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ABSTRACT Anaplastic large cell lymphoma (ALCL) and classical Hodgkin lymphoma (HL) share a similar cytological and high surface expression of CD30, and novel therapeutic strategies are

needed. The EP300 and CREBBP acetyltransferases play essential roles in the pathogenesis of non-Hodgkin B cell lymphoma, but their functions in ALCL and HL are unknown. In the current study,

we investigated the physiological roles of EP300 and CREBBP in both ALCL and HL, and exploited the therapeutic potential of EP300/CREBBP small molecule inhibitors that target either the HAT

or bromodomain activities. Our studies demonstrated distinct roles for EP300 and CREBBP in supporting the viability of ALCL and HL, which was bolstered by the transcriptome analyses.

Specifically, EP300 but not CREBBP directly modulated the expression of oncogenic MYC/IRF4 network, surface receptor CD30, immunoregulatory cytokines IL10 and LTA, and immune checkpoint

protein PD-L1. Importantly, EP300/CREBBP HAT inhibitor A-485 and bromodomain inhibitor CPI-637 exhibited strong activities against ALCL and HL in vitro and in xenograft mouse models, and

inhibited PD-L1 mediated tumor immune escape. Thus, our studies revealed critical insights into the physiological roles of EP300/CREBBP in these lymphomas, and provided opportunities for

developing novel strategies for both targeted and immune therapies. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution

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about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS THERAPEUTIC TARGETING OF THE P300/CBP BROMODOMAIN ENHANCES THE EFFICACY OF

IMMUNE CHECKPOINT BLOCKADE THERAPY Article 21 April 2025 HDAC1 ACTS AS A TUMOR SUPPRESSOR IN ALK-POSITIVE ANAPLASTIC LARGE CELL LYMPHOMA: IMPLICATIONS FOR HDAC INHIBITOR THERAPY Article

Open access 02 April 2025 P300/CBP INHIBITION SENSITIZES MANTLE CELL LYMPHOMA TO PI3KΔ INHIBITOR IDELALISIB Article 13 April 2021 DATA AVAILABILITY All data generated or analyzed during this

study are included in this published article and its Supplementary Information files. The high-throughput RNA sequencing data from this study have been submitted to the NCBI Sequence Read

Archive (SRA) under accession number: SUB11100974. REFERENCES * Wright D, McKeever P, Carter R. Childhood non-Hodgkin lymphomas in the United Kingdom: findings from the UK Children’s Cancer

Study Group. J Clin Pathol. 1997;50:128–34. Article  CAS  Google Scholar  * Burkhardt B, Zimmermann M, Oschlies I, Niggli F, Mann G, Parwaresch R, et al. The impact of age and gender on

biology, clinical features and treatment outcome of non-Hodgkin lymphoma in childhood and adolescence. Br J Haematol. 2005;131:39–49. Article  Google Scholar  * Brauninger A, Schmitz R,

Bechtel D, Renne C, Hansmann ML, Kuppers R. Molecular biology of Hodgkin’s and Reed/Sternberg cells in Hodgkin’s lymphoma. Int J Cancer. 2006;118:1853–61. Article  Google Scholar  * Egger G,

Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004;429:457–63. Article  CAS  Google Scholar  * Dawson MA, Kouzarides T, Huntly

BJ. Targeting epigenetic readers in cancer. N. Engl J Med. 2012;367:647–57. Article  CAS  Google Scholar  * Ogryzko VV, Schiltz RL, Russanova V, Howard BH, Nakatani Y. The transcriptional

coactivators p300 and CBP are histone acetyltransferases. Cell. 1996;87:953–9. Article  CAS  Google Scholar  * Attar N, Kurdistani SK. Exploitation of EP300 and CREBBP lysine

acetyltransferases by cancer. Cold Spring Harb Perspect Med. 2017;7:a026534. * Pasqualucci L, Dominguez-Sola D, Chiarenza A, Fabbri G, Grunn A, Trifonov V, et al. Inactivating mutations of

acetyltransferase genes in B-cell lymphoma. Nature. 2011;471:189–95. Article  CAS  Google Scholar  * Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL, Corbett RD, et al. Frequent

mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011;476:298–303. Article  CAS  Google Scholar  * Ogiwara H, Sasaki M, Mitachi T, Oike T, Higuchi S, Tominaga Y, et al.

Targeting p300 addiction in CBP-deficient cancers causes synthetic lethality by apoptotic cell death due to abrogation of MYC expression. Cancer Disco. 2016;6:430–45. Article  CAS  Google

Scholar  * Meyer SN, Scuoppo C, Vlasevska S, Bal E, Holmes AB, Holloman M, et al. Unique and Shared Epigenetic Programs of the CREBBP and EP300 acetyltransferases in germinal center B cells

reveal targetable dependencies in lymphoma. Immunity. 2019;51:535–47. Article  CAS  Google Scholar  * Ng SY, Yoshida N, Christie AL, Ghandi M, Dharia NV, Dempster J, et al. Targetable

vulnerabilities in T- and NK-cell lymphomas identified through preclinical models. Nat Commun. 2018;9:2024. * Lobello C, Tichy B, Bystry V, Radova L, Filip D, Mraz M, et al. STAT3 and TP53

mutations associate with poor prognosis in anaplastic large cell lymphoma. Leukemia. 2021;35:1500–5. Article  CAS  Google Scholar  * Mata E, Diaz-Lopez A, Martin-Moreno AM, Sanchez-Beato M,

Varela I, Mestre MJ, et al. Analysis of the mutational landscape of classic Hodgkin lymphoma identifies disease heterogeneity and potential therapeutic targets. Oncotarget. 2017;8:111386–95.

Article  Google Scholar  * Tiacci E, Ladewig E, Schiavoni G, Penson A, Fortini E, Pettirossi V, et al. Pervasive mutations of JAK-STAT pathway genes in classical Hodgkin lymphoma. Blood.

2018;131:2454–65. Article  CAS  Google Scholar  * Mata E, Fernandez S, Astudillo A, Fernandez R, Garcia-Cosio M, Sanchez-Beato M, et al. Genomic analyses of microdissected Hodgkin and

Reed-Sternberg cells: mutations in epigenetic regulators and p53 are frequent in refractory classic Hodgkin lymphoma. Blood Cancer J. 2019;9:34. Article  Google Scholar  * Zhang JP, Song Z,

Wang HB, Lang L, Yang YZ, Xiao W, et al. A novel model of controlling PD-L1 expression in ALK(+) anaplastic large cell lymphoma revealed by CRISPR screening. Blood. 2019;134:171–85. Article

  CAS  Google Scholar  * Kempf W. CD30+ lymphoproliferative disorders: histopathology, differential diagnosis, new variants, and simulators. J Cutan Pathol. 2006;33:58–70. Article  Google

Scholar  * Falini B, Martelli MP. Anaplastic large cell lymphoma: changes in the World Health Organization classification and perspectives for targeted therapy. Haematologica.

2009;94:897–900. Article  Google Scholar  * Lasko LM, Jakob CG, Edalji RP, Qiu W, Montgomery D, Digiammarino EL, et al. Discovery of a selective catalytic p300/CBP inhibitor that targets

lineage-specific tumours. Nature. 2017;550:128–32. Article  CAS  Google Scholar  * Taylor AM, Cote A, Hewitt MC, Pastor R, Leblanc Y, Nasveschuk CG, et al. Fragment-based discovery of a

selective and cell-active benzodiazepinone CBP/EP300 bromodomain inhibitor (CPI-637). ACS Med Chem Lett. 2016;7:531–6. Article  CAS  Google Scholar  * Shiota M, Fujimoto J, Semba T, Satoh H,

Yamamoto T, Mori S. Hyperphosphorylation of a novel 80 kDa protein-tyrosine kinase similar to Ltk in a human Ki-1 lymphoma cell line, AMS3. Oncogene. 1994;9:1567–74. CAS  Google Scholar  *

Morris SW, Naeve C, Mathew P, James PL, Kirstein MN, Cui X, et al. ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin’s lymphoma, encodes a novel neural receptor tyrosine

kinase that is highly related to leukocyte tyrosine kinase (LTK). Oncogene. 1997;14:2175–88. Article  CAS  Google Scholar  * Chiarle R, Voena C, Ambrogio C, Piva R, Inghirami G. The

anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer. 2008;8:11–23. Article  CAS  Google Scholar  * Lee S, Rauch J, Kolch W. Targeting MAPK signaling in cancer:

mechanisms of drug resistance and sensitivity. Int J Mol Sci. 2020;21:1102. * Wang YC, Nowakowski GS, Wang ML, Ansell SM. Advances in CD30-and PD-1-targeted therapies for classical Hodgkin

lymphoma. J Hematol Oncol. 2018;11:57. * Stein H, Foss HD, Durkop H, Marafioti T, Delsol G, Pulford K, et al. CD30(+) anaplastic large cell lymphoma: a review of its histopathologic,

genetic, and clinical features. Blood. 2000;96:3681–95. Article  CAS  Google Scholar  * Wei W, Lin Y, Song Z, Xiao W, Chen L, Yin J, et al. A20 and RBX1 regulate brentuximab vedotin

sensitivity in hodgkin lymphoma models. Clin Cancer Res. 2020;16:4093–4106. * Weilemann A, Grau M, Erdmann T, Merkel O, Sobhiafshar U, Anagnostopoulos I, et al. Essential role of IRF4 and

MYC signaling for survival of anaplastic large cell lymphoma. Blood. 2015;125:124–32. Article  CAS  Google Scholar  * Boddicker RL, Kip NS, Xing X, Zeng Y, Yang ZZ, Lee JH, et al. The

oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-kappaB positive feedback loop in peripheral T-cell lymphoma. Blood. 2015;125:3118–27. Article  CAS  Google Scholar  *

Bandini C, Pupuleku A, Spaccarotella E, Pellegrino E, Wang R, Vitale N, et al. IRF4 mediates the oncogenic effects of STAT3 in anaplastic large cell lymphomas. Cancers (Basel). 2018;10:21. *

Schleussner N, Merkel O, Costanza M, Liang HC, Hummel F, Romagnani C, et al. The AP-1-BATF and -BATF3 module is essential for growth, survival and TH17/ILC3 skewing of anaplastic large cell

lymphoma. Leukemia. 2018;32:1994–2007. Article  CAS  Google Scholar  * Weniger MA, Kuppers R. NF-kappaB deregulation in Hodgkin lymphoma. Semin Cancer Biol. 2016;39:32–9. Article  CAS 

Google Scholar  * von Hoff L, Kargel E, Franke V, McShane E, Schulz-Beiss KW, Patone G, et al. Autocrine LTA signaling drives NF-kappaB and JAK-STAT activity and myeloid gene expression in

Hodgkin lymphoma. Blood. 2019;133:1489–94. Article  Google Scholar  * Green MR, Monti S, Rodig SJ, Juszczynski P, Currie T, O’Donnell E, et al. Integrative analysis reveals selective 9p24.1

amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood. 2010;116:3268–77.

Article  CAS  Google Scholar  * Roemer MG, Advani RH, Ligon AH, Natkunam Y, Redd RA, Homer H, et al. PD-L1 and PD-L2 genetic alterations define classical hodgkin lymphoma and predict

outcome. J Clin Oncol. 2016;34:2690–7. Article  CAS  Google Scholar  * Green MR, Rodig S, Juszczynski P, Ouyang J, Sinha P, O’Donnell E, et al. Constitutive AP-1 activity and EBV infection

induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res. 2012;18:1611–8. Article  CAS  Google Scholar  * Tumeh

PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515:568–71. Article  CAS  Google

Scholar  * Weniger MA, Kuppers R. Molecular biology of Hodgkin lymphoma. Leukemia. 2021;35:968–81. Article  CAS  Google Scholar  * Mao W, Ghasemzadeh A, Freeman ZT, Obradovic A, Chaimowitz

MG, Nirschl TR, et al. Immunogenicity of prostate cancer is augmented by BET bromodomain inhibition. J Immunother Cancer. 2019;7:277. * Liu KS, Zhou ZF, Gao HY, Yang F, Qian YJ, Jin HT, et

al. JQ1, a BET-bromodomain inhibitor, inhibits human cancer growth and suppresses PD-L1 expression. Cell Biol Int. 2019;43:642–50. Article  CAS  Google Scholar  * Liu J, He D, Cheng L, Huang

C, Zhang Y, Rao X, et al. p300/CBP inhibition enhances the efficacy of programmed death-ligand 1 blockade treatment in prostate cancer. Oncogene. 2020;39:3939–51. Article  CAS  Google

Scholar  * Picaud S, Fedorov O, Thanasopoulou A, Leonards K, Jones K, Meier J, et al. Generation of a selective small molecule inhibitor of the CBP/p300 bromodomain for leukemia therapy.

Cancer Res. 2015;75:5106–19. Article  CAS  Google Scholar  * Conery AR, Centore RC, Neiss A, Keller PJ, Joshi S, Spillane KL, et al. Bromodomain inhibition of the transcriptional

coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma. Elife. 2016;5:e10483. * Garcia-Carpizo V, Ruiz-Llorente S, Sarmentero J, Gonzalez-Corpas A,

Barrero MJ. CREBBP/EP300 bromodomain inhibition affects the proliferation of AR-positive breast cancer cell lines. Mol Cancer Res. 2019;17:720–30. Article  CAS  Google Scholar  * Crawford

TD, Romero FA, Lai KW, Tsui V, Taylor AM, de Leon Boenig G, et al. Discovery of a potent and selective in vivo probe (GNE-272) for the bromodomains of CBP/EP300. J Med Chem.

2016;59:10549–63. Article  CAS  Google Scholar  * Spriano F, Gaudio E, Cascione L, Tarantelli C, Melle F, Motta G, et al. Antitumor activity of the dual BET and CBP/EP300 inhibitor NEO2734.

Blood Adv. 2020;4:4124–35. Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS We thank Dr. Alan L. Epstein (USC Keck School of Medicine) for the TLBR1 and TLBR2 cell lines,

and Dr. Annarosa Del Mistro (The Veneto Institute of Oncology) for the FEPD cell line. FUNDING This research was supported by NIH R01 CA259188 (YY), R01 CA251674 (YY), Scholar Award from

Leukemia & Lymphoma Society (YY), and Cancer Research Conventional Grant from Gabrielle’s Angel Foundation and Mark Foundation (YY). ZS was partially supported by the Greenwald

Postdoctoral Fellowship for Research, FCCC. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, USA Wei Wei,

 Zhihui Song, Wenjun Wu, Subin Jeong, Jing-Ping Zhang & Yibin Yang * Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan Masahiro Chiba & Masao Nakagawa

* Department of Pathology and Laboratory Medicine, Brown University Alpert School of Medicine, 593, Eddy Street, Providence, RI, USA Marshall E. Kadin Authors * Wei Wei View author

publications You can also search for this author inPubMed Google Scholar * Zhihui Song View author publications You can also search for this author inPubMed Google Scholar * Masahiro Chiba

View author publications You can also search for this author inPubMed Google Scholar * Wenjun Wu View author publications You can also search for this author inPubMed Google Scholar * Subin

Jeong View author publications You can also search for this author inPubMed Google Scholar * Jing-Ping Zhang View author publications You can also search for this author inPubMed Google

Scholar * Marshall E. Kadin View author publications You can also search for this author inPubMed Google Scholar * Masao Nakagawa View author publications You can also search for this author

inPubMed Google Scholar * Yibin Yang View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS YY designed and oversaw the project. WW and ZS

performed experiments and collected data. WW and YY analyzed and interpreted the data. MC, WW, SJ, JPZ, MEK, and MN provided technical support and critical materials. YY wrote the

manuscript. CORRESPONDING AUTHOR Correspondence to Yibin Yang. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. ADDITIONAL INFORMATION PUBLISHER’S NOTE

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ARTICLE CITE THIS ARTICLE Wei, W., Song, Z., Chiba, M. _et al._ Analysis and therapeutic targeting of the EP300 and CREBBP acetyltransferases in anaplastic large cell lymphoma and Hodgkin

lymphoma. _Leukemia_ 37, 396–407 (2023). https://doi.org/10.1038/s41375-022-01774-z Download citation * Received: 13 July 2022 * Revised: 18 November 2022 * Accepted: 22 November 2022 *

Published: 01 December 2022 * Issue Date: February 2023 * DOI: https://doi.org/10.1038/s41375-022-01774-z SHARE THIS ARTICLE Anyone you share the following link with will be able to read

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