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Transient stabilization, rather than inhibition of MYC amplifies extrinsic apoptosis and therapeutic responses in refractory B-cell lymphoma

ABSTRACT: Identification of gene expression changes following inhibition of GSK-3 in Burkitt lymphoma

ORGANISM(S): Homo sapiens

PROVIDER: GSE126529 | GEO | 2019/03/28

REPOSITORIES: GEO

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Transient stabilization, rather than inhibition, of MYC amplifies extrinsic apoptosis and therapeutic responses in refractory B-cell lymphoma.

Project description:Therapeutic targeting of initiating oncogenes is the mainstay of precision medicine. Considerable efforts have been expended toward silencing MYC, which drives many human cancers including Burkitt lymphomas (BL). Yet, the effects of MYC silencing on standard-of-care therapies are poorly understood. Here we found that inhibition of MYC transcription renders B-lymphoblastoid cells refractory to chemotherapeutic agents. This suggested that in the context of chemotherapy, stabilization of Myc protein could be more beneficial than its inactivation. We tested this hypothesis by pharmacologically inhibiting glycogen synthase kinase 3β (GSK-3β), which normally targets Myc for proteasomal degradation. We discovered that chemorefractory BL cell lines responded better to doxorubicin and other anti-cancer drugs when Myc was transiently stabilized. In vivo, GSK3 inhibitors (GSK3i) enhanced doxorubicin-induced apoptosis in BL patient-derived xenografts (BL-PDX), as well as in murine MYC-driven lymphoma allografts. This enhancement was accompanied by and required deregulation of several key genes acting in the extrinsic, death-receptor-mediated apoptotic pathway. Consistent with this mechanism of action, GSK3i also facilitated lymphoma cell killing by a death ligand TRAIL and by a death receptor agonist mapatumumab. Thus, GSK3i synergizes with both standard chemotherapeutics and direct engagers of death receptors and could improve outcomes in patients with refractory lymphomas.

| S-EPMC6884148 | biostudies-literature

Transient stabilization, rather than inhibition of MYC amplifies extrinsic apoptosis and therapeutic responses in refractory B-cell lymphoma

Project description:Transient stabilization, rather than inhibition of MYC amplifies extrinsic apoptosis and therapeutic responses in refractory B-cell lymphoma

| PRJNA522272 | ENA

Burkitt Lymphoma beyond MYC translocation:N-MYC and DNA methyl transferases dysregulation

Project description:Identification of miRNA differentially expressed between MYC-translocation positive and and MYC-translocation negative Burkitt Lymphoma and their impact on gene expression profile Study of microRNA profile of MYC-translocation positive and MYC-translocation negative Burkitt Lymphoma cases in order to uncover possible differences at the molecular level

2015-08-05 | E-GEOD-71471 | biostudies-arrayexpress

Burkitt Lymphoma beyond MYC translocation:N-MYC and DNA methyl transferases dysregulation

2015-08-05 | GSE71471 | GEO

Oncogenic MYC amplifies mitotic perturbations.

Project description:The oncogenic transcription factor MYC modulates vast arrays of genes, thereby influencing numerous biological pathways including biogenesis, metabolism, proliferation, apoptosis and pluripotency. When deregulated, MYC drives genomic instability via several mechanisms including aberrant proliferation, replication stress and ROS production. Deregulated MYC also promotes chromosome instability, but less is known about how MYC influences mitosis. Here, we show that deregulating MYC modulates multiple aspects of mitotic chromosome segregation. Cells overexpressing MYC have altered spindle morphology, take longer to align their chromosomes at metaphase and enter anaphase sooner. When challenged with a variety of anti-mitotic drugs, cells overexpressing MYC display more anomalies, the net effect of which is increased micronuclei, a hallmark of chromosome instability. Proteomic analysis showed that MYC modulates multiple networks predicted to influence mitosis, with the mitotic kinase PLK1 identified as a central hub. In turn, we show that MYC modulates several PLK1-dependent processes, namely mitotic entry, spindle assembly and SAC satisfaction. These observations thus underpin the pervasive nature of oncogenic MYC and provide a mechanistic rationale for MYC's ability to drive chromosome instability.

| S-EPMC6731591 | biostudies-literature

Stabilization of the c-Myc Protein by CAMKII? Promotes T Cell Lymphoma.

Project description:Although high c-Myc protein expression is observed alongside MYC amplification in some cancers, in most cases protein overexpression occurs in the absence of gene amplification, e.g., T cell lymphoma (TCL). Here, Ca2+/calmodulin-dependent protein kinase II ? (CAMKII?) was shown to stabilize the c-Myc protein by directly phosphorylating it at serine 62 (S62). Furthermore, CAMKII? was shown to be essential for tumor maintenance. Inhibition of CAMKII? with a specific inhibitor destabilized c-Myc and reduced tumor burden. Importantly, high CAMKII? levels in patient TCL specimens correlate with increased c-Myc and pS62-c-Myc levels. Together, the CAMKII?:c-Myc axis critically influences the development and maintenance of TCL and represents a potential therapeutic target for TCL.

| S-EPMC5552197 | biostudies-literature

Cooperative JAK-STAT/MAP-kinase/MYC deregulation in Plasmablastic Lymphoma

Project description:Plasmablastic lymphoma is an aggressive B-cell lymphoma with an immunoblastic/large cell morphology anda plasmacytic differentiation. The differential diagnosis with Burkitt lymphoma, plasma cell myeloma and some variants of diffuse large B-cell lymphoma may be challenging due to the overlapping morphological, genetic and immunophenotypic features. Furthermore, the profile of chromosomal alterations is not well known.

2021-05-17 | GSE155055 | GEO

Expression data from Burkitt lymphoma cases

Project description:Burkitt lymphoma is the commonest cancer in children in Africa. We compared the gene expression profiles of African Burkitt lymphoma patients with those of cases presented in Western countries in both immunocompetent (sporadic Burkitt lymphoma) and HIV-infected patients (immunodeficiency associated Burkitt lymphoma). We used microarrays to detail the global programme of gene expression in different subtypes of Burkitt lymphoma.

2011-01-20 | GSE26673 | GEO

GSK-3alpha Promotes Oncogenic KRAS Function in Pancreatic Cancer via TAK1-TAB Stabilization and Regulation of Non-Canonical NF-kB

Project description:Mutations in KRAS occur in a variety of tumors of epithelial origin, driving the oncogenic phenotype.The NF-kB transcription factor pathway is important for oncogenic RAS to transform cells and to drive tumorigenesis in animal models. Recently TAK1, an upstream regulator of IKK which controls canonical NF-kB, was shown to be important for chemoresistance in pancreatic cancer and for regulating KRAS+ colorectal cancer cell growth and survival. Here we show that GSK-3alpha is upregulated by KRAS leading to interaction with TAK1 to stabilize the TAK1/TAB complex to promote IKK activity. Additionally, GSK-3alpha is required for promoting critical non-canonical NF-kB signaling in pancreatic cancer cells. Pharmacologic inhibition of GSK-3 suppresses growth of human pancreatic tumor explants, consistent with loss of expression of genes such as c-myc and TERT. These data identify GSK-3alpha as a key downstream effector of oncogenic RAS via its ability to coordinately regulate distinct NF-kB signaling pathways GSK-3 inhibition at 2 and 8 hours

2013-05-31 | E-GEOD-42559 | biostudies-arrayexpress

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

Project description: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.

2022-01-12 | GSE190587 | GEO

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