Abstract A011: OSTM1 restrains B-cell lymphomagenesis by promoting PDE3B degradation and activating cAMP-PKA-CREB signaling

Abstract Through a genome-wide forward CRISPR/Cas9 screen in interleukin-3 (IL3)-dependent Ba/F3 cells, we identified osteoclastogenesis-associated transmembrane protein 1 (OSTM1) as a previously unrecognized tumor suppressor. Analysis of patient datasets revealed that OSTM1 is frequently deleted or downregulated in human B-cell lymphomas (BCL). In mice, Cd19-Cre-driven B cell–specific monoallelic or biallelic deletion of Ostm1 cooperated with Cdkn2a loss to drive lymphomagenesis with near-complete penetrance. Mechanistically, OSTM1 directly interacts with phosphodiesterase 3B (PDE3B) and promotes its proteasomal degradation. Because PDE3B hydrolyzes cyclic AMP (cAMP), loss of OSTM1 stabilizes PDE3B, leading to suppression of tumor-suppressive cAMP-dependent PKA/CREB signaling and promotion of oncogenic transformation. Consistent with this mechanism, PDE3B is frequently amplified or upregulated in BCL, and expression of CREB/CREBBP transcriptional targets correlates positively with OSTM1 expression but inversely with PDE3B across BCL cohorts. Importantly, silencing Pde3b reverses oncogenic transformation driven by Ostm1 loss. Together, these findings establish OSTM1 as a previously unrecognized tumor suppressor and uncover an OSTM1-PDE3B-cAMP signaling axis that restrains B-cell lymphomagenesis and may represent a therapeutically actionable vulnerability. Citation Format: Muhammad Usama. Tariq, Namratha Sheshadri, Jianliang Shen, Jaeyong Jung, Rongrong Li, Hassan Sajjad, Yi Sun, Richard Lin, Christian Hinrichs, Francesco Bertoni, Lynn Wang, Jean Vacher, Ping Xie, Wei-Xing Zong. OSTM1 restrains B-cell lymphomagenesis by promoting PDE3B degradation and activating cAMP-PKA-CREB signaling [abstract]. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7(3_Suppl):Abstract nr A011.