{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T03:38:11Z","timestamp":1790307491899,"version":"4.1.0"},"reference-count":31,"publisher":"American Society of Hematology","issue":"13","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,9,24]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>The t(4;14) chromosomal translocation drives overexpression of the histone methyltransferase NSD2 and defines a high-risk segment of patients with multiple myeloma (MM). Herein, we report the discovery of NSD2\u2013ligand-directed degrader (NSD2-LDD), a cereblon-recruiting and PWWP1-mediated LDD that selectively and potently eliminates full-length and PWWP1 domain\u2013containing NSD2 protein isoforms. NSD2-LDD treatment induces the global loss of H3K36me2, leading to promoter-proximal spreading of H3K27me3 and rewiring of cis-regulatory interactions that reverse t(4;14) transcriptional programs. These effects suppress MM disease\u2013associated phenotypes, including stromal adhesion, 3-dimensional (3D) colony growth, and paracrine signaling. By integrating patient single-cell profiles with model 3D epigenomic and spatial transcriptomics, we delineate t(4;14) disease state together with the tumor-intrinsic reprogramming and resultant remodeling of the bone marrow microenvironment upon NSD2 degradation. In cell line\u2013derived xenografts and genetically engineered mouse models of t(4;14), NSD2-LDD extends median survival, accompanied by tumoral H3K36me2 loss and niche remodeling. Although the NSD2-LDD response is restricted to PWWP1-containing models, collectively this work validates NSD2 as a tractable dependency and supports the clinical development of NSD2 degradation as a novel, targeted therapeutic strategy in high-risk MM.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2025031998","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T16:57:42Z","timestamp":1782752262000},"page":"1694-1707","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":1,"title":["NSD2 degradation remediates the oncogenic cistrome in t(4;14) multiple myeloma"],"prefix":"10.1182","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8527-3750","authenticated-orcid":false,"given":"Bo","family":"Hu","sequence":"first","affiliation":[{"name":"1Protein Homeostasis Thematic Research Center, Bristol Myers Squibb, San Diego, 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