POU2AF2/OCA-T1 coactivates POU2F2 and defines a lineage-specific dependency in diffuse large B-cell lymphoma

Tulaiha, Rima, Shanley, Liam, Luvisotto, Amanda, Wang, Ping, Shukla, Vipul, Zhao, Zibo, Yue, Feng, Shilatifard, Ali, Vakoc, Christopher R, Wang, Lu (September 2026) POU2AF2/OCA-T1 coactivates POU2F2 and defines a lineage-specific dependency in diffuse large B-cell lymphoma. bioRxiv. ISSN 2692-8205 (Submitted)

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Abstract

Lineage-restricted transcriptional programs establish cell identity and can create selective dependencies in cancer. Here, we identify POU2AF2, encoding the transcriptional co-activator OCA-T1, as a critical lineage-specific dependency in a subset of diffuse large B-cell lymphoma (DLBCL). Pan-cancer dependency analyses and patient cohorts reveal elevated POU2AF2 expression in genetically aggressive DLBCL, where its depletion markedly suppresses tumor growth in vitro and in vivo. Mechanistically, POU2AF2 cooperates with the B-cell lineage– defining transcription factor POU2F2 (OCT2) to activate lymphocyte activation gene programs through direct chromatin engagement, thereby sustaining malignant transcriptional networks. We further identified a key epigenetic regulatory axis composed of the lineage-specific transcription factor TCF3 and the histone methyltransferase SET1A-COMPASS that drives POU2AF2 expression downstream of B-cell receptor signaling. Single-cell transcriptomic analysis reveals that POU2AF2 marks and sustains an innate-like B1 B-cell population in vivo, a candidate cell of origin for lymphoma. Together, these findings define a lineage-restricted POU2AF2/POU2F2 transcriptional module, controlled by a TCF3/SET1A epigenetic network, that sustains both innate-like B-cell identity and malignant fitness in DLBCL. Our study uncovers a previously unrecognized lineage-specific transcriptional dependency and highlights POU2AF2 and its associated regulatory circuitry as potential therapeutic targets in aggressive B-cell malignancies.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > lymphoma diseases & disorders > cancer > cancer types
CSHL Authors:	Vakoc, Christopher R. Shanley, Liam
Communities:	CSHL labs > Vakoc lab CSHL labs > Wigler lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	1 September 2026
Date Deposited:	21 Sep 2026 14:13
Last Modified:	21 Sep 2026 14:13
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/42323

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