Truncation of 3? CCND1 by t(11;22) leads to negative SP4 CCND1 immunohistochemistry in blastoid mantle cell lymphoma
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ABSTRACT:
SUBMITTER: Maekawa F
PROVIDER: S-EPMC7805338 | biostudies-literature | 2021 Jan
REPOSITORIES: biostudies-literature
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Project description:Blastoid-variant mantle-cell lymphoma (MCL-BV), unlike most B-cell non-Hodgkin lymphomas (NHL-Bs), is refractory to conventional chemotherapy and associated with a very poor prognosis. Development of new therapies has been hampered by the lack of valid animal models. We have developed a novel murine model of MCL-BV by crossing interleukin 14alpha (IL-14alpha) transgenic mice with c-Myc transgenic mice (double transgenic [DTG]). IL-14alpha is a B-cell growth factor that is expressed in a number of high-grade lymphomas, including MCL-BV. Ninety-five percent of IL-14alpha transgenic mice develop CD5(+) large B-cell lymphomas by 18 months of age. Sixty percent of c-Myc transgenic mice develop pre-B-cell lymphomas by 12 months of age. Close to 100% of DTG mice develop an aggressive, rapidly fatal lymphoma at 3 to 4 months of age that is CD5(+), CD19(+), CD21(-), CD23(-), sIgM(+). The tumor is found in the blood, bone marrow, liver, spleen, lymph nodes, gastrointestinal tract, and lungs and rarely in the brain, similar to the involvement seen in human MCL-BV. Immunoglobulin gene rearrangements document the monoclonality of the tumor. Cyclin D1 is highly expressed in these tumors, as it is in MCL-BV. DTG represents a novel model for MCL-BV that should reveal important insights into the pathogenesis of the lymphoma and contribute to the development of new forms of therapy.
| S-EPMC1885517 | biostudies-literature
Project description:The neural transcription factor SOX11 is usually highly expressed in typical mantle cell lymphoma (MCL), but it is absent in the more indolent form of MCL. Despite being an important diagnostic marker for this hard-to-treat malignancy, the mechanisms of aberrant SOX11 expression are largely unknown. Herein, we describe 2 modes of SOX11 regulation by the cell-cycle regulator cyclin D1 (CCND1) and the signal transducer and activator of transcription 3 (STAT3). We found that ectopic expression of CCND1 in multiple human MCL cell lines resulted in increased SOX11 transcription, which correlated with increased acetylated histones H3K9 and H3K14 (H3K9/14Ac). Increased H3K9/14Ac and SOX11 expression was also observed after histone deacetylase 1 (HDAC1) or HDAC2 was depleted by RNA interference or inhibited by the HDAC inhibitor vorinostat. Mechanistically, we showed that CCND1 interacted with and sequestered HDAC1 and HDAC2 from the SOX11 locus, leading to SOX11 upregulation. Interestingly, our data revealed a potential inverse relationship between phosphorylated Y705 STAT3 and SOX11 expression in MCL cell lines, primary tumors, and patient-derived xenografts. Functionally, inactivation of STAT3 by inhibiting the upstream Janus kinase (JAK) 1 or JAK2 or by STAT3 knockdown was found to increase SOX11 expression, whereas interleukin-21 (IL-21)-induced STAT3 activation or overexpression of the constitutively active form of STAT3 decreased SOX11 expression. In addition, targeting SOX11 directly by RNA interference or indirectly by IL-21 treatment induced toxicity in SOX11+ MCL cells. Collectively, we demonstrate the involvement of CCND1 and STAT3 in the regulation of SOX11 expression, providing new insights and therapeutic implications in MCL.
| S-EPMC6347093 | biostudies-literature
Project description:Mantle cell lymphoma (MCL) is characterized by the t(11;14) translocation, which leads to deregulated expression of the cell cycle regulatory protein cyclin D1 (CCND1). Genomic studies of MCL have also identified recurrent mutations in the coding region of CCND1. However, the functional consequence of these mutations is not known. Here, we showed that, compared to wild type (WT), single E36K, Y44D or C47S CCND1 mutations increased CCND1 protein levels in MCL cell lines. Mechanistically, these mutations stabilized CCND1 protein through attenuation of threonine-286 phosphorylation, which is important for proteolysis through the ubiquitin-proteasome pathway. In addition, the mutant proteins preferentially localized to the nucleus. Interestingly, forced expression of WT or mutant CCND1 increased resistance of MCL cell lines to ibrutinib, an FDA-approved Bruton tyrosine kinase inhibitor for MCL treatment. The Y44D mutant sustained the resistance to ibrutinib even at supraphysiologic concentrations (5-10 μM). Furthermore, primary MCL tumors with CCND1 mutations also expressed stable CCND1 protein and were resistant to ibrutinib. These findings uncover a new mechanism that is critical for the regulation of CCND1 protein levels, and is directly relevant to primary ibrutinib resistance in MCL.
| S-EPMC5341999 | biostudies-literature
Project description:SOX11 is a transcription factor that is normally expressed in the fetal brain and has also been detected in some malignant tumors, including mantle cell lymphoma (MCL). MCL is a mature B-cell lymphoma that characteristically expresses cyclin D1, which has been used as a diagnostic tumor marker. SOX11 has also recently emerged as a tumor marker for MCL, particularly in cyclin D1-negative MCLs and to distinguish between MCLs and other cyclin D1-positive lymphomas. In this study, we evaluated the diagnostic accuracy of SOX11 immunohistochemistry for the diagnosis of MCL using a meta-analysis. A comprehensive literature search was performed using the PubMED, EMBASE, and Cochrane library through May 9, 2018. In total, 14 studies were included in our meta-analysis. The sensitivity, specificity, and area under the curve calculated from the summary receiver operator characteristic were 0.9, 0.95, and 0.934, respectively. Effect sizes of log positive likelihood ratios, log negative likelihood ratios, and log diagnostic odds ratios were 2.67, -2.12, and 5.27, respectively. Statistically significant substantial heterogeneity was observed for specificity (I2 = 95%), but not for sensitivity. Subgroup analysis and meta-regression were performed to explain the heterogeneity in specificity and showed that the proportions of Burkitt's lymphoma, lymphoblastic lymphoma, and hairy cell leukemia were significant covariates among studies using rabbit polyclonal antibodies. Overall, this meta-analysis showed that SOX11 was a useful diagnostic marker for MCL, with the clone MRQ-58 mouse monoclonal antibody showing particularly robust performance.
| S-EPMC6850764 | biostudies-literature
Project description:BACKGROUND: The CCND1 gene generates two mRNAs (cyclin D1a and D1b) through an alternative splicing at the site of a common A/G polymorphism. Cyclin D1a and b proteins differ in their C-terminus, a region involved in protein degradation and sub-cellular localization. Recent data have suggested that cyclin D1b could be a nuclear oncogene. The presence of cyclin D1b mRNA and protein has been studied in two hemopathies in which cyclin D1 could be present: multiple myeloma (MM) and mantle cell lymphoma (MCL). The A/G polymorphism of CCND1 has also been verified in a series of patients. METHODS: The expression of cyclin D1 mRNA isoforms has been studied by real-time quantitative PCR; protein isoforms expression, localization and degradation by western blotting. The CCND1 polymorphism was analyzed after sequencing genomic DNA. RESULTS: Cyclin D1 mRNA isoforms a and b were expressed in mantle cell lymphoma (MCL) and multiple myeloma (MM). Cyclin D1b proteins were present in MCL, rarely in MM. Importantly, both protein isoforms localized the nuclear and cytoplasmic compartments. They displayed the same short half-life. Thus, the two properties of cyclin D1b recognized as necessary for its transforming activity are missing in MCL. Moreover, CCND1 polymorphism at the exon/intron boundary had no influence on splicing regulation in MCL cells. CONCLUSION: Our results support the notion that cyclin D1b is not crucial for the pathogenesis of MCL and MM.
| S-EPMC1609182 | biostudies-literature
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:Cyclin D1 overexpression is believed to be essential in the pathogenesis of mantle cell lymphoma (MCL). Hence, the existence of cyclin D1-negative MCL has been controversial and difficult to substantiate. Our previous gene expression profiling study identified several cases that lacked cyclin D1 expression, but had a gene expression signature typical of MCL. Herein, we report the clinical, pathologic, and genetic features of 6 cases of cyclin D1-negative MCL. All 6 cases exhibited the characteristic morphologic features and the unique gene expression signature of MCL but lacked the t(11;14)(q13; q32) by fluorescence in situ hybridization (FISH) analysis. The tumor cells also failed to express cyclin D1 protein, but instead expressed either cyclin D2 (2 cases) or cyclin D3 (4 cases). There was good correlation between cyclin D protein expression and the corresponding mRNA expression levels by gene expression analysis. Using interphase FISH, we did not detect chromosomal translocations or amplifications involving CCND2 and CCND3 loci in these cases. Patients with cyclin D1-negative MCL were similar clinically to those with cyclin D1-positive MCL. In conclusion, cases of cyclin D1-negative MCL do exist and are part of the spectrum of MCL. Up-regulation of cyclin D2 or D3 may substitute for cyclin D1 in the pathogenesis of MCL.
| S-EPMC1895253 | biostudies-literature
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.
| EGAS00001003060 | EGA
Project description:While classical nodal mantle cell lymphoma (cMCL) is often associated with involvement of multiple extranodal sites, isolated extranodal disease (ED) at the time of diagnosis is a rare event; data on the outcome of these forms are lacking. On behalf of the European MCL Network, we conducted a retrospective analysis on the clinical characteristics and outcomes of MCL presenting with isolated or predominant ED (MALT MCL). We collected data on 127 patients with MALT MCL diagnosed from 1998 to 2015: 78 patients (61%) were male with a median age of 65 years. The involved sites include: upper airways + Waldeyer ring (40; 32%), gastrointestinal tract (32; 25%), ocular adnexa (17; 13%), oral cavity and salivary glands (17; 13%) and others (13; 1%); 7 patients showed multiple extranodal sites. The median follow-up was 80 months (range: 6-182), 5-year progression-free survival (PFS) was 45% (95% CI: 35-54) and 5-year overall survival (OS) was 71% (95% CI: 62-79). In an explorative setting, we compared MALT MCL with a group of 128 cMCL patients: MALT MCL patients showed a significantly longer PFS and OS compared with nodal cMCL; with a median PFS of 4.5 years vs 2.8 years (p?=?0.001) and median OS of 9.8 years vs 6.9 years (p?=?0.018), respectively. Patients with MALT MCL at diagnosis showed a more favorable prognosis and indolent course than classical nodal type. This clinical variant of MCL should be acknowledged to avoid possible over-treatment.
| S-EPMC7000480 | biostudies-literature