Antitumoral activity of acadesine and rituximab in MCL
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE47871 | GEO | 2013/06/13
SECONDARY ACCESSION(S): PRJNA208230
REPOSITORIES: GEO
Similar Datasets
Project description:Acadesine is a nucleoside analogue with known antileukemic effects in different neoplasms. We investigated the activity of acadesine ne exerts a cytotoxic effect in MCL and synergizes with rituximab supporting clinical examination of this strategy for MCL patients We used microarrays to detail the gene expression changes in acadesine-, rituximab- and combination-treated tumors. Global RNA expression in tumors treated with acadesine, rituximab and the combination in a xenograft model of MCL (Jeko-1). Tumors were collected 18 days after the initiation of the treatments.
2013-06-13 | E-GEOD-47871 | biostudies-arrayexpress
Project description:We investigated the differential regulation patterns of type I anti-CD20 monoclonal antibody (mAb) rituximab and type II obinutuzumab on a transcriptional level. Using a panel of MCL cell lines, we determined the effects of obinutuzumab and rituximab as monotherapies as well as in combination on cell viability and proliferation. Obinutuzumab induced a higher reduction in cell proliferation in each mantle cell lymphoma cell line than rituximab did. Results indicate a common pattern of expression changes after binding of anti-CD20 mAbs, but also reveal a significant difference between type I and type II treatment. Combination treatment resulted in a rituximab-like expression pattern. Many deregulated genes were associated with stress signalling, cell death, immune response and other functional clusters. Our analyses identified different and antibody-specific downstream expression patterns of obinutuzumab and rituximab, which may represent the molecular basis of the superior effect of obinutuzumab in comparison to rituximab.
2014-12-31 | GSE54169 | GEO
Project description:Poor prognosis BCR-ABL+ B-ALL leukemic cells are highly dependent on the expression of endogenous anti-apoptotic MCL-1. However, the survival of most normal blood cells (e.g. progenitors, lymphocytes, and granulocytes) and other normal cell types (e.g. cardiomyocytes and neurons) are also exquisitely dependent on Mcl-1 gene expression, suggesting that effective therapeutic inhibition of MCL-1 could be acutely toxic, especially when combined with standard chemotherapy. Therefore, as an alternative to MCL-1 inhibition, we have identified dihydroarteminisin (DHA), a water-soluble metabolite of the anti-malarial arteminisin, which induces the down-modulation of MCL-1 protein expression by triggering an endoplasmic reticulum stress response. The DHA induced repression of MCL-1 expression renders leukemic cells highly sensitive to synergistic cell death induced by BH3-mimetic agents such as navitoclax (ABT-263) in a mouse model of BCR-ABL+ B-ALL. Furthermore, DHA also synergizes with navitoclax in human Ph+ ALL cell lines, and primary patient derived xenografts of Ph+ ALL. These data demonstrate that combining DHA with BH3-mimetic agents can improve therapeutic response in poor prognosis leukemia.
2018-02-14 | GSE95809 | GEO
Project description:Mantle cell lymphoma (MCL) is a rare, highly heterogeneous type of B-cell non-Hodgkin’s lymphoma (NHL) driven by multiple genetic mutations disrupting cell cycle regulation and DNA damage response. Despite advances in therapy, novel treatment approaches are needed especially for highly proliferative MCL which has a particularly progressive clinical course even in the era of Bruton’s tyrosine kinase therapy. The sumoylation pathway is known to be upregulated in many cancers including lymphoid malignancies. However, little is currently known about the role of the sumoylation pathway and its oncogenic potential in MCL. We found extensive upregulation of the sumoylation pathway in MCL, particularly at the level of the E1 enzymes SAE1 and SAE2, with elevated expression levels of sumoylation enzyme components showing a worse prognosis and a strong positive correlation with cell cycle associated genes. Targeting the sumoylation pathway with TAK-981, a first in class sumoylation inhibitor currently being investigated in a clinical study of B-cell NHL in combination with rituximab (NCT04074330), resulted in potent loss of sumoylation in MCL cells with significant activity in in-vitro and in vivo models of MCL, including ibrutinib resistance cases. We found mitotic dysregulation to be an important, although not all encompassing mechanism of cell death upon loss of sumoylation of TAK-981 in MCL cells. We uncovered a diverse sumoylation program upon mitosis entry that was significantly reduced with TAK-981. Centromeric localization of the well known sumoylation substrate topoisomeraseIIA (TopIIA) was significantly abrogated upon mitosis entry, likely contributing at least in part to the mitotic dysregulation seen in MCL cells. This mechanism is highly relevant as TopIIA is significantly upregulated in MCL with SAE1/2 overexpression. Our study, in addition to the recently described immunomodulatory activity of TAK-981, not only validates SAE1/2 as a therapeutic target in MCL but also opens the door to further mechanistic work to uncover how to best use desumoylation therapy to treat MCL and other lymphoid malignancies.
2022-09-02 | GSE184031 | GEO
Project description:Thermotoga neapolitana Mcl Genome sequencing
| PRJNA176358 | ENA
Project description:Comparison of CLL and MCL primary cells obtained from a patient with MCL variant Richter syndrome
2016-07-13 | GSE84286 | GEO
Project description:To analyze the molecular mechanisms by which MCL may induce apoptosis, microarray gene expression profiling of MCL-treated KG1a cells was performed.
2015-12-30 | GSE76384 | GEO
Project description:Patients with conventional mantle cell lymphoma (MCL) show an aggressive clinical behavior. However, cases fulfilling the WHO criteria for MCL, but that remain asymptomatic without treatment, have been reported. In an attempt to understand this heterogeneity, we have compared 17 typical cases of MCL with a homogeneous group of 13 asymptomatic individuals with monoclonal expansion of t(11;14)(q13;q32) cyclin D1-positive B-cells in peripheral blood (MALD1). None of these cases have received treatment (minimum follow-up of 26 months; median, 71 months). Gene expression analysis has shown enrichment of signatures associated to neoplastic behavior and cell proliferation in MCL but not in MALD1. In contrast, MALD1 was highly enriched in gene sets related to immune activation and inflammatory responses. CD38 and CD200 genes were differentially expressed between MCL and MALD1. The combined assessment of both proteins by flow cytometry allowed classifying 85% of MALD1 cases. In summary, we have shown for the first time that MALD1, in contrast to MCL, is characterized by immune activation and driven by inflammatory cues. We have also shown that CD38 and CD200 flow cytometry assessment is useful to discern most cases of MALD1 from MCL in the clinical setting. MALD1 should be identified and segregated from the current MCL category to avoid overdiagnosis and unnecessary treatment.
2013-12-23 | GSE45717 | GEO
Project description:Patients with conventional mantle cell lymphoma (MCL) show an aggressive clinical behavior. However, cases fulfilling the WHO criteria for MCL, but that remain asymptomatic without treatment, have been reported. In an attempt to understand this heterogeneity, we have compared 17 typical cases of MCL with a homogeneous group of 13 asymptomatic individuals with monoclonal expansion of t(11;14)(q13;q32) cyclin D1-positive B-cells in peripheral blood (MALD1). None of these cases have received treatment (minimum follow-up of 26 months; median, 71 months). Gene expression analysis has shown enrichment of signatures associated to neoplastic behavior and cell proliferation in MCL but not in MALD1. In contrast, MALD1 was highly enriched in gene sets related to immune activation and inflammatory responses. CD38 and CD200 genes were differentially expressed between MCL and MALD1. The combined assessment of both proteins by flow cytometry allowed classifying 85% of MALD1 cases. In summary, we have shown for the first time that MALD1, in contrast to MCL, is characterized by immune activation and driven by inflammatory cues. We have also shown that CD38 and CD200 flow cytometry assessment is useful to discern most cases of MALD1 from MCL in the clinical setting. MALD1 should be identified and segregated from the current MCL category to avoid overdiagnosis and unnecessary treatment. 18 samples were analyzed: 5 MALD1, 5 MCL and 8 Healthy Controls
2013-12-23 | E-GEOD-45717 | biostudies-arrayexpress