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In this study, we used RNA-targeting CRISPR-Cas13d to uncover and characterize hundreds of tumor-essential lncRNA (te-lncRNA) isoforms with clinical relevance. Focusing on multiple myeloma (MM), we targeted the lncRNA transcriptome expressed in tumor cells from patients with MM and revealed both MM-specific and pan-cancer dependencies across diverse cancer cell lines, which we further validated in animal models. Additionally, we mapped the subcellular localization of these te-lncRNAs, identifying &amp;gt;30 cytosolic isoforms that proved essential when targeted by cytosol-localized Cas13d. Notably, a specific isoform of small nucleolar RNA host gene 6, enriched in the endoplasmic reticulum, interacts with heat shock proteins to maintain cellular proteostasis. We also integrated functional and clinical data into the publicly accessible LongDEP Portal, providing a valuable resource for the research community. Our study offers a comprehensive characterization of te-lncRNAs, underscoring their oncogenic roles and therapeutic potential.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2025028746","type":"journal-article","created":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T16:11:27Z","timestamp":1747930287000},"page":"847-860","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":9,"title":["CRISPR-Cas13d functional transcriptomics reveals widespread isoform-selective cancer dependencies on lncRNAs"],"prefix":"10.1182","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8850-0442","authenticated-orcid":false,"given":"Eugenio","family":"Morelli","sequence":"first","affiliation":[{"name":"1Candiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia-Istituto di Ricovero e Cura a Carattere Scientifico, Candiolo, Italy"},{"name":"2Department of Oncology, University of Turin, Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0183-0562","authenticated-orcid":false,"given":"Anil","family":"Aktas-Samur","sequence":"additional","affiliation":[{"name":"3Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA"},{"name":"4Department of Medical Oncology, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Maisano","sequence":"additional","affiliation":[{"name":"3Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA"},{"name":"4Department of Medical Oncology, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Gao","sequence":"additional","affiliation":[{"name":"3Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Favasuli","sequence":"additional","affiliation":[{"name":"3Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA"},{"name":"4Department of Medical Oncology, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitrios","family":"Papaioannou","sequence":"additional","affiliation":[{"name":"5Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9889-1134","authenticated-orcid":false,"given":"Giovanni","family":"De Nola","sequence":"additional","affiliation":[{"name":"6David H. 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