CRISPR-Cas13d functional transcriptomics reveals widespread isoform-selective cancer dependencies on lncRNAs
Long noncoding RNAs (lncRNAs) are a significant yet largely uncharted component of the cancer transcriptome, with their isoform-specific functions remaining poorly understood. 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 >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.
Authors
- Domenico Maisano (ORCID: https://orcid.org/0000-0002-1221-9320)
- Jonathan E. Henninger (ORCID: https://orcid.org/0000-0002-9604-2007)
- Eugenio Morelli (ORCID: https://orcid.org/0000-0002-8850-0442)
- Marcello Turi (ORCID: https://orcid.org/0000-0002-8760-1794)
- Liang Chen (ORCID: https://orcid.org/0000-0002-5706-6559)
- Kenneth Carl Anderson (ORCID: https://orcid.org/0000-0002-6418-0886)
- Claire Gao (ORCID: https://orcid.org/0000-0002-8832-5103)
- Mehmet Samur (ORCID: https://orcid.org/0000-0002-9978-5682)
- Abigail K. R. Lytton‐Jean (ORCID: https://orcid.org/0000-0002-1582-0066)
- Dimitrios Papaioannou (ORCID: https://orcid.org/0000-0003-1404-279X)
- Michela Cumerlato (ORCID: https://orcid.org/0009-0006-8229-3047)
- Giovanni de Nola (ORCID: https://orcid.org/0009-0008-9889-1134)
- Mariateresa Fulciniti (ORCID: https://orcid.org/0000-0002-1432-9742)
- Anıl Aktaş Samur (ORCID: https://orcid.org/0000-0002-0183-0562)
- Laure Vreux (ORCID: https://orcid.org/0009-0005-1387-6129)
- Vanessa Favasuli (ORCID: https://orcid.org/0000-0001-6466-7961)
- Annamaria Gullà (ORCID: https://orcid.org/0000-0003-4569-0095)
- Iannis Aifantis (ORCID: https://orcid.org/0000-0001-6857-1035)
- Pietro Folino
- Na Liu (ORCID: https://orcid.org/0000-0001-8654-3636)
- Nikhil Munshi (ORCID: https://orcid.org/0000-0002-8397-100X)
- Richard A. Young
Institutions
- NYU Langone Health (US)
- Dana-Farber Cancer Institute (US)
- Candiolo Cancer Institute (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Whitehead Institute for Biomedical Research (US)
- New York University (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Blood
- Published
- 2025-05-22
- DOI
- https://doi.org/10.1182/blood.2025028746
- Citations
- 4
- Primary Topic
- Cancer-related molecular mechanisms research
- Type
- article
- Field-Weighted Citation Impact
- 3.75
Funders
- U.S. Department of Veterans Affairs
- Ministero della Salute
- Associazione Italiana per la Ricerca sul Cancro
- National Institutes of Health
- National Cancer Institute