A capture-sequencing strategy identifies IRF8, EBF1, and APRIL as novel IGH fusion partners in B-cell lymphoma

Bouamar, Hakim; Abbas, Saman; An, Lin; Wang, Long; Jiang, Daifeng; Holder, Kenneth N.; Kinney, Marsha C.; Hunicke-Smith, Scott Patrick; Aguiar, Ricardo C.T.

doi:10.1182/blood-2013-04-495804

Cited by 48 publications

(57 citation statements)

References 39 publications

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“…Protein isolation, electrophoresis, and transfer to polyvinylidene difluoride (PVDF) membranes were performed as we previously described (24). Filters were immunoblotted with antibodies against p53 (sc-6243; Santa Cruz Biotechnology), phospho-p53 (Ser15, 9284; Cell Signaling Technology), p21 (F-5, sc-6246; Santa Cruz Biotechnology), phospho-STAT5-Tyr694 (4322; Cell Signaling Technology), Aicda (4975; Cell Signaling Technology), Socs1 (3950; Cell Signaling Technology), and ␤-actin (Sigma).…”

Section: Methodsmentioning

confidence: 99%

MicroRNA 155 Control of p53 Activity Is Context Dependent and Mediated by Aicda and Socs1

Bouamar

Jiang

Wang

et al. 2015

Molecular and Cellular Biology

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In biological processes, the balance between positive and negative inputs is critical for an effective physiological response and to prevent disease. A case in point is the germinal center (GC) reaction, wherein high mutational and proliferation rates are accompanied by an obligatory suppression of the DNA repair machinery. Understandably, when the GC reaction goes awry, loss of immune cells or lymphoid cancer ensues. Here, we detail the functional interactions that make microRNA 155 (miR-155) a key part of this process. Upon antigen exposure, miR-155 ؊/؊ mature B cells displayed significantly higher double-strand DNA break (DSB) accumulation and p53 activation than their miR-155 ؉/؉ counterparts. Using B cell-specific knockdown strategies, we confirmed the role of the miR-155 target Aicda (activation-induced cytidine deaminase) in this process and, in combination with a gain-of-function model, unveiled a previously unappreciated role for Socs1 in directly modulating p53 activity and the DNA damage response in B lymphocytes. Thus, miR-155 controls the outcome of the GC reaction by modulating its initiation (Aicda) and termination (Socs1/p53 response), suggesting a mechanism to explain the quantitative defect in germinal center B cells found in mice lacking or overexpressing this miRNA. Somatic hypermutation (SHM) and class switch recombination (CSR) of the immunoglobulin genes are critical steps for the development of fully functional mature B cells. Several components of the cellular machinery that promotes SHM and CSR have been identified. Activation-induced cytidine deaminase (Aicda), an enzyme that deaminates cytosine to produce uracil in DNA, is thought to initiate and be essential for both SHM and CSR (1). Activation of uracil DNA glycosylase (UNG), ATM, histone H2AX, p53 binding protein 1 (53BP1), and the nonhomologous end joining protein Ku70/80, among others, also plays important roles in these processes (1, 2).The physiological SHM and CSR involve DNA mutagenesis and double-strand DNA breaks (DSB). Thus, the cellular response to these injuries must be fine-tuned so as to neither excessively engage the repair checkpoints nor compromise the integrity of the rest of the genome (3). Transient transcription repression of multiple DNA repair genes by BCL6 and high-fidelity repair of nonimmunoglobulin genes account, at least in part, for a successful germinal center (GC) response (3-7). Furthermore, timely engagement of the p53 pathway protects against AID-dependent aberrant DNA damage and chromosomal translocations (8). However, less is known about the termination of these activities, which is a critical step to prevent loss of normal B lymphocytes.MicroRNAs (miRNAs) are non-protein-coding small RNAs that regulate a vast array of physiological functions. miRNAs subtly downmodulate the expression of multiple proteins, thus functioning primarily as rheostats that match the cell needs seamlessly but effectively (9, 10). This unique property suggests that miRNAs may contribute to the control of SHM and CSR react...

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Section: Methodsmentioning

confidence: 99%

MicroRNA 155 Control of p53 Activity Is Context Dependent and Mediated by Aicda and Socs1

Bouamar

Jiang

Wang

et al. 2015

Molecular and Cellular Biology

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“…Capture sequencing using frozen or formalinfixed paraffin-embedded tissue (FFPET) has proven sensitive for resolving single base-pair somatic mutations and SRs in multiple tumor types. [10][11][12][13][14] However, this approach remains unexplored for large-scale SR detection in lymphoma FFPET. Here, we report specific breakpoint anatomy for 36 novel PDL SRs, including 19 previously undescribed translocations and 17 intrachromosomal SRs.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive characterization of programmed death ligand structural rearrangements in B-cell non-Hodgkin lymphomas

Chong

Twa

Mottok

et al. 2016

Blood

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Key Points• Capture sequencing reveals that PDL SRs cluster into 2 discrete breakpoint regions.• PDL SRs are significantly associated with increased protein expression and limit T-cell activation.Programmed death ligands (PDLs) are immune-regulatory molecules that are frequently affected by chromosomal alterations in B-cell lymphomas. Although PDL copy-number variations are well characterized, a detailed and comprehensive analysis of structural rearrangements (SRs) and associated phenotypic consequences is largely lacking. Here, we used oligonucleotide capture sequencing of 67 formalin-fixed paraffin-embedded tissues derived from primary B-cell lymphomas and 1 cell line to detect and characterize, at base-pair resolution, SRs of the PDL locus (9p24.1; harboring PDL1/CD274 and PDL2/ PDCD1LG2). We describe 36 novel PDL SRs, including 17 intrachromosomal events (inversions, duplications, deletions) and 19 translocations involving BZRAP-AS1, CD44, GET4, IL4R, KIAA0226L, MID1, RCC1, PTPN1 and segments of the immunoglobulin loci. Moreover, analysis of the precise chromosomal breakpoints reveals 2 distinct cluster breakpoint regions (CBRs) within either CD274 (CBR1) or PDCD1LG2 (CBR2). To determine the phenotypic consequences of these SRs, we performed immunohistochemistry for CD274 and PDCD1LG2 on primary pretreatment biopsies and found that PDL SRs are significantly associated with PDL protein expression. Finally, stable ectopic expression of wild-type PDCD1LG2 and the PDCD1LG2-IGHV7-81 fusion showed, in coculture, significantly reduced T-cell activation. Taken together, our data demonstrate the complementary utility of fluorescence in situ hybridization and capture sequencing approaches and provide a classification scheme for PDL SRs with implications for future studies using PDL immune-checkpoint inhibitors in B-cell lymphomas. (Blood. 2016;128(9):1206-1213

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“…IRF8 has also been implicated in the development of B cell-driven systemic autoimmune diseases in humans and mice (31,32). Finally, several recent studies have identified roles for IRF8 in the pathogenesis of human diffuse large B cell lymphoma (33,34) and probably mouse diffuse large B cell lymphoma as well (15).…”

Section: Discussionmentioning

confidence: 99%

Interferon Regulatory Factor 8 (IRF8) Interacts with the B Cell Lymphoma 6 (BCL6) Corepressor BCOR

Yoon

Feng

Kim

et al. 2014

Journal of Biological Chemistry

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Background: Protein partnerships regulate specific functions of cells. BCOR protein-protein interactions are critical to aspects of B cell biology. Results: IRF8 pairs with BCOR in the nucleus to enhance its transcriptional repressive activity. Conclusion: Partnering of IRF8 with BCOR defines a novel mechanism for controlling B cell gene expression. Significance: Understanding gene regulation in specific cell types requires identification of protein complexes that modulate expression.

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A capture-sequencing strategy identifies IRF8, EBF1, and APRIL as novel IGH fusion partners in B-cell lymphoma

Cited by 48 publications

References 39 publications

MicroRNA 155 Control of p53 Activity Is Context Dependent and Mediated by Aicda and Socs1

MicroRNA 155 Control of p53 Activity Is Context Dependent and Mediated by Aicda and Socs1

Comprehensive characterization of programmed death ligand structural rearrangements in B-cell non-Hodgkin lymphomas

Interferon Regulatory Factor 8 (IRF8) Interacts with the B Cell Lymphoma 6 (BCL6) Corepressor BCOR

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