<i>CREBBP</i>Inactivation Promotes the Development of HDAC3-Dependent Lymphomas

Jiang, Yanwen; Ortega-Molina, Ana; Geng, Huimin; Ying, Hsia Yuan; Hatzi, Katerina; Parsa, Sara; McNally, Dylan; Wang, Ling; Doane, Ashley S.; Agirre, Xabier; Teater, Matt; Meydan, Cem; Li, Zhuoning; Poloway, David; Wang, Shenqiu; Ennishi, Daisuke; Scott, David W.; Stengel, Kristy R.; Kranz, Janice E.; Holson, Edward B.; Sharma, Sneh; Young, James W.; Chu, Chi Shuen; Roeder, Robert G.; Shaknovich, Rita; Hiebert, Scott W.; Gascoyne, Randy D.; Tam, Wayne; Elemento, Olivier; Wendel, Hans Guido; Melnick, Ari

doi:10.1158/2159-8290.cd-16-0975

Cited by 242 publications

(301 citation statements)

References 42 publications

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“…While this paper was under review, 2 papers interrogating the role of Crebbp inactivation in murine B-cell lymphoma models were published. 34,49 Jiang et al reported downregulation of MHC class II genes with short hairpin RNA-mediated knock-down of Crebbp, but this was not reported by Zhang et al, using B-cell-specific deletion of Crebbp with cre recombinase, and only modest changes were shown in our study. The role of Crebbp loss compared with Crebbp KATdomain point mutation in the deregulation of MHC class II expression therefore requires further functional interrogation.…”

Section: Discussioncontrasting

confidence: 90%

“…GCB-cell development was significantly higher in all mice carrying the EmBcl2 transgene (P , .001) compared with strains without the transgene, and GCB-cell development was not significantly affected by Crebbp deletion in this background ( Figure 2). We observed only minor changes in the expression of MHC class II with Crebbp inactivation (supplemental Figure 5), similar to those observed with short hairpin RNA-mediated knock-down of Crebbp, 34 but far below the magnitude of those changes observed in primary FL with CREBBP mutation.…”

Section: Impaired B-cell Development Associated With Crebbp Losssupporting

confidence: 79%

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Crebbp loss cooperates with Bcl2 overexpression to promote lymphoma in mice

García-Ramírez

Tadros

González-Herrero

et al. 2017

Blood

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• Crebbp inactivation perturbs B-cell development, but cooperates with Bcl2 overexpression to promote lymphoma.• Transcriptional and epigenetic signatures of Crebbp loss implicate Myc in disease etiology.CREBBP is targeted by inactivating mutations in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Here, we provide evidence from transgenic mouse models that Crebbp deletion results in deficits in B-cell development and can cooperate with Bcl2 overexpression to promote B-cell lymphoma. Through transcriptional and epigenetic profiling of these B cells, we found that Crebbp inactivation was associated with broad transcriptional alterations, but no changes in the patterns of histone acetylation at the proximal regulatory regions of these genes. However, B cells with Crebbp inactivation showed high expression of Myc and patterns of altered histone acetylation that were localized to intragenic regions, enriched for Myc DNA binding motifs, and showed Myc binding. Through the analysis of CREBBP mutations from a large cohort of primary human FL and DLBCL, we show a significant difference in the spectrum of CREBBP mutations in these 2 diseases, with higher frequencies of nonsense/ frameshift mutations in DLBCL compared with FL. Together, our data therefore provide important links between Crebbp inactivation and Bcl2 dependence and show a role for Crebbp inactivation in the induction of Myc expression. We suggest this may parallel the role of CREBBP frameshift/nonsense mutations in DLBCL that result in loss of the protein, but may contrast the role of missense mutations in the lysine acetyltransferase domain that are more frequently observed in FL and yield an inactive protein.

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Section: Discussioncontrasting

confidence: 90%

Section: Impaired B-cell Development Associated With Crebbp Losssupporting

confidence: 79%

Crebbp loss cooperates with Bcl2 overexpression to promote lymphoma in mice

García-Ramírez

Tadros

González-Herrero

et al. 2017

Blood

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“…To determine possible sources of NOTCH signaling in FLs and GC B-cells we measured expression of these genes in the principle FL and DLBCL cell lines used for this study (DoHH2, SC-1, OCI-Ly1 and SUD-HL-4), purified primary mature B-cell populations: NB, GC, CB, CC, MB (memory B), TPC (tonsillar plasma cell), BMPC (bone marrow plasma cell), and in a cohort of primary FL patients by RNA-seq (30,31). Expression of NOTCH ligands DLL1, DLL3, DLL4 and JAG1 was low in all of four cell lines, although JAG2 was expressed, and possibly relevant to NOTCH activation in vitro (Figs.…”

Section: Resultsmentioning

confidence: 99%

BCL6 Antagonizes NOTCH2 to Maintain Survival of Human Follicular Lymphoma Cells

et al. 2017

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Summary Although the BCL6 transcriptional repressor is frequently expressed in human follicular lymphomas (FL), its biological role in this disease remains unknown. Herein we comprehensively identify the set of gene promoters directly targeted by BCL6 in primary human FLs. We noted that BCL6 binds and represses NOTCH2 and Notch pathway genes. Moreover, BCL6 and NOTCH2 pathway gene expression is inversely correlated in FL. Notably BCL6 up-regulation is associated with repression of Notch2 and its target genes in primary human and murine germinal center cells. Repression of Notch2 is an essential function of BCL6 in FL and GC B-cells since inducible expression of Notch2 abrogated GC formation in mice and kills FL cells. Indeed BCL6-targeting compounds or gene silencing leads to the induction of NOTCH2 activity and compromises survival of FL cells whereas NOTCH2 depletion or pathway antagonists rescue FL cells from such effects. Moreover, BCL6 inhibitors induced NOTCH2 expression and suppressed growth of human FL xenografts in vivo and primary human FL specimens ex vivo. These studies suggest that established FLs are thus dependent on BCL6 through its suppression of NOTCH2.

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“…70) or EP300 (3%-8%; ref. 71), both affecting a pathway that is also implicated in cancer (72). Several case reports indicate that individuals with RSTS are at increased risk of developing cancer, but the cancer risk is unknown and may be only moderately increased.…”

Section: Rubinstein-taybi Syndromementioning

confidence: 99%

Recommendations for Cancer Surveillance in Individuals with RASopathies and Other Rare Genetic Conditions with Increased Cancer Risk

Villani

Greer

Kalish

et al. 2017

Clinical Cancer Research

138

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In October 2016, the American Association for Cancer Research held a meeting of international childhood cancer predisposition syndrome experts to evaluate the current knowledge of these syndromes and to propose consensus surveillance recommendations. Herein, we summarize clinical and genetic aspects of RASopathies and Sotos, Weaver, Rubinstein-Taybi, Schinzel-Giedion, and NKX2-1 syndromes as well as specific metabolic disorders known to be associated with increased childhood cancer risk. In addition, the expert panel reviewed whether sufficient data exist to make a recommendation that all patients with these disorders be offered cancer surveillance. For all syndromes, the panel recommends increased awareness and prompt assessment of clinical symptoms. Patients with Costello syndrome have the highest cancer risk, and cancer surveillance should be considered. Regular physical examinations and complete blood counts can be performed in infants with Noonan syndrome if specific PTPN11 or KRAS mutations are present, and in patients with CBL syndrome. Also, the high brain tumor risk in patients with L-2 hydroxyglutaric aciduria may warrant regular screening with brain MRIs. For most syndromes, surveillance may be needed for nonmalignant health problems. Clin Cancer Res; 23(12); e83–e90. ©2017 AACR. See all articles in the online-only CCR Pediatric Oncology Series.

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CREBBPInactivation Promotes the Development of HDAC3-Dependent Lymphomas

Cited by 242 publications

References 42 publications

Crebbp loss cooperates with Bcl2 overexpression to promote lymphoma in mice

Crebbp loss cooperates with Bcl2 overexpression to promote lymphoma in mice

BCL6 Antagonizes NOTCH2 to Maintain Survival of Human Follicular Lymphoma Cells

Recommendations for Cancer Surveillance in Individuals with RASopathies and Other Rare Genetic Conditions with Increased Cancer Risk

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