Epigenetic Dysregulation in Follicular Lymphoma

Araf, Shamzah; Okosun, Jessica; Koniali, Lola; Fitzgibbon, Jude; Heward, James A.

doi:10.2217/epi.15.96

Cited by 22 publications

(14 citation statements)

References 62 publications

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“…There are now well over 200 recurring gene mutations described, although only a minority occur in greater than 5-10% of patients. The significance of gene translocations targeting MYC, BCL2, and BCL6 are all well established, as is the recognition of widespread disruption of the epigenome, predominantly driven by somatic mutations within KMT2D, CREBBP, EZH2 and linker histones [1][2][3][4][5][6][7][8][9][10][11][12][13]. DLBCL displays a greater degree of genetic heterogeneity than FL, and can be readily divided into at least two major subtypes based on the "cell of origin" (COO): GC B cell (GCB)-like and activated B cell (ABC)-like DLBCL [14,15].…”

Section: The Molecular Landscape Of Gc Lymphomasmentioning

confidence: 99%

Precision medicine and lymphoma

Heward

Kumar²,

Korfi³

et al. 2018

Current Opinion in Hematology

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Section: The Molecular Landscape Of Gc Lymphomasmentioning

confidence: 99%

Precision medicine and lymphoma

Heward

Kumar²,

Korfi³

et al. 2018

Current Opinion in Hematology

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“…The analytes measured by GCP include nearly every well-studied post-translational modification on the core nucleosomal histone proteins. These modifications convey epigenetic information in cells and their dysregulation is associated with a wide range of diseases (Araf et al, 2016;Aumann and Abdel-Wahab, 2014;Gräff and Mansuy, 2009;Ntziachristos et al, 2016;Peña et al, 2014). We adopted guiding principles governing the generation of the resource (Supplemental Note 1).…”

Section: Structure and Scope Of The Proteomic Signature Resourcementioning

confidence: 99%

A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations

Litichevskiy

Peckner

Abelin

et al. 2017

Preprint

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Though the added value of proteomic measurements to gene expression profiling has been demonstrated, profiling of gene expression on its own remains the dominant means of understanding cellular responses to perturbation. Direct protein measurements are typically limited due to issues of cost and scale; however, the recent development of high-throughput, targeted sentinel mass spectrometry assays provides an opportunity for proteomics to contribute at a meaningful scale in high-value areas for drug development. To demonstrate the feasibility of a systematic and comprehensive library of perturbational proteomic signatures, we profiled 90 drugs (in triplicate) in six cell lines using two different proteomic assays -one measuring global changes of epigenetic marks on histone proteins and another measuring a set of peptides reporting on the phosphoproteome -for a total of more than 3,400 samples. This effort represents a first-of-its-kind resource for proteomics. The majority of tested drugs generated reproducible responses in both phosphosignaling and chromatin states, but we observed differences in the responses that were cell line-and assay-specific. We formalized the process of comparing response signatures within the data using a concept called connectivity, which enabled us to integrate data across cell types and assays. Furthermore, it facilitated incorporation of transcriptional signatures. Consistent connectivity among cell types revealed cellular responses that transcended cell-specific effects, while consistent connectivity among assays revealed unexpected associations between drugs that were confirmed by experimental follow-up. We further demonstrated how the resource could be leveraged against public domain external datasets to recognize therapeutic hypotheses that are consistent with ongoing clinical trials for the treatment of multiple myeloma and acute lymphocytic leukemia (ALL).

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“…This may be caused by a lack of proper tools to interpret the large number of non-coding variations in FL. Gene expression and function is affected not only by mutations in the genes, but also by non-coding mutations in regulatory regions 10 , 25 , thus it is essential to investigate the relationship between the non-coding mutation and FL. Motivated by aforementioned challenges, we developed a novel genome-wide analysis pipeline based on the newly updated BayesPI-BAR program, and applied it on a set whole-genome sequencing datasets of FL patients 26 , to explore unknown regulatory mutation in FL in the present study.…”

Section: Introductionmentioning

confidence: 99%

Integrative whole-genome sequence analysis reveals roles of regulatory mutations in BCL6 and BCL2 in follicular lymphoma

Batmanov

Wang

Bjørås

et al. 2017

Sci Rep

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The contribution of mutations in regulatory regions to tumorigenesis has been the subject of many recent studies. We propose a new framework for integrative analysis of genome-wide sequencing data by considering diverse genetic information. This approach is applied to study follicular lymphoma (FL), a disease for which little is known about the contribution of regulatory gene mutations. Results from a test FL cohort revealed three novel highly recurrent regulatory mutation blocks near important genes implicated in FL, BCL6 and BCL2. Similar findings were detected in a validation FL cohort. We also found transcription factors (TF) whose binding may be disturbed by these mutations in FL: disruption of FOX TF family near the BCL6 promoter may result in reduced BCL6 expression, which then increases BCL2 expression over that caused by BCL2 gene translocation. Knockdown experiments of two TF hits (FOXD2 or FOXD3) were performed in human B lymphocytes verifying that they modulate BCL6/BCL2 according to the computationally predicted effects of the SNVs on TF binding. Overall, our proposed integrative analysis facilitates non-coding driver identification and the new findings may enhance the understanding of FL.

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Epigenetic Dysregulation in Follicular Lymphoma

Cited by 22 publications

References 62 publications

Precision medicine and lymphoma

Precision medicine and lymphoma

A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations

Integrative whole-genome sequence analysis reveals roles of regulatory mutations in BCL6 and BCL2 in follicular lymphoma

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