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LYMPHOMA

Analysis and therapeutic targeting of the EP300 and CREBBP acetyltransferases in anaplastic large cell lymphoma and Hodgkin lymphoma

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.

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Fig. 1: EP300 supports the viability and surface CD30 expression of ALCL and HL cells.
Fig. 2: The transcriptional programs regulated by EP300/CREBBP inhibitors in ALCL.
Fig. 3: EP300 and CREBBP modulate distinct functional programs in ALCL.
Fig. 4: Gene expression programs regulated by EP300/CREBBP inhibitors in HL.
Fig. 5: EP300 promotes NF-κB activation in HL.
Fig. 6: EP300 mediates PD-L1 expression and immune escape in ALCL and HL.
Fig. 7: Targeting EP300 in ALCL and HL xenograft mouse models.

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.

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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.

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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.

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Correspondence to Yibin Yang.

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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

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