RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia
Open accessAbstract
Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
TRIM33 was identified as a unique requirement in B-ALL, whereas the majority of other dependencies had been identified in a prior AML screen.
“The majority of these factors had been identified in a prior screen that evaluated the requirement of chromatin regulators in MLL-AF9/NrasG12D acute myeloid leukemia (AML) (Zuber et al., 2011b), however TRIM33 was identified here as a unique requirement in B-ALL.”
From The transcriptional cofactor TRIM33 prevents apoptosis in B lymphoblastic leukemia by deactivating a single enhancer (2015) · cites this paper as Zuber et al., 2011b
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · see citing works
Transformation from committed progenitor to leukaemia stem cell initiated by MLL–AF9
Krivtsov, A. V., Twomey, D., Feng, Z., Stubbs, M. C., Wang, Y., Faber, J., Levine, J. E., Wang, J., Hahn, W. C., Gilliland, D. G., et al. (2006) · Nature · doi:10.1038/nature04980 · Cited by 1,513 · see citing works
Flagged first, then by citations
Research works printed but not linked: 39
- [31]Taylor J Schenck I Blankenberg D Nekrutenko A Using galaxy to perform large-scale interactive data analyses in Curr. Protoc. Bioinformatics Ch 2007 10 Unit 10.5 PMC3418382 18428782
- [32]Dickins RA Probing tumor phenotypes using stable and regulated synthetic microRNA precursors Nature Genet 2005 37 1289 1295 16200064
- [33]Hemann MT An epi-allelicseries of p53 hypomorphs created by stable RNAi produces distinct tumor phenotypes in vivo Nature Genet 2003 33 396 400 12567186
- [34]Wei J Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia Cancer Cell 2008 13 483 495 18538732 PMC2486365
- [35]Wunderlich M Mulloy JC Model systems for examining effects of leukemia-associated oncogenes in primary human CD34+ cells via retroviral transduction Methods Mol. Biol 2009 538 263 285 19277588 PMC2825883
- [36]Bennett JM Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group Br. J. Haematol 1976 33 451 458 188440
- [37]Bennett JM Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British cooperative group Ann. Intern. Med 1985 103 620 625 3862359
- [38]Vardiman JW The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes Blood 2009 114 937 951 19357394
- [39]Reich M GenePattern 2.0 Nature Genet 2006 38 500 501 16642009
- [40]Steger DJ DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells Mol. Cell. Biol 2008 28 2825 2839 18285465 PMC2293113
- [41]Zeng PY Vakoc CR Chen ZC Blobel GA Berger SL In vivo dual cross-linking for identification of indirect DNA-associated proteins by chromatin immunoprecipitation Biotechniques 2006 41 694 698 17191611
- [1]Chi P Allis CD Wang GG Covalent histone modifications—miswritten, misinterpreted and mis-erased in human cancers Nature Rev. Cancer 2010 10 457 469 20574448 PMC3262678
- [2]Chen J Odenike O Rowley JD Leukaemogenesis: more than mutant genes Nature Rev. Cancer 2010 10 23 36 20029422 PMC2972637
- [3]Gilliland DG Jordan CT Felix CA The molecular basis of leukemia Hematology (Am. Soc. Hematol. Educ. Program) 2004 80 97 15561678
- [4]Figueroa ME DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia Cancer Cell 2010 17 13 27 20060365 PMC3008568
- [5]Dick JE Stem cell concepts renew cancer research Blood 2008 112 4793 4807 19064739
- [6]Wang J Hoshino T Redner RL Kajigaya S Liu JM ETO, fusion partner in t(8;21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC1 complex Proc. Natl Acad. Sci. USA 1998 95 10860 10865 9724795 PMC27986
- [7]Krivtsov AV H3K79 methylation profiles define murine and human MLL-AF4 leukemias Cancer Cell 2008 14 355 368 18977325 PMC2591932
- [8]Delhommeau F Mutation in TET2 in myeloid cancers N. Engl. J. Med 2009 360 2289 2301 19474426
- [9]Ley TJ DNMT3A mutations in acute myeloid leukemia N. Engl. J. Med 2010 363 2424 2433 21067377 PMC3201818
- [10]Zuber J Toolkit for evaluating genes required for proliferation and survival using tetracycline-regulated RNAi Nature Biotechnol 2011 29 79 83 21131983 PMC3394154
- [11]Yokoyama A Cleary ML Menin critically links MLL proteins with LEDGF on cancer-associated target genes Cancer Cell 2008 14 36 46 18598942 PMC2692591
- [12]Yokoyama A The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis Cell 2005 123 207 218 16239140
- [13]Wu SY Chiang CM The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation J. Biol. Chem 2007 282 13141 13145 17329240
- [14]French CA BRD4–NUT fusion oncogene: a novel mechanism in aggressive carcinoma Cancer Res 2003 63 304 307 12543779
- [15]Filippakopoulos P Selective inhibition of BET bromodomains Nature 2010 468 1067 1073 20871596 PMC3010259
- [16]Nicodeme E Suppression of inflammation by a synthetic histone mimic Nature 2010 468 1119 1123 21068722 PMC5415086
- [17]Zuber J Mouse models of human AML accurately predict chemotherapy response Genes Dev 2009 23 877 889 19339691 PMC2666344
- [18]Somervaille TC Cleary ML Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia Cancer Cell 2006 10 257 268 17045204
- [21]Somervaille TC Hierarchical maintenance of MLL myeloid leukemia stem cells employs a transcriptional program shared with embryonic rather than adult stem cells Cell Stem Cell 2009 4 129 140 19200802 PMC2670853
- [22]Kim J A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs Cell 2010 143 313 324 20946988 PMC3018841
- [23]Wong P The miR-17-92 microRNA polycistron regulates MLL leukemia stem cell potential by modulating p21 expression Cancer Res 2010 70 3833 3842 20406979 PMC2862107
- [24]Jang MK The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription Mol. Cell 2005 19 523 534 16109376
- [25]Yang Z He N Zhou Q Brd4 recruits P-TEFb to chromosomes at late mitosis to promote G1 gene expression and cell cycle progression Mol. Cell. Biol 2008 28 967 976 18039861 PMC2223388
- [26]Schuhmacher M The transcriptional program of a human B cell line in response to Myc Nucleic Acids Res 2001 29 397 406 11139609 PMC29676
- [27]Schmidt M Nazarov V Stevens L Watson R Wolff L Regulation of the resident chromosomal copy of c-myc by c-Myb is involved in myeloid leukemogenesis Mol. Cell. Biol 2000 20 1970 1981 10688644 PMC110814
- [28]Soucek L Modelling Myc inhibition as a cancer therapy Nature 2008 455 679 683 18716624 PMC4485609
- [29]Felsher DW Bishop JM Reversible tumorigenesis by MYC in hematopoietic lineages Mol. Cell 1999 4 199 207 10488335
- [30]Wilson A c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation Genes Dev 2004 18 2747 2763 15545632 PMC528895
Cited by
Sorted by citations
Cancer epigenetics: from mechanism to therapy
Dawson, M. A., & Kouzarides, T. (2012) · Cell · doi:10.1016/j.cell.2012.06.013 · Cited by 3,203 · see citing works
Selective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers
Lovén, J., Hoke, H. A., Lin, C. Y., Lau, A., Orlando, D. A., Vakoc, C. R., Bradner, J. E., Lee, T. I., & Young, R. A. (2013) · Cell · doi:10.1016/j.cell.2013.03.036 · Cited by 2,961 · see citing works
Self-citationA decade of exploring the cancer epigenome—biological and translational implications
Baylin, S. B., & Jones, P. A. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3130 · Cited by 2,871 · see citing works
The PI3K Pathway in Human Disease
Fruman, D. A., Chiu, H., Hopkins, B. D., Bagrodia, S., Cantley, L. C., & Abraham, R. T. (2017) · Cell · doi:10.1016/j.cell.2017.07.029 · Cited by 2,749 · see citing works
Phthalimide conjugation as a strategy for in vivo target protein degradation
Winter, G. E., Buckley, D. L., Paulk, J., Roberts, J. M., Souza, A., Dhe-Paganon, S., & Bradner, J. E. (2015) · Science · doi:10.1126/science.aab1433 · Cited by 1,760 · see citing works
Self-citationHistone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders
Falkenberg, K. J., & Johnstone, R. W. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4360 · Cited by 1,564 · see citing works
Transcriptional enhancers: from properties to genome-wide predictions
Shlyueva, D., Stampfel, G., & Stark, A. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3682 · Cited by 1,356 · see citing works
Epigenetic protein families: a new frontier for drug discovery
Arrowsmith, C. H., Bountra, C., Fish, P. V., Lee, K., & Schapira, M. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3674 · Cited by 1,327 · see citing works
Structural basis of PROTAC cooperative recognition for selective protein degradation
Gadd, M. S., Testa, A., Lucas, X., Chan, K.-H., Chen, W., Lamont, D. J., Zengerle, M., & Ciulli, A. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2329 · Cited by 1,242 · see citing works
Senescence-associated reprogramming promotes cancer stemness
Milanovic, M., Fan, D. N. Y., Belenki, D., Däbritz, J. H. M., Zhao, Z., Yu, Y., Dörr, J. R., Dimitrova, L., Lenze, D., Monteiro Barbosa, I. A., et al. (2018) · Nature · doi:10.1038/nature25167 · Cited by 1,131 · see citing works
Self-citationHijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4
Lu, J., Qian, Y., Altieri, M., Dong, H., Wang, J., Raina, K., Hines, J., Winkler, J. D., Crew, A. P., Coleman, K., et al. (2015) · Chemistry & Biology · doi:10.1016/j.chembiol.2015.05.009 · Cited by 1,140 · see citing works
Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials
Cheng, Y., He, C., Wang, M., Ma, X., Mo, F., Yang, S., Han, J., & Wei, X. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0095-0 · Cited by 1,097 · see citing works
Lujambio, A., & Lowe, S. W. (2012) · Nature · doi:10.1038/nature10888 · Cited by 1,084 · see citing works
Self-citationSelective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4
Zengerle, M., Chan, K.-H., & Ciulli, A. (2015) · ACS Chemical Biology · doi:10.1021/acschembio.5b00216 · Cited by 1,056 · see citing works
Getting up to speed with transcription elongation by RNA polymerase II
Jonkers, I., & Lis, J. T. (2015) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3953 · Cited by 876 · see citing works
Tzelepis, K., Koike-Yusa, H., De Braekeleer, E., Li, Y., Metzakopian, E., Dovey, O. M., Mupo, A., Grinkevich, V., Li, M., Mazan, M., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.09.079 · Cited by 761 · see citing works
Non-Cell-Autonomous Tumor Suppression by p53
Lujambio, A., Akkari, L., Simon, J., Grace, D., Tschaharganeh, D. F., Bolden, J. E., Zhao, Z., Thapar, V., Joyce, J. A., Krizhanovsky, V., et al. (2013) · Cell · doi:10.1016/j.cell.2013.03.020 · Cited by 766 · see citing works
Self-citationA Single Oncogenic Enhancer Rearrangement Causes Concomitant EVI1 and GATA2 Deregulation in Leukemia
Gröschel, S., Sanders, M. A., Hoogenboezem, R., de Wit, E., Bouwman, B. A. M., Erpelinck, C., van der Velden, V. H. J., Havermans, M., Avellino, R., van Lom, K., et al. (2014) · Cell · doi:10.1016/j.cell.2014.02.019 · Cited by 687 · see citing works
Self-citationSchenk, T., Chen, W. C., Göllner, S., Howell, L., Jin, L., Hebestreit, K., Klein, H.-U., Popescu, A. C., Burnett, A., Mills, K., et al. (2012) · Nature Medicine · doi:10.1038/nm.2661 · Cited by 672 · see citing works
Plasticity in binding confers selectivity in ligand-induced protein degradation
Nowak, R. P., DeAngelo, S. L., Buckley, D., He, Z., Donovan, K. A., An, J., Safaee, N., Jedrychowski, M. P., Ponthier, C. M., Ishoey, M., et al. (2018) · Nature Chemical Biology · doi:10.1038/s41589-018-0055-y · Cited by 615 · see citing works
Self-citationThe histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells
Harris, W. J., Huang, X., Lynch, J. T., Spencer, G. J., Hitchin, J. R., Li, Y., Ciceri, F., Blaser, J. G., Greystoke, B. F., Jordan, A. M., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.03.014 · Cited by 566 · see citing works
BET inhibitor resistance emerges from leukaemia stem cells
Fong, C. Y., Gilan, O., Lam, E. Y. N., Rubin, A. F., Ftouni, S., Tyler, D., Stanley, K., Sinha, D., Yeh, P., Morison, J., et al. (2015) · Nature · doi:10.1038/nature14888 · Cited by 545 · see citing works
Genetics and biology of pancreatic ductal adenocarcinoma
Ying, H., Dey, P., Yao, W., Kimmelman, A. C., Draetta, G. F., Maitra, A., & DePinho, R. A. (2016) · Genes & Development · doi:10.1101/gad.275776.115 · Cited by 527 · see citing works
Differentiation therapy revisited
de Thé, H. (2018) · Nature reviews. Cancer · doi:10.1038/nrc.2017.103 · Cited by 462 · see citing works
BET Proteins as Targets for Anticancer Treatment
Stathis, A., & Bertoni, F. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-0605 · Cited by 463 · see citing works
Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated <i>Myc</i> regulation
Shi, J., Whyte, W. A., Zepeda-Mendoza, C. J., Milazzo, J. P., Shen, C., Roe, J.-S., Minder, J. L., Mercan, F., Wang, E., Eckersley-Maslin, M. A., et al. (2013) · Genes & Development · doi:10.1101/gad.232710.113 · Cited by 463 · see citing works
Self-citationBRD4 Connects Enhancer Remodeling to Senescence Immune Surveillance
Tasdemir, N., Banito, A., Roe, J.-S., Alonso-Curbelo, D., Camiolo, M., Tschaharganeh, D. F., Huang, C.-H., Aksoy, O., Bolden, J. E., Chen, C.-C., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0217 · Cited by 415 · see citing works
“When indicated, cells were cotransduced with vectors encoding validated GFP-linked shRNAs targeting BRD4 (53), p65 (26), p53 (33), p53/RB (49), or p21/p16 (49).”
MethodSelf-citationWapl is an essential regulator of chromatin structure and chromosome segregation
Tedeschi, A., Wutz, G., Huet, S., Jaritz, M., Wuensche, A., Schirghuber, E., Davidson, I. F., Tang, W., Cisneros, D. A., Bhaskara, V., et al. (2013) · Nature · doi:10.1038/nature12471 · Cited by 359 · see citing works
BET Bromodomains Mediate Transcriptional Pause Release in Heart Failure
Anand, P., Brown, J. D., Lin, C. Y., Qi, J., Zhang, R., Artero, P. C., Alaiti, M. A., Bullard, J., Alazem, K., Margulies, K. B., et al. (2013) · Cell · doi:10.1016/j.cell.2013.07.013 · Cited by 406 · see citing works
Self-citationAn Overview of MYC and Its Interactome
Conacci-Sorrell, M., McFerrin, L., & Eisenman, R. N. (2014) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a014357 · Cited by 408 · see citing works
Zhang, L., Riley-Gillis, B., Vijay, P., & Shen, Y. (2019) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-18-1129 · Cited by 365 · see citing works
Hines, J., Lartigue, S., Dong, H., Qian, Y., & Crews, C. M. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-2918 · Cited by 348 · see citing works
A Differentiation Checkpoint Limits Hematopoietic Stem Cell Self-Renewal in Response to DNA Damage
Wang, J., Sun, Q., Morita, Y., Jiang, H., Groß, A., Lechel, A., Hildner, K., Guachalla, L. M., Gompf, A., Hartmann, D., et al. (2012) · Cell · doi:10.1016/j.cell.2012.01.040 · Cited by 343 · see citing works
Targeting an RNA-Binding Protein Network in Acute Myeloid Leukemia
Wang, E., Lu, S. X., Pastore, A., Chen, X., Imig, J., Chun-Wei Lee, S., Hockemeyer, K., Ghebrechristos, Y. E., Yoshimi, A., Inoue, D., et al. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.01.010 · Cited by 338 · see citing works
Self-citationThe switch from fetal to adult hemoglobin.
Sankaran, V. G., & Orkin, S. H. (2013) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a011643 · Cited by 333 · see citing works
Core circadian clock genes regulate leukemia stem cells in AML
Puram, R. V., Kowalczyk, M. S., de Boer, C. G., Schneider, R. K., Miller, P. G., McConkey, M., Tothova, Z., Tejero, H., Heckl, D., Järås, M., et al. (2016) · Cell · doi:10.1016/j.cell.2016.03.015 · Cited by 274 · see citing works
Vangamudi, B., Paul, T. A., Shah, P. K., Kost-Alimova, M., Nottebaum, L., Shi, X., Zhan, Y., Leo, E., Mahadeshwar, H. S., Protopopov, A., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-3798 · Cited by 281 · see citing works
Duan, Q., McMahon, S., Anand, P., Shah, H., Thomas, S., Salunga, H. T., Huang, Y., Zhang, R., Sahadevan, A., Lemieux, M. E., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aah5084 · Cited by 262 · see citing works
Self-citationBromodomain Protein BRD4 Is a Transcriptional Repressor of Autophagy and Lysosomal Function
Sakamaki, J.-I., Wilkinson, S., Hahn, M., Tasdemir, N., O’Prey, J., Clark, W., Hedley, A., Nixon, C., Long, J. S., New, M., et al. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.04.027 · Cited by 249 · see citing works
Self-citationPapillon, J. P. N., Nakajima, K., Adair, C. D., Hempel, J., Jouk, A. O., Karki, R. G., Mathieu, S., Möbitz, H., Ntaganda, R., Smith, T., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01318 · Cited by 244 · see citing works
PROTACs: An Emerging Targeting Technique for Protein Degradation in Drug Discovery
Gu, S., Cui, D., Chen, X., Xiong, X., & Zhao, Y. (2018) · BioEssays · doi:10.1002/bies.201700247 · Cited by 231 · see citing works
Place your BETs: the therapeutic potential of bromodomains
Prinjha, R. K., Witherington, J., & Lee, K. (2012) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2011.12.002 · Cited by 197 · see citing works
Targeted Degradation of BET Proteins in Triple-Negative Breast Cancer
Bai, L., Zhou, B., Yang, C.-Y., Ji, J., McEachern, D., Przybranowski, S., Jiang, H., Hu, J., Xu, F., Zhao, Y., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-2622 · Cited by 199 · see citing works
Role of MYC in medulloblastoma
Roussel, M. F., & Robinson, G. W. (2013) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a014308 · Cited by 180 · see citing works
Histone Deacetylases Positively Regulate Transcription through the Elongation Machinery
Greer, C. B., Tanaka, Y., Kim, Y. J., Xie, P., Zhang, M. Q., Park, I.-H., & Kim, T. H. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.10.013 · Cited by 174 · see citing works
Requirement for CDK6 in MLL-rearranged acute myeloid leukemia
Placke, T., Faber, K., Nonami, A., Putwain, S. L., Salih, H. R., Heidel, F. H., Krämer, A., Root, D. E., Barbie, D. A., Krivtsov, A. V., et al. (2014) · Blood · doi:10.1182/blood-2014-02-558114 · Cited by 170 · see citing works
Histone Acetyltransferase p300 Induces De Novo Super-Enhancers to Drive Cellular Senescence
Sen, P., Lan, Y., Li, C. Y., Sidoli, S., Donahue, G., Dou, Z., Frederick, B., Chen, Q., Luense, L. J., Garcia, B. A., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.01.021 · Cited by 164 · see citing works
A Direct In Vivo RNAi Screen Identifies MKK4 as a Key Regulator of Liver Regeneration
Wuestefeld, T., Pesic, M., Rudalska, R., Dauch, D., Longerich, T., Kang, T.-W., Yevsa, T., Heinzmann, F., Hoenicke, L., Hohmeyer, A., et al. (2013) · Cell · doi:10.1016/j.cell.2013.03.026 · Cited by 149 · see citing works
Click chemistry enables preclinical evaluation of targeted epigenetic therapies
Tyler, D. S., Vappiani, J., Cañeque, T., Lam, E. Y. N., Ward, A., Gilan, O., Chan, Y.-C., Hienzsch, A., Rutkowska, A., Werner, T., et al. (2017) · Science · doi:10.1126/science.aal2066 · Cited by 146 · see citing works
Qin, Z.-Y., Wang, T., Su, S., Shen, L.-T., Zhu, G.-X., Liu, Q., Zhang, L., Liu, K.-W., Zhang, Y., Zhou, Z.-H., et al. (2019) · Cancer Research · doi:10.1158/0008-5472.can-19-0442 · Cited by 123 · see citing works
Histone H2B ubiquitin ligase RNF20 is required for <i>MLL</i> -rearranged leukemia
Wang, E., Kawaoka, S., Yu, M., Shi, J., Ni, T., Yang, W., Zhu, J., Roeder, R. G., & Vakoc, C. R. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1301045110 · Cited by 121 · see citing works
Self-citationShirasaki, R., Matthews, G. M., Gandolfi, S., de Matos Simoes, R., Buckley, D. L., Raja Vora, J., Sievers, Q. L., Brüggenthies, J. B., Dashevsky, O., Poarch, H., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2020.108532 · Cited by 123 · see citing works
Self-citationTargeting protein–protein interactions, a wide open field for drug design
Bakail, M., & Ochsenbein, F. (2016) · Comptes Rendus. Chimie · doi:10.1016/j.crci.2015.12.004 · Cited by 117 · see citing works
Banerji, V., Frumm, S. M., Ross, K. N., Li, L. S., Schinzel, A. C., Hahn, C. K., Kakoza, R. M., Chow, K. T., Ross, L., Alexe, G., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci46465 · Cited by 105 · see citing works
Epigenetic targeting of bromodomain protein BRD4 counteracts cancer cachexia and prolongs survival
Segatto, M., Fittipaldi, R., Pin, F., Sartori, R., Dae Ko, K., Zare, H., Fenizia, C., Zanchettin, G., Pierobon, E. S., Hatakeyama, S., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01645-7 · Cited by 101 · see citing works
Stanlie, A., Yousif, A. S., Akiyama, H., Honjo, T., & Begum, N. A. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.05.018 · Cited by 101 · see citing works
Synthetic Lethal Vulnerabilities in <i>KRAS</i>-Mutant Cancers
Aguirre, A. J., & Hahn, W. C. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a031518 · Cited by 90 · see citing works
Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia
Järås, M., Miller, P. G., Chu, L. P., Puram, R. V., Fink, E. C., Schneider, R. K., Al-Shahrour, F., Peña, P., Breyfogle, L. J., Hartwell, K. A., et al. (2014) · Journal of Experimental Medicine · doi:10.1084/jem.20131033 · Cited by 92 · see citing works
Cereblon and its downstream substrates as molecular targets of immunomodulatory drugs
Ito, T., & Handa, H. (2016) · International Journal of Hematology · doi:10.1007/s12185-016-2073-4 · Cited by 84 · see citing works
Digging deep into “dirty” drugs – modulation of the methylation machinery
Pleyer, L., & Greil, R. (2015) · Drug Metabolism Reviews · doi:10.3109/03602532.2014.995379 · Cited by 84 · see citing works
“…in primary AML patient samples and murine models of acute leukemia, partially through the down-regulation of the critical oncogenes, MYC and Bcl2 (Chen et al., 2014; Dawson et al., 2014; Delmore et al., 2011; Fiskus et al., 2014b; Mertz et al., 2011; Valent & Zuber, 2014; Zuber et al., 2011).”
BackgroundWu, S., Jiang, Y., Hong, Y., Chu, X., Zhang, Z., Tao, Y., Fan, Z., Bai, Z., Li, X., Chen, Y., et al. (2021) · Cancer Cell International · doi:10.1186/s12935-021-01908-w · Cited by 81 · see citing works
BRD4 regulates cellular senescence in gastric cancer cells via E2F/miR-106b/p21 axis
Dong, X., Hu, X., Chen, J., Hu, D., & Chen, L.-F. (2018) · Cell Death & Disease · doi:10.1038/s41419-017-0181-6 · Cited by 75 · see citing works
BET Bromodomain Proteins as Cancer Therapeutic Targets
Shu, S., & Polyak, K. (2016) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2016.81.030908 · Cited by 72 · see citing works
Surface antigen-guided CRISPR screens identify regulators of myeloid leukemia differentiation
Wang, E., Zhou, H., Nadorp, B., Cayanan, G., Chen, X., Yeaton, A. H., Nomikou, S., Witkowski, M. T., Narang, S., Kloetgen, A., et al. (2021) · Cell Stem Cell · doi:10.1016/j.stem.2020.12.005 · Cited by 66 · see citing works
Self-citationMLL-AF9 initiates transformation from fast-proliferating myeloid progenitors
Chen, X., Burkhardt, D. B., Hartman, A. A., Hu, X., Eastman, A. E., Sun, C., Wang, X., Zhong, M., Krishnaswamy, S., & Guo, S. (2019) · Nature Communications · doi:10.1038/s41467-019-13666-5 · Cited by 58 · see citing works
Feng, L., Wang, G., Chen, Y., He, G., Liu, B., Liu, J., Chiang, C., & Ouyang, L. (2022) · Medicinal Research Reviews · doi:10.1002/med.21859 · Cited by 65 · see citing works
Direct inhibition of c-Myc-Max heterodimers by celastrol and celastrol-inspired triterpenoids
Wang, H., Teriete, P., Hu, A., Raveendra-Panickar, D., Pendelton, K., Lazo, J. S., Eiseman, J., Holien, T., Misund, K., Oliynyk, G., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.6116 · Cited by 53 · see citing works
Wang, E., Kawaoka, S., Roe, J.-S., Shi, J., Hohmann, A. F., Xu, Y., Bhagwat, A. S., Suzuki, Y., Kinney, J. B., & Vakoc, C. R. (2015) · eLife · doi:10.7554/elife.06377 · Cited by 54 · see citing works
“A previously described LMN shRNA library targeting chromatin regulatory proteins was used (Zuber et al., 2011b).”
BackgroundMethodInfluentialSelf-citationCierpicki, T., & Grembecka, J. (2015) · Immunological Reviews · doi:10.1111/imr.12244 · Cited by 53 · see citing works
Loss of Kat2a enhances transcriptional noise and depletes acute myeloid leukemia stem-like cells
Domingues, A. F., Kulkarni, R., Giotopoulos, G., Gupta, S., Vinnenberg, L., Arede, L., Foerner, E., Khalili, M., Adao, R. R., Johns, A., et al. (2020) · eLife · doi:10.7554/elife.51754 · Cited by 52 · see citing works
BRD4 inhibitors block telomere elongation
Wang, S., Pike, A. M., Lee, S. S., Strong, M. A., Connelly, C. J., & Greider, C. W. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx561 · Cited by 45 · see citing works
BET bromodomain proteins regulate transcriptional reprogramming in genetic dilated cardiomyopathy
Antolic, A., Wakimoto, H., Jiao, Z., Gorham, J. M., DePalma, S. R., Lemieux, M. E., Conner, D. A., Lee, D. Y., Qi, J., Seidman, J. G., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.138687 · Cited by 41 · see citing works
Self-citationIdentification and characterization of cancer vulnerabilities via targeted protein degradation
Mayor-Ruiz, C., & Winter, G. E. (2019) · Drug Discovery Today: Technologies · doi:10.1016/j.ddtec.2018.12.003 · Cited by 33 · see citing works
Protein–Protein Interaction Modulators for Epigenetic Therapies
(2018) · Advances in Protein Chemistry and Structural Biology · doi:10.1016/bs.apcsb.2017.06.002 · Cited by 31 · see citing works
PTEN in Regulating Hematopoiesis and Leukemogenesis
Wu, Y., Zhu, H., & Wu, H. (2020) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a036244 · Cited by 22 · see citing works
The role of enhancer RNAs in epigenetic regulation of gene expression
Rahnamoun, H., Orozco, P., & Lauberth, S. M. (2020) · Transcription · doi:10.1080/21541264.2019.1698934 · Cited by 16 · see citing works
- Authors
- Zuber, J., Shi, J., Wang, E., Rappaport, A. R., Herrmann, H., Sison, E. A., Magoon, D., Qi, J., Blatt, K., Wunderlich, M., Taylor, M. J., Johns, C., Chicas, A., Mulloy, J. C., Kogan, S. C., Brown, P., Valent, P., Bradner, J. E., Lowe, S. W., & Vakoc, C. R.
- Affiliations
- Cold Spring Harbor Laboratory (US)
- Ludwig Boltzmann Institute for Hematology and Oncology (AT)
- Johns Hopkins University (US)
- Harvard University (US)
- Medical University of Vienna (AT)
- Cincinnati Children's Hospital Medical Center (US)
- University of California, San Francisco (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Lowe, Scott W.
- Vakoc, Christopher R.
- ORCID
- Venue
- Nature
- Published
- 2011-08-03
- Volume
- 478
- Issue
- 7370
- Pages
- 524-528
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3328300
- OpenAlex
- W2129129812
- Cited by
- 1,870
- References
- 2
- Citations by year
- 2026: 41 · 2025: 68 · 2024: 83 · 2023: 97 · 2022: 92 · 2021: 139 · 2020: 128 · 2019: 140 · 2018: 132 · 2017: 157 · 2016: 183 · 2015: 154 · 2014: 182 · 2013: 150 · 2012: 100
- FWCI
- 59.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (K08CA128972)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- BRD4, acute myeloid leukemia, JQ1, chromatin regulators, epigenetic vulnerability, c-Myc, histone acetylation, bromodomain, leukemia stem cells, self-renewal, RNAi screen, small molecule inhibitors, therapeutic target
- MeSH terms
- Bromodomain Containing Proteins, Acetylation, Animals, Azepines, Cell Differentiation, Chromatin, Histones, Humans, Neoplasm Transplantation, Nuclear Proteins, Transcription Factors, Triazoles, Neoplastic Stem Cells, Leukemia, Myeloid, Acute, Gene Expression Regulation, Neoplastic, Genes, myc, Disease Progression, RNA Interference, RNA, Small Interfering, Epigenesis, Genetic, Cell Line, Tumor, Cell Proliferation, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
