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Targeting refractory mantle cell lymphoma for imaging and therapy using C-X-C chemokine receptor type 4 radioligands

ABSTRACT: CXCR4 is widely expressed in hematological malignancies, including MCL The Cancer Cell Line Encyclopedia (CCLE) showed relatively high levels of CXCR4 mRNA in hematological malignancies but had no MCL cell lines within its collection. To better assess the suitability of targeting CXCR4 in MCL, we screened 11 MCL cell lines for CXCR4 mRNA expression (Cancer Research Centre, CRC). For comparison, we profiled other lymphoma subtypes, including Burkitt (n=3), activated B cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) (n=6), and germinal center B cell-like (GBC) DLBCL (n=14). On average, all lymphoma cell lines had high mRNA expression of CXCR4, though MCL cell lines had a higher expression of CXCR4 compared to GBC DLBCL (p<0.05). Hematological malignancy cell lines in both CRC and CCLE collections showed a significant increase in CXCR4 mRNA expression compared to a randomly selected sample of other cell lines in the CCLE (Supplementary Figure 6). The CXCR4 expression levels of the DLBCL and Burkitt lymphoma cell lines in the CCLE were in good agreement with our cell line RNA sequencing data when adjusted for batch effects.

ORGANISM(S): Homo sapiens

PROVIDER: GSE190587 | GEO | 2022/01/12

REPOSITORIES: GEO

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Genomic alterations of 332 malignant lymphoma using BAC array CGH analysis

Project description:Clonal heterogeneity in lymphoid malignancies has been recently reported in adult T-Cell lymphoma/leukemia, peripheral T-cell lymphoma, not otherwise specified, and mantle cell lymphoma (MCL). Our analysis was extended to other types of lymphoma including marginal zone lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma (DLBCL). We examined the results of array comparative genomic hybridization analysis for 332 cases to determine if clonal heterogeneity existed in each case. Results showed that frequencies of clonal heterogeneity varied from 25% to 69% among different types of lymphoma. Multivariate analysis indicated that MCL and DLBCL with clonal heterogeneity showed a significantly poorer prognosis. Interestingly, 9p21.3 (CDKN2A/ 2B) loss and 17p13 (TP53, ATP1B2, SAT2, SHBG) loss were common regions among various types of lymphoma with clonal heterogeneity, suggesting at least in part that loss of these genes may play a role in clonal heterogeneity. We analyzed previously untreated 332 cases of lymphoma (comprising 29 cases of mantle cell lymphoma, 117 cases of diffuse large B-cell lymphoma (DLBCL), 79 cases of Follicular lymphoma, 24 cases of Burkitt lymphoma, 31 cases of mucosa-associated lymphoid tissue (MALT) lymphoma, and 51 peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS)).

2014-04-01 | E-GEOD-54303 | biostudies-arrayexpress

S63845 resistance mechnism

Project description:MCL-1 plays a central role in B-cell lymphoma progression and drug resistance. Pharmacologically targeting MCL-1, therefore, represents an attractive strategy to combat these lymphomas. S63845, a MCL1 inhibitor, was shown to have high response rates in mantle cell lymphoma (MCL) and burkitt lymphoma.

2022-12-02 | GSE160742 | GEO

Targeting of the CD161 Inhibitory Receptor Enhances T cell-mediated Immunity Against Hematological Malignancies

Project description:The CD161 inhibitory receptor is highly upregulated by tumor-infiltrating T cells in a number of human solid tumor types, and its ligand CLEC2D is expressed by both tumor cells and infiltrating myeloid cells. Here we assessed the role of the CD161 receptor in hematological malignancies. Systematic analysis of CLEC2D expression using the Cancer Cell Line Encyclopedia (CCLE) revealed that CLEC2D mRNA was most abundant in hematological malignancies, including B cell and T cell lymphomas as well as lymphocytic and myelogenous leukemias. CLEC2D protein was detected by flow cytometry on a panel of cell lines representing a diverse set of hematological malignancies. We therefore used yeast display to generate a panel of high-affinity, fully human CD161 monoclonal antibodies (mAbs) that blocked CLEC2D binding. These mAbs were specific for CD161 and had a similar affinity for human and non-human primate CD161, a property relevant for clinical translation. A high-affinity CD161 mAb enhanced key aspects of T cell function, including cytotoxicity, cytokine production and proliferation, against cell lines originating from patients with AML, DLBCL and Burkitt lymphoma. In humanized mouse models, this CD161 mAb enhanced T cell-mediated immunity resulting in a significant survival benefit. ScRNA-seq data demonstrated that CD161 mAb treatment enhanced expression of cytotoxicity genes by CD4 T cells as well as a tissue-resident memory program by CD4 and CD8 T cells that is associated with favorable survival outcomes in multiple human cancer types. These fully human monoclonal antibodies thus represent potential immunotherapy agents for hematological malignancies.

2024-01-02 | GSE220200 | GEO

c-myc-3'RR/p53+/- mice lymphomas

Project description:c-myc-3'RR mice prone to develop Burkitt lymphoma (BL) were crossed with p53+/- mice in order to obtain c-myc-3'RR/p53+/- mice. These mice develop a wider spectrum of lymphoma including BL, mantle cell lymphoma (MCL) and plasma cell lymphoma (PCL). Transcriptoma analysis of these lymphomas is investigated in these arrays. Four different plasma cell lymphoma (PCL1-4), three different mantle cell lymphoma (MCL1-4) and four different Burkitt lymphoma (BL1-4) were compared.

2012-01-05 | E-GEOD-31814 | biostudies-arrayexpress

Expression of TCF3 target genes defines a subclass of diffuse large B-cell lymphoma characterized by up-regulation of MYC target genes and poor clinical outcome following R-CHOP therapy

Project description:Fifty-eight retrospectively-ascertained local cases of diffuse large B-cell lymphoma (DLBCL) were segregated into two large subgroups with divergent overall survival through expression profiling of 135 transcripts including 92 regulated downstream of TCF3 or recurrently mutated in DLBCL or Burkitt lymphoma

2022-11-10 | GSE212114 | GEO

A defect of the INK4-Cdk4 checkpoint and c-myc collaborate in blastoid mantle cell lymphoma (MCL)-like lymphoma formation in mice

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

Transcriptoma comparison of mantle cell lymphoma of c-myc-3'RR/Cdk4R24C mice and c-myc-3'RR/p53+/- mice

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

Transcriptoma comparison of mantle cell lymphoma of c-myc-3'RR/Cdk4R24C mice and c-myc-3'RR/p53+/- mice

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

SUMO pulldown, U2OS, proteomics, 4 hour 20 hour 5-Aza-2' deoxycytidine treatment

Project description:Combination therapies targeting malignancies aim to increase treatment efficacy and reduce toxicity. Hypomethylating drug 5-Aza-2’-deoxycytidine (5-Aza-2’) enhances transcription of tumor suppressor genes and induces replication errors via entrapment of DNMT1. Post-translational modification by SUMO plays major roles in the DNA damage response and is required for degradation of entrapped DNMT1. Here, we combine SUMOylation inhibitor TAK981 and DNA-hypomethylating agent 5-Aza-2’ to improve treatment of MYC driven hematopoietic malignancies, since MYC overexpressing tumors are sensitive to SUMOylation inhibition. We studied the classical MYC driven malignancy Burkitt lymphoma, as well as diffuse large B-cell lymphoma (DLBCL) with and without MYC translocation. SUMO inhibition prolonged the entrapment of DNMT1 to DNA, resulting in DNA damage. An increase in DNA damage was observed in cells co-treated with TAK981 and 5-Aza-2’. Both drugs synergized to reduce cell proliferation in vitro in a B cell lymphoma cell panel, including Burkitt lymphoma and DLBCL. In vivo experiments combining TAK981 (25 mg/kg) and 5-Aza-2’ (2.5 mg/kg) showed a significant reduction in outgrowth of Burkitt lymphoma in an orthotopic xenograft model. In contrast, single dosing of TAK981 was ineffective and single dosing of 5-Aza-2’ only led to a modest outgrowth reduction. TAK981 and 5-Aza-2’ synergize to reduce B cell Lymphoma outgrowth in vitro and in vivo. SUMOylation is a key-player in the repair of DNA damage, hence upon TAK981 treatment the repair of DNA damage induced by 5-Aza-2’ treatment is impaired. Our results demonstrate the potential of tailored combination of drugs, based on insight in molecular mechanisms, to improve the efficacy of cancer therapies.

2023-03-17 | PXD038617 | Pride

SUMO pulldown proteomics Namalwa 5-Aza-2' deoxycytidine treatment

2023-03-17 | PXD038620 | Pride

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