Inactivation of CREBBP expands the germinal center B cell compartment, down-regulates MHCII expression and promotes DLBCL growth.

Abstract:

:The genes encoding the histone acetyl-transferases (HATs) CREB binding protein (CREBBP) and EP300 are recurrently mutated in the activated B cell-like and germinal center (GC) B cell-like subtypes of diffuse large B cell lymphoma (DLBCL). Here, we introduced a patient mutation into a human DLBCL cell line using CRISPR and deleted Crebbp and Ep300 in the GC B cell compartment of mice. CREBBP-mutant DLBCL clones exhibited reduced histone H3 acetylation, expressed significantly less MHCII, and grew faster than wild-type clones in s.c. and orthotopic xenograft models. Mice lacking Crebbp in GC B cells exhibited hyperproliferation of their GC compartment upon immunization, had reduced MHCII surface expression on GC cells, and developed accelerated MYC-driven lymphomas. Ep300 inactivation reproduced some, but not all, consequences of Crebbp inactivation. MHCII deficiency phenocopied the effects of CREBBP loss in spontaneous and serial transplantation models of MYC-driven lymphomagenesis, supporting the idea that the mutational inactivation of CREBBP promotes immune evasion. Indeed, the depletion of CD4+ T cells greatly facilitated the engraftment of lymphoma cells in serial transplantation models. In summary, we provide evidence that both HATs are bona fide tumor suppressors that control MHCII expression and promote tumor immune control; mutational inactivation of CREBBP, but not of EP300, has additional cell-intrinsic engraftment and growth-promoting effects.

authors

Hashwah H,Schmid CA,Kasser S,Bertram K,Stelling A,Manz MG,Müller A

doi

10.1073/pnas.1619555114

subject

Has Abstract

pub_date

2017-09-05 00:00:00

pages

9701-9706

issue

36

eissn

0027-8424

issn

1091-6490

pii

1619555114

journal_volume

114

pub_type

杂志文章
  • The Vibrio cholerae O139 O-antigen polysaccharide is essential for Ca2+-dependent biofilm development in sea water.

    abstract::Vibrio cholerae is both an inhabitant of estuarine environments and the etiologic agent of the diarrheal disease cholera. Previous work has demonstrated that V. cholerae forms both an exopolysaccharide-dependent biofilm and a Ca2+-dependent biofilm. In this work, we demonstrate a role for the O-antigen polysaccharide ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.2334614100

    authors: Kierek K,Watnick PI

    更新日期:2003-11-25 00:00:00

  • Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers.

    abstract::The use of proteasome inhibitors to target cancer's dependence on altered protein homeostasis has been greatly limited by intrinsic and acquired resistance. Analyzing data from thousands of cancer lines and tumors, we find that those with suppressed expression of one or more 19S proteasome subunits show intrinsic prot...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1619067114

    authors: Tsvetkov P,Sokol E,Jin D,Brune Z,Thiru P,Ghandi M,Garraway LA,Gupta PB,Santagata S,Whitesell L,Lindquist S

    更新日期:2017-01-10 00:00:00

  • Canonical Wnt signaling negatively regulates platelet function.

    abstract::Wnts regulate important intracellular signaling events, and dysregulation of the Wnt pathway has been linked to human disease. Here, we uncover numerous Wnt canonical effectors in human platelets where Wnts, their receptors, and downstream signaling components have not been previously described. We demonstrate that th...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0906268106

    authors: Steele BM,Harper MT,Macaulay IC,Morrell CN,Perez-Tamayo A,Foy M,Habas R,Poole AW,Fitzgerald DJ,Maguire PB

    更新日期:2009-11-24 00:00:00

  • Temporal and regional differences in the olfactory proteome as a consequence of MeCP2 deficiency.

    abstract::Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the gene encoding MeCP2. By binding to methylated CpG dinucleotide promoter regions, MeCP2 acts as a transcriptional repressor, predicting that its absence might result in widespread aberrant gene transcription, leading to the RTT phenotype. C...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0307083101

    authors: Matarazzo V,Ronnett GV

    更新日期:2004-05-18 00:00:00

  • Inducible response required for repair of low-dose radiation damage in human fibroblasts.

    abstract::Ionizing radiation (IR) induces a variety of DNA lesions among which DNA double-strand breaks (DSBs) are the biologically most significant. It is currently unclear if DSB repair is equally efficient after low and high doses. Here, we use gamma-H2AX, phospho-ATM (pATM), and 53BP1 foci analysis to monitor DSB repair. We...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1002213107

    authors: Grudzenski S,Raths A,Conrad S,Rübe CE,Löbrich M

    更新日期:2010-08-10 00:00:00

  • A widely expressed betaIII spectrin associated with Golgi and cytoplasmic vesicles.

    abstract::Spectrin is an important structural component of the plasma membrane skeleton. Heretofore-unidentified isoforms of spectrin also associate with Golgi and other organelles. We have discovered another member of the beta-spectrin gene family by homology searches of the GenBank databases and by 5' rapid amplification of c...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.95.24.14158

    authors: Stankewich MC,Tse WT,Peters LL,Ch'ng Y,John KM,Stabach PR,Devarajan P,Morrow JS,Lux SE

    更新日期:1998-11-24 00:00:00

  • Characterization of 80-million-year-old mollusk shell proteins.

    abstract::Fossil glycoproteins of the soluble organic matrix are present in an 80-million-year-old mollusk shell from the Late Cretaceous Period. Discrete molecular weight components, as determined by gel electrophoresis, are preserved. The fossil organic matrix was compared with the organic matrix of a living representative sp...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 历史文章,杂志文章

    doi:10.1073/pnas.73.8.2541

    authors: Weiner S,Lowenstam HA,Hood L

    更新日期:1976-08-01 00:00:00

  • Autologous engineering of cartilage.

    abstract::Treatment of full-thickness damage to hyaline cartilage is hampered by the limited availability of autologous healthy cartilage and the lengthy, cost-prohibitive cell isolation and expansion steps associated with autologous cartilage implantation (ACI). Here we report a strategy for de novo engineering of ectopic auto...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0907774107

    authors: Emans PJ,van Rhijn LW,Welting TJ,Cremers A,Wijnands N,Spaapen F,Voncken JW,Shastri VP

    更新日期:2010-02-23 00:00:00

  • Assembly of functional proton-translocating ATPase complex in yeast mitochondria with cytoplasmically synthesized subunit 8, a polypeptide normally encoded within the organelle.

    abstract::A mitochondrial gene from Saccharomyces cerevisiae encoding a hydrophobic membrane protein, subunit 8 of the F0/F1-type mitochondrial ATPase complex, has been functionally replaced by an artificial nuclear gene specifying an imported version of this protein. The experiments reported here utilized a multicopy expressio...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.85.7.2091

    authors: Nagley P,Farrell LB,Gearing DP,Nero D,Meltzer S,Devenish RJ

    更新日期:1988-04-01 00:00:00

  • Porcine pituitary dynorphin: complete amino acid sequence of the biologically active heptadecapeptide.

    abstract::The full primary structure of the very potent opioid peptide dynorphin, from porcine pituitary, has been determined. It is (H)Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln(OH). The synthetic peptide with this sequence behaves identically to natural dynorphin in a number of ways, and it has the sa...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.78.11.7219

    authors: Goldstein A,Fischli W,Lowney LI,Hunkapiller M,Hood L

    更新日期:1981-11-01 00:00:00

  • Platelet-derived growth factor gene expression in human atherosclerotic plaques and normal artery wall.

    abstract::We previously demonstrated that the B chain of platelet-derived growth factor (PDGF-B) is transcribed in human atherosclerotic plaques, indicating that production of growth factors within plaques could occur during atherogenesis. However, since atherosclerotic plaques are composed of several cell types and three of th...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.85.8.2810

    authors: Barrett TB,Benditt EP

    更新日期:1988-04-01 00:00:00

  • Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity.

    abstract::Colon carcinoma is one of the leading causes of death from cancer and is characterized by a heterogenic pool of cells with distinct differentiation patterns. Recently, it was reported that a population of undifferentiated cells from a primary tumor, so-called cancer stem cells (CSC), can reconstitute the original tumo...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0805706105

    authors: Vermeulen L,Todaro M,de Sousa Mello F,Sprick MR,Kemper K,Perez Alea M,Richel DJ,Stassi G,Medema JP

    更新日期:2008-09-09 00:00:00

  • Mobile device data reveal the dynamics in a positive relationship between human mobility and COVID-19 infections.

    abstract::Accurately estimating human mobility and gauging its relationship with virus transmission is critical for the control of COVID-19 spreading. Using mobile device location data of over 100 million monthly active samples, we compute origin-destination travel demand and aggregate mobility inflow at each US county from Mar...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.2010836117

    authors: Xiong C,Hu S,Yang M,Luo W,Zhang L

    更新日期:2020-11-03 00:00:00

  • Nuclear magnetic resonance study of the globular domain of chicken histone H5: resonance assignment and secondary structure.

    abstract::A 1H NMR study of the 79-residue globular domain of chicken erythrocyte histone H5 (GH5) is presented. Using a combination of two-dimensional NMR techniques to demonstrate through-bond and through-space (less than 5 A) connectivities, the resonances of GH5 are assigned in a sequential manner. From a qualitative interp...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.83.20.7628

    authors: Zarbock J,Clore GM,Gronenborn AM

    更新日期:1986-10-01 00:00:00

  • Cryoprotectant-free cryopreservation of mammalian cells by superflash freezing.

    abstract::Cryopreservation is widely used to maintain backups of cells as it enables the semipermanent storage of cells. During the freezing process, ice crystals that are generated inside and outside the cells can lethally damage the cells. All conventional cryopreservation methods use at least one cryoprotective agent (CPA) t...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1808645116

    authors: Akiyama Y,Shinose M,Watanabe H,Yamada S,Kanda Y

    更新日期:2019-04-16 00:00:00

  • Extensive and specific responses of a eukaryote to bacterial quorum-sensing signals.

    abstract::Many bacteria use N-acyl homoserine lactone (AHL) signals to coordinate the behavior of individual cells in a local population. The successful infection of eukaryotic hosts by bacteria seems to depend particularly on such AHL-mediated "quorum-sensing" regulation. We have used proteome analysis to show that a eukaryoti...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.262672599

    authors: Mathesius U,Mulders S,Gao M,Teplitski M,Caetano-Anolles G,Rolfe BG,Bauer WD

    更新日期:2003-02-04 00:00:00

  • Is there a single pathway for the folding of a polypeptide chain?

    abstract::We argue that folding of the compact domains of proteins can occur with adequate rapidity in the absence of a unique directed mechanism, provided that native-like local structure dominates the folding process. We further suggest that the evolution of amino acid sequences should favor multiple paths to the folded state...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.82.12.4028

    authors: Harrison SC,Durbin R

    更新日期:1985-06-01 00:00:00

  • Dermorphin-related peptides from the skin of Phyllomedusa bicolor and their amidated analogs activate two mu opioid receptor subtypes that modulate antinociception and catalepsy in the rat.

    abstract::Three naturally occurring dermorphin-like peptides from the skin of the frog Phyllomedusa bicolor, the related carboxyl-terminal amides, and some substituted analogs were synthesized, their binding profiles to opioid receptors were determined, and their biological activities were studied in isolated organ preparations...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.89.15.7203

    authors: Negri L,Erspamer GF,Severini C,Potenza RL,Melchiorri P,Erspamer V

    更新日期:1992-08-01 00:00:00

  • Mathematical theory of group selection: Structure of group selection in founder populations determined from convexity of the extinction operator.

    abstract::Genetic analysis for group selection is developed for the case of a biallelic locus (A, a) undergoing group selection of founder populations only. By contrast to R. Levins"E = E(x) models, extinction now depends on genetics at the propagule stage but acts uniformly on larger populations. Biological evidence supports t...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.75.4.1909

    authors: Boorman SA

    更新日期:1978-04-01 00:00:00

  • Structure and evolution of four POU domain genes expressed in mouse brain.

    abstract::Four mouse POU domain genomic DNA clones--Brain-1, Brain-2, Brain-4, and Scip--and Brain-2 cDNA, which are expressed in adult brain, were cloned and the coding and noncoding regions of the genes were sequenced. The amino acid sequences of the four POU domains are highly conserved; sequences in other regions of the pro...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.89.8.3280

    authors: Hara Y,Rovescalli AC,Kim Y,Nirenberg M

    更新日期:1992-04-15 00:00:00

  • Intrathymic maturation of murine T lymphocytes from CD8+ precursors.

    abstract::The CD4-8- thymocyte subset contains immature precursors for phenotypically and functionally mature CD4+8- and CD4-8+ thymocytes and peripheral T cells, as well as nonmature CD4+8+ thymocytes, most of which die in situ. The intrathymic death of most thymocytes is probably related to selective influences that ensure th...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.86.19.7542

    authors: Guidos CJ,Weissman IL,Adkins B

    更新日期:1989-10-01 00:00:00

  • Population genetics of multigene family with special reference to decrease of genetic correlation with distance between gene members on a chromosome.

    abstract::A mathematical method is developed which enables us to treat exactly the process of coincidental evolution under mutation, unequal intrachromosomal crossing-over as well as ordinary crossing-over between homologous chromosomes in a finite population of the effective size N. It makes use of finite difference equations ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.76.8.4001

    authors: Kimura M,Ohta T

    更新日期:1979-08-01 00:00:00

  • Evidence for an ancient adaptive episode of convergent molecular evolution.

    abstract::Documented cases of convergent molecular evolution due to selection are fairly unusual, and examples to date have involved only a few amino acid positions. However, because convergence mimics shared ancestry and is not accommodated by current phylogenetic methods, it can strongly mislead phylogenetic inference when it...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0900233106

    authors: Castoe TA,de Koning AP,Kim HM,Gu W,Noonan BP,Naylor G,Jiang ZJ,Parkinson CL,Pollock DD

    更新日期:2009-06-02 00:00:00

  • Evidence for insulin-induced internalization and degradation of insulin receptors in rat adipocytes.

    abstract::We have investigated the theory that the insulin-induced loss of insulin binding from adipocytes is due to internalization of insulin receptors. Cell-surface receptors were assessed by the binding capacity of intact cells at 16 degrees C. Total (i.e., cell-surface plus intracellular) receptors were assessed by solubil...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.79.2.427

    authors: Green A,Olefsky JM

    更新日期:1982-01-01 00:00:00

  • Construction and characterization of an Escherichia coli plasmid bearing a functional gene G of bacteriophage phiX174.

    abstract::In order to study the mutagenic effects of site-specific, covalent modifications of biologically active DNA, we need host cells that are permissive for any type of mutation that might be produced in vivo from the modified DNA. Specifically, we require a general, in vivo complementation system for the bacteriophage phi...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.75.2.774

    authors: Humayun MZ,Chambers RW

    更新日期:1978-02-01 00:00:00

  • An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma.

    abstract::The incidence of pediatric adrenal cortical carcinoma (ACC) in southern Brazil is 10-15 times higher than that of pediatric ACC worldwide. Because childhood ACC is associated with Li-Fraumeni syndrome, we examined the cancer history and p53 status of 36 Brazilian patients and their families. Remarkably, 35 of 36 patie...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.161479898

    authors: Ribeiro RC,Sandrini F,Figueiredo B,Zambetti GP,Michalkiewicz E,Lafferty AR,DeLacerda L,Rabin M,Cadwell C,Sampaio G,Cat I,Stratakis CA,Sandrini R

    更新日期:2001-07-31 00:00:00

  • Cerebellar theta oscillations are synchronized during hippocampal theta-contingent trace conditioning.

    abstract::The hippocampus and cerebellum are critically involved in trace eyeblink classical conditioning (EBCC). The mechanisms underlying the hippocampal-cerebellar interaction during this task are not well-understood, although hippocampal theta (3-7 Hz) oscillations are known to reflect a favorable state for EBCC. Two groups...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0908403106

    authors: Hoffmann LC,Berry SD

    更新日期:2009-12-15 00:00:00

  • Racemization as a stereochemical measure of dynamics and robustness in shape-shifting organic molecules.

    abstract::Bullvalene is a structurally unique dynamic molecule thought to interconvert among 1.2 million degenerate isomers. The incorporation of different chemical substituents onto the bullvalene core should lead to a "shape-shifting" molecule that can interconvert among thousands of discrete structural isomers. Previous NMR ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1108170108

    authors: He M,Bode JW

    更新日期:2011-09-06 00:00:00

  • Progression from a stem cell-like state to early differentiation in the C. elegans germ line.

    abstract::Controls of stem cell maintenance and early differentiation are known in several systems. However, the progression from stem cell self-renewal to overt signs of early differentiation is a poorly understood but important problem in stem cell biology. The Caenorhabditis elegans germ line provides a genetically defined m...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0912704107

    authors: Cinquin O,Crittenden SL,Morgan DE,Kimble J

    更新日期:2010-02-02 00:00:00

  • Microangiectasias: structural regulators of lymphocyte transmigration.

    abstract::The migration of lymphocytes into inflammatory tissue requires the migrating cell to overcome mechanical forces produced by blood flow. A generally accepted hypothesis is that these forces are overcome by a multistep sequence of adhesive interactions between lymphocytes and endothelial cells. This hypothesis has been ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1232173100

    authors: Secomb TW,Konerding MA,West CA,Su M,Young AJ,Mentzer SJ

    更新日期:2003-06-10 00:00:00