Abstract 617: OSTM1 is a ubiquitin E3 ligase that suppresses B-cell malignancy by activating the cAMP/PKA pathway.

Abstract Osteoclastogenesis-associated transmembrane protein 1 (OSTM1) is a membrane-integral glycosylated protein that regulates lysosomal homeostasis and osteoclast maturation. Its loss-of-function mutations cause autosomal recessive osteopetrosis (ARO). In addition, OSTM1 was described as a putative ubiquitin E3 ligase yet with ill-defined substrates and biological functions. Using a whole-genome CRISPR/Cas9 screening in the interleukin-3 (IL3)-dependent Ba/F3 murine pro-B cell line, we identified OSTM1 whose silencing confers IL3-independent growth and in vivo transformation of Ba/F3 cells. In humans, OSTM1 is frequently deleted or downregulated across a wide range of B cell malignancies. In mice, B cell-specific monoallelic and biallelic ablations of Ostm1 cooperates with Cdkn2a ablation to drive lymphomagenesis with a near 100% penetrance. Mechanistically, a fraction of OSTM1, non-glycosylated and cytosol located, acts as an E3 ligase and interacts with phosphodiesterase 3B (PDE3B) to promote its proteasomal degradation. As PDE3B catalyzes the conversion of cAMP to AMP hence negatively regulates the cAMP-dependent PKA/CREB/CREBBP tumor suppressive pathway, loss of OSTM1 leads to PDE3B stabilization and increased cell growth. Together, our findings uncover OSTM1 as a tumor-suppressive E3 ligase by promoting the proteasomal degradation of PDE3B and activating the cAMP-dependent PKA pathway. Citation Format: Muhammad Usama Tariq, Namratha Sheshadri, Julia Shen, Jaeyong Jung, Rongrong Li, Kevin Lu, Junrong Yan, Mark Koch, Hassan Sajjad, Barbara Rosati, Giuseppe Caso, Richard LIN, Brinda Vallat, Stephen Burley, Tong Liu, Hong Li, Christian Hinrichs, Jun Wang, Lynn Wang, Jean Vacher, Ping Xie, Wei-Xing Zong. OSTM1 is a ubiquitin E3 ligase that suppresses B-cell malignancy by activating the cAMP/PKA pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 617.