Inhibition of KDM5A/B promotes antitumor innate immune responses in HHV-8/KSHV2 positive B-cell lymphomas

Zhou, D.; Fiches, G. N.; Wu, Z.; Eleya, S.; Park, Y.; He, J.; Shanaka, K. A.; Lepcha, T. T.; Liu, Y.; Oliva, J.; Lurain, K.; Jung, J. U.; Qi, J.; Zhao, W.; Zhu, J.; Santoso, N. G.

doi:10.64898/2026.01.28.702275

bioRxiv · 10.64898/2026.01.28.702275

Inhibition of KDM5A/B promotes antitumor innate immune responses in HHV-8/KSHV2 positive B-cell lymphomas

Zhou, D.·Fiches, G. N.·Wu, Z.·Eleya, S.·Park, Y.·He, J.·Shanaka, K. A.·Lepcha, T. T.·Liu, Y.·Oliva, J.·Lurain, K.·Jung, J. U.·Qi, J.·Zhao, W.·Zhu, J.·Santoso, N. G.

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Abstract

Summary/AbstractHistone methylation is a dynamic and reversible epigenetic modification that critically controls the progression of human diseases, including infections and cancers. Here we reported that histone lysine demethylases (KDMs) in the KDM5 family KDM5A/B play profound roles in suppressing lytic reactivation of oncogenic human herpesvirus 8 (HHV-8), i.e., Kaposis sarcoma-associated herpesvirus (KSHV), as well as antiviral/antitumor innate immune responses in KSHV-infected B-cell lymphomas. We showed that KSHV lytic replication decreases KDM5A/B protein stability by enhancing their K-48 linked polyubiquitination while KDM5A/B depletion facilitates KSHV lytic reactivation. Mechanistic studies illustrated that KDM5A/B associate with KSHV LANA protein and dampen its chromatin association at both KSHV viral lytic promoter and promoters of antitumor immune-responsive genes (IRGs). In comparisons to normal B cells, KDM5A/B expression significantly increased in B-cell lymphoma cells, including KSHV-positive primary effusion lymphoma (PEL). We demonstrated that KDM5A/B inhibition remarkably induces both KSHV lytic reactivation and innate immune responses in PEL cells, resulting in a strong viral oncolytic effect, both in vitro in cell cultures and in vivo using a PEL xenograft mouse model. Overall, our studies identified the novel functions of KDM5A/B to silence KSHV lytic replication and antiviral/antitumor innate immune responses, which can be blocked to benefit the treatment of KSHV-associated B-cell lymphomas that are usually aggressive and difficult to treat.

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Zhou, D., Fiches, G. N., Wu, Z., Eleya, S., Park, Y., He, J., Shanaka, K. A., Lepcha, T. T., Liu, Y., Oliva, J., Lurain, K., Jung, J. U., Qi, J., Zhao, W., Zhu, J., Santoso, N. G.. 2026-01-28. Inhibition of KDM5A/B promotes antitumor innate immune responses in HHV-8/KSHV2 positive B-cell lymphomas. https://doi.org/10.64898/2026.01.28.702275

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