The Eph-Receptor A7 Is a Soluble Tumor Suppressor for Follicular Lymphoma

Oricchio, Elisa; Nanjangud, Gouri J.; Wolfe, Andrew L.; Schatz, Jonathan H.; Mavrakis, Konstantinos J.; Jiang, Man; Li, Xiaoping; Bruno, JoAnne; Heguy, Adriana; Olshen, Adam B.; Socci, Nicholas D.; Teruya‐Feldstein, Julie; Weis-Garcia, Frances; Tam, Wayne; Shaknovich, Rita; Melnick, Ari; Himanen, Juha P.; Chaganti, R. S. K.; Wendel, Hans Guido

doi:10.1016/j.cell.2011.09.035

Cited by 151 publications

(154 citation statements)

References 60 publications

(83 reference statements)

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“…S10G). To ensure this effect was not the result of cosegregation between CREBBP mutations and deletions of the MHC class II locus, we interrogated somatic copy number data from our exome series and additional publicly available high-resolution data (12,13,(22)(23)(24). Although we detected deletions of the MHC class II locus in a subset of patients (SI Appendix, Fig.…”

Section: Frequent Cooccurring Mutations Of Chromatin-modifying Genes mentioning

confidence: 99%

Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation

Green

Kihira²,

Liu³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

325

372

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Follicular lymphoma (FL) is incurable with conventional therapies and has a clinical course typified by multiple relapses after therapy. These tumors are genetically characterized by B-cell leukemia/lymphoma 2 (BCL2) translocation and mutation of genes involved in chromatin modification. By analyzing purified tumor cells, we identified additional novel recurrently mutated genes and confirmed mutations of one or more chromatin modifier genes within 96% of FL tumors and two or more in 76% of tumors. We defined the hierarchy of somatic mutations arising during tumor evolution by analyzing the phylogenetic relationship of somatic mutations across the coding genomes of 59 sequentially acquired biopsies from 22 patients. Among all somatically mutated genes, CREBBP mutations were most significantly enriched within the earliest inferable progenitor. These mutations were associated with a signature of decreased antigen presentation characterized by reduced transcript and protein abundance of MHC class II on tumor B cells, in line with the role of CREBBP in promoting class II transactivator (CIITA)-dependent transcriptional activation of these genes. CREBBP mutant B cells stimulated less proliferation of T cells in vitro compared with wild-type B cells from the same tumor. Transcriptional signatures of tumor-infiltrating T cells were indicative of reduced proliferation, and this corresponded to decreased frequencies of tumor-infiltrating CD4 helper T cells and CD8 memory cytotoxic T cells. These observations therefore implicate CREBBP mutation as an early event in FL evolution that contributes to immune evasion via decreased antigen presentation. lymphoma | exome | hierarchy | antigen presentation | CREBBP

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Section: Frequent Cooccurring Mutations Of Chromatin-modifying Genes mentioning

confidence: 99%

Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation

Green

Kihira²,

Liu³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

325

372

View full text Add to dashboard Cite

show abstract

“…More recently, Oricchio et al performed a systematic screen of genes within commonly deleted regions on the long arm of chromosome 6 (45), motivated by the high frequency of 6q deletions in FL as well as their association with adverse outcome (41). This screen revealed TNFAIP3/A20, a negative regulator of NF-κB signaling, as well as the receptor tyrosine kinase EPHA7 as potential tumor suppressors in FL (45). The authors demonstrated that silencing of EPHA7 decreased lymphomagenesis latency in VavP-BCL2 transgenic mice, and that restoration of its tumor suppressor function through administration of exogenous EPHA7 delayed tumor formation in xenograft models.…”

Section: Genetic Landscape Of Flmentioning

confidence: 99%

Pathogenesis of follicular lymphoma

Lackraj

Goswami

Kridel

2018

Best Practice & Research Clinical Haematology

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The hallmark t(14;18)(q32;q21) in follicular lymphoma (FL) results in constitutive overexpression of the BCL2 protein, allowing B cells to abrogate the default germinal center apoptotic program. Most tumors are characterized by recurrent secondary genetic alterations including genomic gains, losses, and mutations, some providing a growth advantage, including alterations in MLL2, EPHA7, TNFRSF14, and EZH2. The sequence in which these events occur and how they contribute to progression and ultimately to transformation is unclear. Lastly, crosstalk between neoplastic B cells and non-neoplastic immune and stromal cells in the microenvironment plays an important role in sustaining tumor cell growth, cultivating immune privilege, and promoting transformation.

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“…To ensure potent knock down as single-copy integrants, the shRNAs were cloned in the context of an miR-30 backbone in an MSCV-based, GFP-expressing vector (32). Based on initial "reconstruction" studies, the Cancer 1,000 library was subdivided in six pools, each containing 288 shRNAs, and supplemented with a seventh pool comprising 260 additional shRNAs against cancer-related genes (1-7 shRNAs per gene) (33). After transduction with the seven pools of shRNAs from the modified Cancer 1,000 library, the 4TO7-TGL cells were injected into the tail vein of 49 recipient mice (Fig.…”

Section: Gain-of-function Screens Identify Micrornas That Promote Metmentioning

confidence: 99%

Forward genetic screens in mice uncover mediators and suppressors of metastatic reactivation

Gao

Chakraborty²,

Lee-Lim³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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We have developed a screening platform for the isolation of genetic entities involved in metastatic reactivation. Retroviral libraries of cDNAs from fully metastatic breast-cancer cells or pooled microRNAs were transduced into breast-cancer cells that become dormant upon infiltrating the lung. Upon inoculation in the tail vein of mice, the cells that had acquired the ability to undergo reactivation generated metastatic lesions. Integrated retroviral vectors were recovered from these lesions, sequenced, and subjected to a second round of validation. By using this strategy, we isolated canonical genes and microRNAs that mediate metastatic reactivation in the lung. To identify genes that oppose reactivation, we screened an expression library encoding shRNAs, and we identified target genes that encode potential enforcers of dormancy. Our screening strategy enables the identification and rapid biological validation of single genetic entities that are necessary to maintain dormancy or to induce reactivation. This technology should facilitate the elucidation of the molecular underpinnings of these processes.forward genetic screens | metastatic reactivation | cDNA library screen | shRNA library screen | microRNA library screen T he majority of cancer-related deaths are caused by metastatic relapse (1). The process through which cancer cells acquire metastatic capacity is complex. Unrestrained proliferation, resistance to proapoptotic insults, and invasion through tissue boundaries are not sufficient for metastasis. To colonize distant organs, cancer cells must also adapt to the local microenvironment of the target organ and finally outgrow (2, 3). Mathematical modeling of clinical data and experiments in mouse models suggest that cancer cells disseminating from prevalent cancers, such as those of the breast and prostate, undergo an extended period of dormancy at premetastatic sites (4). Insights into the mechanisms that enable disseminated cancer cells to survive during dormancy and then outgrow into life-threatening lesions may lead to the identification of novel therapeutic targets for the prevention or treatment of metastatic disease.Advances in genomics and mouse modeling have fostered a renaissance of studies on metastasis (2, 3). Current approaches to the study of metastasis can be divided in two categories. In the first, genetic methods are used to modify the function of a candidate gene in intact mice or in cells that are subsequently transplanted in mice (5, 6). In the second, genomic methods, such as DNA microarray analysis or array comparative genomic hybridization (aCGH), are used to identify a restricted number of candidate genes, which are then tested in appropriate mouse models (7,8). Although these approaches have been extremely successful, they are very laborious and do not necessarily yield biologically potent mediators of metastasis. Functional genetic screens can lead to the rapid identification of strong mediators of a selectable phenotype (9, 10). In agreement with this notion, recent studies have ...

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The Eph-Receptor A7 Is a Soluble Tumor Suppressor for Follicular Lymphoma

Cited by 151 publications

References 60 publications

Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation

Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation

Pathogenesis of follicular lymphoma

Forward genetic screens in mice uncover mediators and suppressors of metastatic reactivation

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