Targeting Monoallelic CREBBP/EP300 Mutations in Germinal Center-Derived B-Cell Lymphoma with a First-in-Class Histone Acetyltransferase Activator

Liu, Y.; Piorczynski, T. B.; Estrella, B.; Ricker, E. C.; Pazos, M.; Gonzalez, Y.; Tolu, S. S.; Ryu Tiger, Y. K.; Karan, C.; Cremers, S.; Nandakumar, R.; Honig, B.; Hwang, H.; Kelleher, N. L.; Camarillo, J. M.; Abshiru, N. A.; Amengual, J. E.

doi:10.1101/2025.03.13.642871

bioRxiv · 10.1101/2025.03.13.642871

Targeting Monoallelic CREBBP/EP300 Mutations in Germinal Center-Derived B-Cell Lymphoma with a First-in-Class Histone Acetyltransferase Activator

Liu, Y.·Piorczynski, T. B.·Estrella, B.·Ricker, E. C.·Pazos, M.·Gonzalez, Y.·Tolu, S. S.·Ryu Tiger, Y. K.·Karan, C.·Cremers, S.·Nandakumar, R.·Honig, B.·Hwang, H.·Kelleher, N. L.·Camarillo, J. M.·Abshiru, N. A.·Amengual, J. E.

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Abstract

Germinal center B-cell lymphomas frequently exhibit monoallelic loss-of-function mutations in the histone acetyltransferases CREBBP and p300, which contribute to lymphoma development, disrupt normal germinal center biology, and promote immune evasion. This study evaluates YF2, a histone acetyltransferase activator that increases CREBBP/p300 activity, as a potential therapeutic approach for B-cell lymphoma. YF2 binds the bromodomain of CREBBP/p300, increasing their auto-acetylation and enzymatic activity. It also induces cytotoxicity in B-cell lymphoma cell lines, with a stronger response in those carrying CREBBP/EP300 mutations. Additionally, YF2 increases the acetylation of key CREBBP/p300 substrates, including H3K27, p53, and BCL6, leading to enhanced apoptosis and altered B-cell diTerentiation. YF2 is well tolerated in vivo and extends survival in both cell line- and patient-derived xenograft mouse models. Moreover, YF2 exposure upregulates antigen-presentation markers and reshapes the immune microenvironment, strengthening responses to immune checkpoint blockade. Taken together, these findings support pharmacologic activation of CREBBP/p300 with YF2 as a compelling therapeutic strategy for B-cell lymphoma. SignificanceYF2 stimulates CREBBP/p300 activity to normalize B-cell diTerentiation and enhance immune recognition, oTering a potential approach to limit lymphoma progression and strengthen immunotherapy responses.

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Liu, Y., Piorczynski, T. B., Estrella, B., Ricker, E. C., Pazos, M., Gonzalez, Y., Tolu, S. S., Ryu Tiger, Y. K., Karan, C., Cremers, S., Nandakumar, R., Honig, B., Hwang, H., Kelleher, N. L., Camarillo, J. M., Abshiru, N. A., Amengual, J. E.. 2025-03-17. Targeting Monoallelic CREBBP/EP300 Mutations in Germinal Center-Derived B-Cell Lymphoma with a First-in-Class Histone Acetyltransferase Activator. https://doi.org/10.1101/2025.03.13.642871

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