treat patients with B cell lymphoma.

HDAC Class I Inhibition Acetylates a Non-Histone Protein STAT3 by Modulating p300-STAT3-HDAC1 Interaction In Activated B- Cell Like (ABC) Diffuse Large B Cell Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 115-115
Author(s):  
Mamta Gupta ◽  
Jing Jing Han ◽  
Mary Stenson ◽  
Linda Wellik ◽  
Thomas E. Witzig
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Dependent Manner ◽  
Hdac Inhibition ◽  
Over Expression ◽  
Stat3 Signaling ◽  
Large B Cell Lymphoma ◽  
Dose Dependent

Abstract Abstract 115 Patients with diffuse large B- cell lymphoma (DLBCL) tumors that have an activated B-cell like (ABC) gene expression profile have a poorer prognosis. Understanding the mechanism(s) used by ABC tumor cells to resist the effects of common chemotherapy agents may lead to alternative approaches for the treatment of these tumors. ABC cell lines have been shown to have high levels of phosphorylated STAT3 (pSTAT3); however, the mechanisms that regulate STAT3 signaling in ABC DLBCL remain unclear. Histone deacetylases (HDACs) are enzymes that can deacetylate both non-histone and histone substrates. In this study we tested the hypothesis that HDACs in the tumor cells target a non-histone protein STAT3 in ABC DLBCL. In studies of HDAC expression in DLBCL tumors, we found over-expression of the type 1 HDACs, specifically HDAC1and HDAC3, in the pSTAT3- positive ABC tumors as compared to germinal centre B like (GCB) tumors. We then performed a co-immunoprecipitation (Co-IP) assay to learn the functional interaction between STAT3 and HDAC1. We found that STAT3 formed complexes with HDAC1 or HDAC3. Further Co-IP studies demonstrated that p300, a histone acetyltransferase (HAT), STAT3, and HDAC1 are all in the same complex. To determine whether p300 acetylates STAT3 in ABC cells, we immuno-precipitated endogenous p300 and blotted with acetylated STAT3 and showed that p300 acetylates STAT3 at lysine 685. We next tested whether HDAC inhibition could affect p300 mediated STAT3 acetylation in ABC cells. Inhibition of HDAC activity through the HDAC inhibitor LBH589 (LBH, Novartis Pharmaceuticals) increased STAT3 acetylation in a dose- dependent manner. Similar results were obtained when we used antiacetyl- lysine antibody. Furthermore HDAC1 over-expression inhibits STAT3 acetylation at lysine 685. This data implies a tight regulation of STAT3 acetylation and deacetylases in vivo in ABC lymphoma. In addition to acetylation, STAT3 can be modified by phosphorylation, thus the effect of HDAC inhibition on pSTAT3 both at serine and tyrosine residues was studied. We observed a dose-dependent decrease in pSTAT3 with some inhibitory effect on total STAT3. LBH was found to mediate STAT3 dephosphorylation by inhibiting the tyrosine phosphorylation of JAK2 and TYK2, the STAT3 upstream activators, in a dose- dependent manner. Since ABC lymphoma has higher levels of HDAC1 or HDAC3 and pSTAT3/STAT3 than GCB, we hypothesized that ABC cells will be more sensitive to HDAC inhibition than GCB. In fact, when ABC and GCB DLBCL cells were treated with LBH we observed that LBH was more cytotoxic to ABC than GCB as evidenced by annexin/PI staining and PARP cleavage. LD90 was 25 nM for ABC cells, however GCB cells required 5 times more LBH to kill 90% cells. STAT3 activation regulates genes involved in cell survival, including Bcl-2, Mcl-1, Bcl-XL, and c-Myc. LBH treatment resulted in down-regulation of Mcl-1 and c-Myc in ABC cells but has no effect in GCB cells; however, Bcl-2 and Bcl-XL levels were not decreased in both the subtype. Having established that HDAC1 physically associated with STAT3 and that LBH treatment elevated STAT3 acetylation in ABC cells, we proceeded to deplete endogenous HDAC1 with siRNA in Ly3 cells and found that HDAC1 knockdown up-regulated STAT3 acetylation indicating that HDAC1 negatively regulates the acetylation in vivo. HDAC1 inhibition also prevented phopshorylation of STAT3 and induces aopotosis in ABC cells. In summary, we have demonstrated that a key consequence of HATs and HDACs expression and activity is modulation of the STAT3 pathway in ABC lymphoma. Inhibition of this pathway with the HDAC inhibitor LBH inhibits constitutive STAT3 signaling and induces Mcl-1 mediated apoptosis. These studies provide the rationale for targeting the poorly responsive ABC-type DLBCL by inhibiting HDAC activity with epigenetic inhibitors such as LBH. We are currently testing LBH589 in relapsed DLBCL in a phase I clinical trial. Disclosures: No relevant conflicts of interest to declare.

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