{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T16:57:28Z","timestamp":1790528248953,"version":"4.1.0"},"posted":{"date-parts":[[2026,1,26]]},"group-title":"Cancer Biology","reference-count":71,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T00:00:00Z","timestamp":1769385600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Osteoclastogenesis-associated transmembrane protein 1 (OSTM1) is a membrane-integral glycosylated protein known for regulating lysosomal homeostasis, with loss-of-function mutations causing autosomal recessive osteopetrosis. Through a whole-genome CRISPR\/Cas9 screen, we identified OSTM1 as a critical tumor suppressor in B-cell malignancies. In humans, OSTM1 is frequently deleted or downregulated across a wide range of B-cell malignancies. In mice, B-cell-specific monoallelic or biallelic\n                  <jats:italic>Ostm1<\/jats:italic>\n                  ablation cooperates with\n                  <jats:italic>Cdkn2a<\/jats:italic>\n                  loss to drive lymphomagenesis with near 100% penetrance. Mechanistically, we reveal that a cytosolic, non-glycosylated fraction of OSTM1 functions as an E3 ligase that targets phosphodiesterase 3B (PDE3B) for proteasomal degradation. Because PDE3B catalyzes the conversion of cAMP to AMP and thereby negatively regulating the cAMP-dependent PKA\/CREB\/CREBBP tumor suppressive pathway, the loss of OSTM1 leads to PDE3B stabilization and enhanced cell transformation. Our findings establish OSTM1 as a pivotal E3 ligase that prevents B-cell lymphomagenesis through the regulation of the cAMP\/PKA\/CREB pathway.\n                <\/jats:p>","DOI":"10.64898\/2026.01.23.701155","type":"posted-content","created":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T19:50:12Z","timestamp":1769457012000},"source":"Crossref","is-referenced-by-count":0,"title":["OSTM1 is a ubiquitin E3 ligase that suppresses B-cell malignancy by activating the cAMP\/PKA\/CREB pathway"],"prefix":"10.64898","author":[{"given":"Muhammad Usama","family":"Tariq","sequence":"first","affiliation":[{"name":"Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Namratha","family":"Sheshadri","sequence":"additional","affiliation":[{"name":"Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, 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