The synergistic effect of BCR signaling inhibitors combined with an HDAC inhibitor on cell death in a mantle cell lymphoma cell line

Abstract Mantle cell lymphoma (MCL) is a B cell malignancy characterized by aberrant expression of cyclin D1 due to a t(11;14) translocation. MCL is refractory to conventional chemotherapy, and treatment remains challenging. We investigated the efficacy of the histone deacetylase (HDAC) inhibitor vorinostat combined with one of several B-cell receptor (BCR) signaling inhibitors on MCL cell death and the underlying mechanisms, using MCL cell lines. The Bruton’s tyrosine kinase inhibitor PCI-32765 and the spleen tyrosine kinase inhibitor R406 showed synergistic effects with vorinostat on growth inhibition. Treatment with PCI-32765 or R406 alone induced 27.3 ± 2.1 or 25.1 ± 3.2 % apoptosis. When combined with vorinostat, these apoptotic fractions significantly increased to 50.8 ± 4.9 and 63.1 ± 5.0 %, respectively. Activation of caspase-3 and poly-(ADP-ribose) polymerase cleavage were markedly increased. We performed gene expression profiling following treatment with the combination of vorinostat and individual BCR signaling inhibitors using a microarray, and differentially expressed genes were identified. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that the nuclear factor (NF)-κB signaling pathway was significantly enriched following treatment with the combination of vorinostat and R406. Protein expression analysis confirmed the down-regulation of NF...
Source: Apoptosis - Category: Molecular Biology Source Type: research

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Unlike systemic anaplastic large cell lymphoma, the vast majority of primary cutaneous anaplastic large cell lymphomas (C-ALCL) do not carry translocations involving the ALK gene and do not express ALK. Expression of ALK protein therefore strongly suggests secondary cutaneous involvement of a systemic anaplastic large cell lymphoma. Recent studies described a small subgroup of ALK-positive C-ALCL, but information on frequency, prognosis, and translocation partners is virtually lacking. A total of 6/309 (2%) C-ALCL patients included in the Dutch registry for cutaneous lymphomas between 1993 and 2019 showed immunohistochemic...
Source: The American Journal of Surgical Pathology - Category: Pathology Tags: Original Articles Source Type: research
Conclusion: ALK positivity suggests an overall favorable prognosis of ALCL as compared to ALK-negative cases. However, in the rare published cases of TRAF1-ALK, an aggressive clinical course has been observed, which may reflect the aggressive propensity of this particular fusion, as these cases appear to be refractory to standard chemotherapy and also to the first generation ALK inhibitors. This study highlights the advantage of using NGS in RNA-based fusion assays to detect rare translocations, which can be of some clinical importance in detecting rare but aggressive fusion partners of ALK. As these technologies become mo...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
This article examines the molecular landscape of MCL, drug resistance mechanisms and the data on emerging targeted therapies.Expert opinion: DNA damage pathway, with ATM mutation, TP53 and epigenetic abnormalities are key drivers of MCL. sBCL2, PARP, ATR, CDK inhibitors or epigenetic modifiers are among the most promising drugs under investigation in clinical trials.The genomic landscape of MCL suggests two types of disease based on the presence of ATM or TP53 alterations which should be the framework of future molecular driven strategies. Among novel drugs, those interacting with the DNA damage response pathway offer the ...
Source: Expert Opinion on Investigational Drugs - Category: Drugs & Pharmacology Tags: Expert Opin Investig Drugs Source Type: research
AbstractSouth Africa (SA) has a high prevalence of human immunodeficiency virus (HIV) infection. People living with HIV are at markedly increased risk of developing Burkitt lymphoma (BL), which is characterized by theMYC translocation. There is a paucity of survival data of HIV-associated Burkitt lymphoma/leukaemia (HIV-BL) cases from SA, and the relationship between karyotype and outcomes has not been widely reported. Here we report the clinico-pathological characteristics of a cohort of cytogenetically confirmed HIV-BL cases. A retrospective, descriptive review was conducted of clinico-pathological features of HIV-BL pat...
Source: Annals of Hematology - Category: Hematology Source Type: research
Authors: Ruan J Abstract Mantle cell lymphoma (MCL) is a distinct subtype of B-cell non-Hodgkin lymphoma characterized by the t(11;14)(q13;q32) translocation leading to cyclin D1 overexpression and cell cycle dysregulation. Molecular profiling with gene expression and deep sequencing analyses has identified genomic and epigenomic alterations in pathways regulating the cell cycle, DNA damage response, proliferation, and survival, which contribute to disease progression with important prognostic and therapeutic implications. Clinically, the nonnodal MCL subset is notable for leukemic presentation, indolent behavior, ...
Source: Hematology ASH Education Program - Category: Hematology Tags: Hematology Am Soc Hematol Educ Program Source Type: research
Contributors : Yuki Kagiyama ; Issay KitabayashiSeries Type : Expression profiling by high throughput sequencingOrganism : Homo sapiensMantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin ’s lymphoma, which is characterized by the translocation of t(11:14)(q13;q32) resulting in overexpression of cyclin D1. Patients with MCL often acquire resistance to conventional chemotherapy such as R-CHOP, BR, and ibrutinib. Therefore, novel therapeutic targets for relapsed MCL are needed. EZH1/ 2 are catalytic components of PRC2, which trimethylates H3K27 to repress transcription of target genes and play critical roles in ...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research
ConclusionThrough Nrf2 induction in normal cells and inhibition of Bcl-2 in tumor cells, RRx-001 selectively protects normal cells against lethality in normal cells, but induces apoptosis in tumor cells.
Source: Journal of Cancer Research and Clinical Oncology - Category: Cancer & Oncology Source Type: research
Conditions:   BCL2 Gene Translocation;   C-Myc Translocation;   Diffuse Large B-Cell Lymphoma;   Double-Expressor Lymphoma;   High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements;   High Grade B-Cell Lymphoma, Not Otherwise Specified;   Neoplastic Cells With Double Expression of MY C and BCL2 Proteins Present Interventions:   Drug: Cyclophosphamide;   Drug: Doxorubicin;   Drug: Doxorubicin Hydrochloride;   Drug: Etoposide;   Drug: Prednisone;   Biological: Rituximab;   D...
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
ConclusionMAF deletion was more frequent than MAF translocation with IgH in patients with MM and was more commonly observed in women. Moreover, MAF deletion was often combined with 13q, FGFR3, and IgH deletion. MAF deletion did not influence prognosis in patients with MM who were given a bortezomib-based chemotherapy regimen.
Source: Clinical Lymphoma Myeloma and Leukemia - Category: Cancer & Oncology Source Type: research
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