Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Lymphoma

CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300-mutated lymphomas

Leukemia volume 34, pages 3269–3285 (2020)Cite this article

Subjects

Abstract

Somatic mutations affecting CREBBP and EP300 are a hallmark of diffuse large B-cell lymphoma (DLBCL). These mutations are frequently monoallelic, within the histone acetyltransferase (HAT) domain and usually mutually exclusive, suggesting that they might affect a common pathway, and their residual WT expression is required for cell survival. Using in vitro and in vivo models, we found that inhibition of CARM1 activity (CARM1i) slows DLBCL growth, and that the levels of sensitivity are positively correlated with the CREBBP/EP300 mutation load. Conversely, treatment of DLBCLs that do not have CREBBP/EP300 mutations with CARM1i and a CBP/p300 inhibitor revealed a strong synergistic effect. Our mechanistic data show that CARM1i further reduces the HAT activity of CBP genome wide and downregulates CBP-target genes in DLBCL cells, resulting in a synthetic lethality that leverages the mutational status of CREBBP/EP300 as a biomarker for the use of small-molecule inhibitors of CARM1 in DLBCL and other cancers.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Human DLBCL cells are dependent on CARM1 arginine methyltransferase activity.
Fig. 2: Transcriptional networks regulated by CARM1 activity in human DLBCL cells.
Fig. 3: Deregulation of promoter and enhancer regions bound by CBP/p300 upon CARM1 inhibition.
Fig. 4: CREBBP/EP300 mutation load correlates with sensitivity to CARM1 inhibition.
Fig. 5: CARM1 and CBP/p300 small-molecule inhibition displays synergistic effects in human DLBCL cells.
Fig. 6: CARM1 and CBP/p300 inhibition synergistically reduces CBP-dependent histone acetylation and CBP-target gene expression in human DLBCL cells.
Fig. 7: In vivo therapeutic potential of CARM1 inhibition against human DLBCL with lesions in CREBBP/EP300.

Similar content being viewed by others

Data availability

All raw and normalized RNA-Seq and ChIP-seq data that support the findings of this study have been deposited in the GEO SuperSeries under accession number GSE152668.

References

  1. Al-Tourah AJ, Gill KK, Chhanabhai M, Hoskins PJ, Klasa RJ, Savage KJ, et al. Population-based analysis of incidence and outcome of transformed non-Hodgkin’s lymphoma. J Clin Oncol. 2008;26:5165–9.

    Article  PubMed  Google Scholar 

  2. Guo L, Lin P, Xiong H, Tu S, Chen G. Molecular heterogeneity in diffuse large B-cell lymphoma and its implications in clinical diagnosis and treatment. Biochim Biophys Acta. 2018;1869:85–96.

    CAS  Google Scholar 

  3. Klein U, Dalla-Favera R. Germinal centres: role in B-cell physiology and malignancy. Nat Rev Immunol. 2008;8:22–33.

    Article  CAS  PubMed  Google Scholar 

  4. MacLennan IC. Germinal centers. Annu Rev Immunol. 1994;12:117–39.

    Article  CAS  PubMed  Google Scholar 

  5. Victora GD, Nussenzweig MC. Germinal centers. Annu Rev Immunol. 2012;30:429–57.

    Article  CAS  PubMed  Google Scholar 

  6. Green MR, Kihira S, Liu CL, Nair RV, Salari R, Gentles AJ, et al. Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation. Proc Natl Acad Sci USA. 2015;112:E1116–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Lohr JG, Stojanov P, Lawrence MS, Auclair D, Chapuy B, Sougnez C, et al. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc Natl Acad Sci USA. 2012;109:3879–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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  PubMed  PubMed Central  Google Scholar 

  9. 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  PubMed  PubMed Central  Google Scholar 

  10. Pasqualucci L, Trifonov V, Fabbri G, Ma J, Rossi D, Chiarenza A, et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet. 2011;43:830–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhang J, Grubor V, Love CL, Banerjee A, Richards KL, Mieczkowski PA, et al. Genetic heterogeneity of diffuse large B-cell lymphoma. Proc Natl Acad Sci USA. 2013;110:1398–403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ceschin DG, Walia M, Wenk SS, Duboe C, Gaudon C, Xiao Y, et al. Methylation specifies distinct estrogen-induced binding site repertoires of CBP to chromatin. Genes Dev. 2011;25:1132–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chevillard-Briet M, Trouche D, Vandel L. Control of CBP co-activating activity by arginine methylation. EMBO J. 2002;21:5457–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lee YH, Coonrod SA, Kraus WL, Jelinek MA, Stallcup MR. Regulation of coactivator complex assembly and function by protein arginine methylation and demethylimination. Proc Natl Acad Sci USA. 2005;102:3611–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Xu W, Chen H, Du K, Asahara H, Tini M, Emerson BM, et al. A transcriptional switch mediated by cofactor methylation. Science. 2001;294:2507–11.

    Article  CAS  PubMed  Google Scholar 

  16. Bedford MT, Frankel A, Yaffe MB, Clarke S, Leder P, Richard S. Arginine methylation inhibits the binding of proline-rich ligands to Src homology 3, but not WW, domains. J Biol Chem. 2000;275:16030–6.

    Article  CAS  PubMed  Google Scholar 

  17. Yang Y, Lu Y, Espejo A, Wu J, Xu W, Liang S, et al. TDRD3 is an effector molecule for arginine-methylated histone marks. Mol Cell. 2010;40:1016–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chen D, Ma H, Hong H, Koh SS, Huang SM, Schurter BT, et al. Regulation of transcription by a protein methyltransferase. Science. 1999;284:2174–7.

    Article  CAS  PubMed  Google Scholar 

  19. Bedford MT, Richard S. Arginine methylation an emerging regulator of protein function. Mol Cell. 2005;18:263–72.

    Article  CAS  PubMed  Google Scholar 

  20. Lupien M, Eeckhoute J, Meyer CA, Krum SA, Rhodes DR, Liu XS, et al. Coactivator function defines the active estrogen receptor alpha cistrome. Mol Cell Biol. 2009;29:3413–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yadav N, Lee J, Kim J, Shen J, Hu MC, Aldaz CM, et al. Specific protein methylation defects and gene expression perturbations in coactivator-associated arginine methyltransferase 1-deficient mice. Proc Natl Acad Sci USA. 2003;100:6464–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kim J, Lee J, Yadav N, Wu Q, Carter C, Richard S, et al. Loss of CARM1 results in hypomethylation of thymocyte cyclic AMP-regulated phosphoprotein and deregulated early T cell development. J Biol Chem. 2004;279:25339–44.

    Article  CAS  PubMed  Google Scholar 

  23. Yadav N, Cheng D, Richard S, Morel M, Iyer VR, Aldaz CM, et al. CARM1 promotes adipocyte differentiation by coactivating PPARgamma. EMBO Rep. 2008;9:193–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ito T, Yadav N, Lee J, Furumatsu T, Yamashita S, Yoshida K, et al. Arginine methyltransferase CARM1/PRMT4 regulates endochondral ossification. BMC Dev Biol. 2009;9:47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. O’Brien KB, Alberich-Jorda M, Yadav N, Kocher O, Diruscio A, Ebralidze A, et al. CARM1 is required for proper control of proliferation and differentiation of pulmonary epithelial cells. Development. 2010;137:2147–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Kim D, Lee J, Cheng D, Li J, Carter C, Richie E, et al. Enzymatic activity is required for the in vivo functions of CARM1. J Biol Chem. 2010;285:1147–52.

    Article  CAS  PubMed  Google Scholar 

  27. Yang Y, Bedford MT. Protein arginine methyltransferases and cancer. Nat Rev Cancer. 2013;13:37–50.

    Article  CAS  PubMed  Google Scholar 

  28. El Messaoudi S, Fabbrizio E, Rodriguez C, Chuchana P, Fauquier L, Cheng D, et al. Coactivator-associated arginine methyltransferase 1 (CARM1) is a positive regulator of the Cyclin E1 gene. Proc Natl Acad Sci USA. 2006;103:13351–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hong H, Kao C, Jeng MH, Eble JN, Koch MO, Gardner TA, et al. Aberrant expression of CARM1, a transcriptional coactivator of androgen receptor, in the development of prostate carcinoma and androgen-independent status. Cancer. 2004;101:83–9.

    Article  CAS  PubMed  Google Scholar 

  30. Kim YR, Lee BK, Park RY, Nguyen NT, Bae JA, Kwon DD, et al. Differential CARM1 expression in prostate and colorectal cancers. BMC Cancer 2010;10:197.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Osada S, Suzuki S, Yoshimi C, Matsumoto M, Shirai T, Takahashi S, et al. Elevated expression of coactivator-associated arginine methyltransferase 1 is associated with early hepatocarcinogenesis. Oncol Rep. 2013;30:1669–74.

    Article  CAS  PubMed  Google Scholar 

  32. Mann M, Cortez V, Vadlamudi R. PELP1 oncogenic functions involve CARM1 regulation. Carcinogenesis. 2013;34:1468–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang L, Zhao Z, Meyer MB, Saha S, Yu M, Guo A, et al. CARM1 methylates chromatin remodeling factor BAF155 to enhance tumor progression and metastasis. Cancer Cell. 2014;25:21–36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Karakashev S, Zhu H, Wu S, Yokoyama Y, Bitler BG, Park PH, et al. CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity. Nat Commun. 2018;9:631.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Bao J, Di Lorenzo A, Lin K, Lu Y, Zhong Y, Sebastian MM, et al. Mouse models of overexpression reveal distinct oncogenic roles for different type I protein arginine methyltransferases. Cancer Res. 2019;79:21–32.

    Article  CAS  PubMed  Google Scholar 

  36. Nakayama K, Szewczyk MM, Dela Sena C, Wu H, Dong A, Zeng H, et al. TP-064, a potent and selective small molecule inhibitor of PRMT4 for multiple myeloma. Oncotarget. 2018;9:18480–93.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Drew AE, Moradei O, Jacques SL, Rioux N, Boriack-Sjodin AP, Allain C, et al. Identification of a CARM1 inhibitor with potent in vitro and in vivo activity in preclinical models of multiple myeloma. Sci Rep. 2017;7:17993.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Greenblatt SM, Man N, Hamard PJ, Asai T, Karl D, Martinez C, et al. CARM1 is essential for myeloid leukemogenesis but dispensable for normal hematopoiesis. Cancer Cell. 2018;33:1111–27.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cheng D, Vemulapalli V, Lu Y, Shen J, Aoyagi S, Fry CJ, et al. CARM1 methylates MED12 to regulate its RNA-binding ability. Life Sci Alliance. 2018;1:e201800117.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Lee J, Bedford MT. PABP1 identified as an arginine methyltransferase substrate using high-density protein arrays. EMBO Rep. 2002;3:268–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhang J, Vlasevska S, Wells VA, Nataraj S, Holmes AB, Duval R, et al. The CREBBP acetyltransferase is a haploinsufficient tumor suppressor in B-cell lymphoma. Cancer Discov. 2017;7:322–37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Creyghton MP, Cheng AW, Welstead GG, Kooistra T, Carey BW, Steine EJ, et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci USA. 2010;107:21931–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Andersen CL, Asmar F, Klausen T, Hasselbalch H, Gronbaek K. Somatic mutations of the CREBBP and EP300 genes affect response to histone deacetylase inhibition in malignant DLBCL clones. Leuk Res Rep. 2012;2:1–3.

    PubMed  PubMed Central  Google Scholar 

  44. Hashwah H, Schmid CA, Kasser S, Bertram K, Stelling A, Manz MG, et al. Inactivation of CREBBP expands the germinal center B cell compartment, down-regulates MHCII expression and promotes DLBCL growth. Proc Natl Acad Sci USA. 2017;114:9701–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Haery L, Lugo-Pico JG, Henry RA, Andrews AJ, Gilmore TD. Histone acetyltransferase-deficient p300 mutants in diffuse large B cell lymphoma have altered transcriptional regulatory activities and are required for optimal cell growth. Mol Cancer. 2014;13:29.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Hammitzsch A, Tallant C, Fedorov O, O’Mahony A, Brennan PE, Hay DA, et al. CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses. Proc Natl Acad Sci USA. 2015;112:10768–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Han K, Jeng EE, Hess GT, Morgens DW, Li A, Bassik MC. Synergistic drug combinations for cancer identified in a CRISPR screen for pairwise genetic interactions. Nat Biotechnol. 2017;35:463–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Jiang Y, Ortega-Molina A, Geng H, Ying HY, Hatzi K, Parsa S, et al. CREBBP inactivation promotes the development of HDAC3-dependent lymphomas. Cancer Discov. 2017;7:38–53.

    Article  CAS  PubMed  Google Scholar 

  49. 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. e9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kasper LH, Fukuyama T, Biesen MA, Boussouar F, Tong C, de Pauw A, et al. Conditional knockout mice reveal distinct functions for the global transcriptional coactivators CBP and p300 in T-cell development. Mol Cell Biol. 2006;26:789–809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Xu W, Fukuyama T, Ney PA, Wang D, Rehg J, Boyd K, et al. Global transcriptional coactivators CREB-binding protein and p300 are highly essential collectively but not individually in peripheral B cells. Blood. 2006;107:4407–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Chan-Penebre E, Kuplast KG, Majer CR, Boriack-Sjodin PA, Wigle TJ, Johnston LD, et al. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat Chem Biol. 2015;11:432–7.

    Article  CAS  PubMed  Google Scholar 

  53. Kaushik S, Liu F, Veazey KJ, Gao G, Das P, Neves LF, et al. Genetic deletion or small-molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AML. Leukemia 2018;32:499–509.

    Article  CAS  PubMed  Google Scholar 

  54. Tarighat SS, Santhanam R, Frankhouser D, Radomska HS, Lai H, Anghelina M, et al. The dual epigenetic role of PRMT5 in acute myeloid leukemia: gene activation and repression via histone arginine methylation. Leukemia. 2016;30:789–99.

    Article  CAS  PubMed  Google Scholar 

  55. Lu X, Fernando TM, Lossos C, Yusufova N, Liu F, Fontan L, et al. PRMT5 interacts with the BCL6 oncoprotein and is required for germinal center formation and lymphoma cell survival. Blood. 2018;132:2026–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. George J, Lim JS, Jang SJ, Cun Y, Ozretic L, Kong G, et al. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015;524:47–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kishimoto M, Kohno T, Okudela K, Otsuka A, Sasaki H, Tanabe C, et al. Mutations and deletions of the CBP gene in human lung cancer. Clin Cancer Res. 2005;11:512–9.

    CAS  PubMed  Google Scholar 

  58. Gui Y, Guo G, Huang Y, Hu X, Tang A, Gao S, et al. Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nat Genet. 2011;43:875–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Mullighan CG, Zhang J, Kasper LH, Lerach S, Payne-Turner D, Phillips LA, et al. CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature. 2011;471:235–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Okosun J, Bodor C, Wang J, Araf S, Yang CY, Pan C, et al. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat Genet. 2014;46:176–81.

    Article  CAS  PubMed  Google Scholar 

  61. Wilson BG, Helming KC, Wang X, Kim Y, Vazquez F, Jagani Z, et al. Residual complexes containing SMARCA2 (BRM) underlie the oncogenic drive of SMARCA4 (BRG1) mutation. Mol Cell Biol. 2014;34:1136–44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Peifer M, Fernandez-Cuesta L, Sos ML, George J, Seidel D, Kasper LH, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet. 2012;44:1104–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. So CK, Nie Y, Song Y, Yang GY, Chen S, Wei C, et al. Loss of heterozygosity and internal tandem duplication mutations of the CBP gene are frequent events in human esophageal squamous cell carcinoma. Clin Cancer Res. 2004;10:19–27.

    Article  CAS  PubMed  Google Scholar 

  64. 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 Discov. 2016;6:430–45.

    Article  CAS  PubMed  Google Scholar 

  65. Gao G, Zhang L, Villarreal OD, He W, Su D, Bedford E, et al. PRMT1 loss sensitizes cells to PRMT5 inhibition. Nucleic Acids Res. 2019;47:5038–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Manu Sebastian Ph.D., Abhinav Jain Ph.D., Michelle Barton Ph.D., Carlos Perez, and members of the MAS laboratory for technical support and helpful discussions. Core facilities were supported by the NIH Grant P30CA16672 and Cancer Prevention Research Institute of Texas (CPRIT) Grants RP120348, RP170002, and RP170628. This work was supported by CPRIT Recruitment of First-time Tenure-Track Faculty award RR160097 (to HX), NIH grant GM126421 (to MTB), Andrew Sabin Family Fellow Award, American Society of Hematology Junior Faculty Scholar Award, and CPRIT First-time Tenure-Track Faculty award RR150039 (to MAS). MAS and HX are CPRIT scholars in cancer research.

Author information

Authors and Affiliations

  1. Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Kylee J. Veazey, Kevin Lin, Oscar D. Villarreal, Guozhen Gao, Mabel Perez-Oquendo, Hieu T. Van, Sabrina A. Stratton, Han Xu, Yue Lu, Mark T. Bedford & Margarida Almeida Santos

  2. Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Donghang Cheng

  3. Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Michael Green

  4. Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Han Xu, Yue Lu, Mark T. Bedford & Margarida Almeida Santos

  5. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Han Xu

Authors
  1. Kylee J. Veazey
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Donghang Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kevin Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Oscar D. Villarreal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guozhen Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mabel Perez-Oquendo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hieu T. Van
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sabrina A. Stratton
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michael Green
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Han Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yue Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Mark T. Bedford
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Margarida Almeida Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

KJV, MG, HX, YL, MTB, and MAS participated in the study design. KJV, DC, GG, MP-O, and HTV participated in cell culture experiments, in vitro drug treatments, protein, and mRNA quantifications, and analyzed data. KJV performed and analyzed all ChIP-qPCR experiments. KJV and SAS performed mouse breeding, xenografts, and in vivo drug treatments, and analyzed data. OV performed the synergistic drug computational analysis. KJV, KL and YL performed all the RNA-seq and ChIP-seq computational analysis. KJV and MAS wrote the paper and all authors reviewed it. MAS supervised the project.

Corresponding author

Correspondence to Margarida Almeida Santos.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Veazey, K.J., Cheng, D., Lin, K. et al. CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300-mutated lymphomas. Leukemia 34, 3269–3285 (2020). https://doi.org/10.1038/s41375-020-0908-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-020-0908-8

This article is cited by

Search

Advanced search

Quick links