Cyclin D2 overexpression drives B1a-derived MCL-like lymphoma in mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE175568 | GEO | 2021/08/10
REPOSITORIES: GEO
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Project description:Cyclin D2 overexpression drives B1a-derived MCL-like lymphoma in mice
| PRJNA732916 | ENA
Project description:A subset of CCND1-negative mantle cell lymphoma MCL (CCND1- MCL) has been recognized, and around half of them harbor CCND2 translocations. To identify other potential mechanisms driving MCL pathogenesis we investigated CCND1− MCL by by whole genome/exome sequencing. We identified a cryptic insertion of IGK and IGL enhancer regions near the CCND3 gene in three cases. Specific FISH probes detected 10 additional cryptic IGK juxtapositions to CCND3 (6 cases) and CCND2 (4 cases). In conclusion, virtually all CCND1-/SOX11+ MCL carry CCND2/CCND3 rearrangement with IG genes, including cryptic IGK/L enhancer regions not detected with currently used FISH probes.
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Project description:Mantle cell lymphoma (MCL) is a B cell malignancy characterized by a monoclonal proliferation of lymphocytes with co-expression of CD5, CD43 but not CD23. We have developed two murine models of MCL-like lymphoma. Breeding Cdk4R24C mice (a knock-in strain that express a Cdk4 protein resistant to inhibition by p16INK4a and other INK4 family members) with c-myc-3’RR transgenic mice (prone to develop aggressive Burkitt lymphoma-like lymphoma) leads in c-myc/Cdk4R24C mice to development of clonal blastoid MCL-like lymphoma. Breeding p53+/- mice with c-myc-3’RR transgenic mice lead to the development of several mature B cell lymphomas including MCL. In this study we compare MCL transcriptomas of c-myc-3'RR/Cdk4R24C mice and c-myc-3'RR/p53+/- mice. B splenocytes from 2 c-myc/Cdk4R24C lymphoma mice and 2 c-myc-3'RR/p53+/- mice were investigated
2013-01-10 | E-GEOD-36808 | biostudies-arrayexpress
Project description:Mantle cell lymphoma (MCL) is a B cell malignancy characterized by a monoclonal proliferation of lymphocytes with co-expression of CD5, CD43 but not CD23. Typical MCL are associated with cyclin D1 overexpression, and blastoid MCL variants are associated with c-myc translocations. We have developed a murine model of MCL-like lymphoma by crossing Cdk4R24C mice with c-myc-3’RR transgenic mice. Cdk4R24C mice is a knock-in strain that express a Cdk4 protein resistant to inhibition by p16INK4a and other INK4 family members. Breeding Cdk4R24C mice with c-myc-3’RR transgenic mice prone to develop aggressive Burkitt lymphoma-like lymphoma leads in c-myc/Cdk4R24C mice to development of clonal blastoid MCL-like lymphoma. A defect of the INK4-Cdk4 checkpoint can participate to lymphomagenesis in conjunction with additional alterations of cell cycle control, a situation which might be reminiscent of the development of human blastoid MCL. B splenocytes from 4 c-myc/Cdk4(R24C) lymphoma mice and 4 wt mice were investigated.
2012-02-01 | E-GEOD-32230 | biostudies-arrayexpress
Project description:Mantle cell lymphoma (MCL) is a B cell malignancy characterized by a monoclonal proliferation of lymphocytes with co-expression of CD5, CD43 but not CD23. Typical MCL are associated with cyclin D1 overexpression, and blastoid MCL variants are associated with c-myc translocations. We have developed a murine model of MCL-like lymphoma by crossing Cdk4R24C mice with c-myc-3’RR transgenic mice. Cdk4R24C mice is a knock-in strain that express a Cdk4 protein resistant to inhibition by p16INK4a and other INK4 family members. Breeding Cdk4R24C mice with c-myc-3’RR transgenic mice prone to develop aggressive Burkitt lymphoma-like lymphoma leads in c-myc/Cdk4R24C mice to development of clonal blastoid MCL-like lymphoma. A defect of the INK4-Cdk4 checkpoint can participate to lymphomagenesis in conjunction with additional alterations of cell cycle control, a situation which might be reminiscent of the development of human blastoid MCL.
2012-02-01 | GSE32230 | 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
Project description:Mantle cell lymphoma (MCL) is a B cell malignancy characterized by a monoclonal proliferation of lymphocytes with co-expression of CD5, CD43 but not CD23. We have developed two murine models of MCL-like lymphoma. Breeding Cdk4R24C mice (a knock-in strain that express a Cdk4 protein resistant to inhibition by p16INK4a and other INK4 family members) with c-myc-3’RR transgenic mice (prone to develop aggressive Burkitt lymphoma-like lymphoma) leads in c-myc/Cdk4R24C mice to development of clonal blastoid MCL-like lymphoma. Breeding p53+/- mice with c-myc-3’RR transgenic mice lead to the development of several mature B cell lymphomas including MCL. In this study we compare MCL transcriptomas of c-myc-3'RR/Cdk4R24C mice and c-myc-3'RR/p53+/- mice.
2013-01-10 | GSE36808 | 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: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:The aggressive clinical behavior of mantle cell lymphoma (MCL) is attributed to specific genetic and molecular mechanisms involved in its pathogenesis, mainly the t(11;14)(q13;q32) traslocation and cyclin D1 (CCND1) overexpression. Nevertheless, evidence of a certain degree of clinical/biological heterogeneity has been disclosed by gene expression profile (GEP) and (immuno)genetic/immunohistochemistry studies. AIM: To use a GEP approach to identify MCL subsets with peculiar clinical/biological features in the context of of MCL patients treated homogeneously with an autologous transplantation-based program.
2017-12-31 | GSE89447 | GEO