Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics

Schmitz, Roland; Young, Ryan M.; Ceribelli, Michele; Jhavar, Sameer; Xiao, Wenming; Zhang, Meili; Wright, George W.; Shaffer, Arthur L.; Hodson, Daniel J.; Buras, Eric D.; Liu, Xuelu; Powell, John; Yang, Yandan; Xu, Weihong; Zhao, Hong; Kohlhammer, Holger; Rosenwald, Andreas; Kluin, Philip M.; Müller‐Hermelink, Hans Konrad; Ott, German; Gascoyne, Randy D.; Connors, Joseph M.; Rimsza, Lisa M.; Campo, Elı́as; Jaffe, Elaine S.; Delabie, Jan; Smeland, Erlend B.; Ogwang, Martin D.; Reynolds, Steven J.; Fisher, Richard I.; Braziel, Rita M.; Tubbs, Raymond R.; Cook, James R.; Weisenburger, Dennis D.; Chan, Wing C.; Pittaluga, Stefania; Wilson, Wyndham H.; Waldmann, Thomas A.; Rowe, Martin; Mbulaiteye, Sam M.; Rickinson, Alan B.; Staudt, Louis M.

doi:10.1038/nature11378

Cited by 754 publications

(885 citation statements)

References 43 publications

(66 reference statements)

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“…In all three cell lines, TSC2 knockdown resulted in increased S6K‐phosphorylation and reduced of cell viability (Fig EV3G). Our findings may seem to be at odds with studies showing that mTORC1 signaling is required for survival of lymphomas in the Eμ‐Myc mouse model (Wall et al , 2013) or in TCF3‐activated tonic BCR signaling that activates mTORC1 (Schmitz et al , 2012). Therefore, we hypothesized that maintaining control of mTORC1 to prevent hypo‐ as well as hyperactivity is important for Burkitt's lymphoma survival.…”

Section: Resultscontrasting

confidence: 82%

“…A database survey revealed that TSC1 ‐mRNA expression is the highest in Burkitt's lymphoma‐derived cell lines compared to 36 different tumor‐type cell lines in the Cancer Cell Line Encyclopedia (CCLE; http://www.broadinstitute.org/ccle) (Fig EV1A). Moreover, the COSMIC database (http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/) lists no mutations for TSC1 or TSC2 in Burkitt's lymphoma and they are not under the recurrently mutated genes in Burkitt's lymphoma identified by genomic approaches in two studies (Richter et al , 2012; Schmitz et al , 2012). Burkitt's lymphoma is an aggressively growing malignancy characterized by a MYC translocation that induces very high expression levels of the proto‐oncogenic transcription factor MYC (Molyneux et al , 2012).…”

Section: Introductionmentioning

confidence: 99%

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Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

et al. 2018

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The tuberous sclerosis complex (TSC) 1/2 is a negative regulator of the nutrient‐sensing kinase mechanistic target of rapamycin complex (mTORC1), and its function is generally associated with tumor suppression. Nevertheless, biallelic loss of function of TSC1 or TSC2 is rarely found in malignant tumors. Here, we show that TSC1/2 is highly expressed in Burkitt's lymphoma cell lines and patient samples of human Burkitt's lymphoma, a prototypical MYC‐driven cancer. Mechanistically, we show that MYC induces TSC1 expression by transcriptional activation of the TSC1 promoter and repression of miR‐15a. TSC1 knockdown results in elevated mTORC1‐dependent mitochondrial respiration enhanced ROS production and apoptosis. Moreover, TSC1 deficiency attenuates tumor growth in a xenograft mouse model. Our study reveals a novel role for TSC1 in securing homeostasis between MYC and mTORC1 that is required for cell survival and tumor maintenance in Burkitt's lymphoma. The study identifies TSC1/2 inhibition and/or mTORC1 hyperactivation as a novel therapeutic strategy for MYC‐driven cancers.

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Section: Resultscontrasting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

et al. 2018

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“…As expected, all samples scored high for the "BCR signaling pathway" gene set, although MYC-induced BL scored lower than the others 33 (mean SES D 9.2 for BL vs. 16.5 for all others, p D 0.003) (Fig. 2C).…”

Section: Ses Detect Hallmarks Of B-nhlsmentioning

confidence: 67%

Large-scale microarray profiling reveals four stages of immune escape in non-Hodgkin lymphomas

et al. 2016

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Non-Hodgkin B-cell lymphoma (B-NHL) are aggressive lymphoid malignancies that develop in patients due to oncogenic activation, chemo-resistance, and immune evasion. Tumor biopsies show that B-NHL frequently uses several immune escape strategies, which has hindered the development of checkpoint blockade immunotherapies in these diseases. To gain a better understanding of B-NHL immune editing, we hypothesized that the transcriptional hallmarks of immune escape associated with these diseases could be identified from the meta-analysis of large series of microarrays from B-NHL biopsies. Thus, 1446 transcriptome microarrays from seven types of B-NHL were downloaded and assembled from 33 public Gene Expression Omnibus (GEO) datasets, and a method for scoring the transcriptional hallmarks in single samples was developed. This approach was validated by matching scores to phenotypic hallmarks of B-NHL such as proliferation, signaling, metabolic activity, and leucocyte infiltration. Through this method, we observed a significant enrichment of 33 immune escape genes in most diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) samples, with fewer in mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL) samples. Comparing these gene expression patterns with overall survival data evidenced four stages of cancer immune editing in B-NHL: non-immunogenic tumors (stage 1), immunogenic tumors without immune escape (stage 2), immunogenic tumors with immune escape (stage 3), and fully immuno-edited tumors (stage 4). This model complements the standard international prognostic indices for B-NHL and proposes that immune escape stages 3 and 4 (76% of the FL and DLBCL samples in this data set) identify patients relevant for checkpoint blockade immunotherapies.

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“…CCND3 mutations that generate highly stable, C-terminal truncated CYCLIN D3 proteins and drive cell cycle progression are common in human Burkitt's Lymphoma. 33 The ability of immature B cells to rapidly trigger the G1/S checkpoint by repressing Ccnd3 transcription likely depends on the relative short halflife of Cyclin D3 protein in these cells. If carboxy-truncating CCND3 mutations arise in immature B lymphocytes, they also might cause mature B cell malignancies by disrupting the control of S phase entry during B cell development.…”

Section: Discussionmentioning

confidence: 99%

Lymphocyte lineage-specific and developmental stage specific mechanisms suppress cyclin D3 expression in response to DNA double strand breaks

et al. 2016

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Mammalian cells are thought to protect themselves and their host organisms from DNA double strand breaks (DSBs) through universal mechanisms that restrain cellular proliferation until DNA is repaired. The Cyclin D3 protein drives G1-to-S cell cycle progression and is required for proliferation of immature T and B cells and of mature B cells during a T cell-dependent immune response. We demonstrate that mouse thymocytes and pre-B cells, but not mature B cells, repress Cyclin D3 protein levels in response to DSBs. This response requires the ATM protein kinase that is activated by DSBs. Cyclin D3 protein loss in thymocytes coincides with decreased association of Cyclin D3 mRNA with the HuR RNA binding protein that ATM regulates. HuR inactivation reduces basal Cyclin D3 protein levels without affecting Cyclin D3 mRNA levels, indicating that thymocytes repress Cyclin D3 expression via ATM-dependent inhibition of Cyclin D3 mRNA translation. In contrast, ATM-dependent transcriptional repression of the Cyclin D3 gene represses Cyclin D3 protein levels in pre-B cells. Retrovirus-driven Cyclin D3 expression is resistant to transcriptional repression by DSBs; this prevents pre-B cells from suppressing Cyclin D3 protein levels and from inhibiting DNA synthesis to the normal extent following DSBs. Our data indicate that immature B and T cells use lymphocyte lineage-and developmental stage-specific mechanisms to inhibit Cyclin D3 protein levels and thereby help prevent cellular proliferation in response to DSBs. We discuss the relevance of these cellular context-dependent DSB response mechanisms in restraining proliferation, maintaining genomic integrity, and suppressing malignant transformation of lymphocytes.

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Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics

Cited by 754 publications

References 43 publications

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

Large-scale microarray profiling reveals four stages of immune escape in non-Hodgkin lymphomas

Lymphocyte lineage-specific and developmental stage specific mechanisms suppress cyclin D3 expression in response to DNA double strand breaks

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