| Literature DB >> 34109316 |
Michael Hamilton1,2,3,4, Yutaka Shima1,2,3,4, Jeevisha Bajaj5,6,7,8,9, Kendall Chambers1,2,3,4, Kyle Spinler1,2,3,4, Eric L Van Nostrand2,3,10,11, Brian A Yee2,3,10,11, Steven M Blue2,3,10,11, Michael Chen1,2,3,4, David Rizzeri12, Charles Chuah13, Vivian G Oehler14, H Elizabeth Broome3,15, Roman Sasik16, James Scott-Browne17,18, Anjana Rao1,2,3,17, Gene W Yeo2,3,10,11, Tannishtha Reya19,20,21,22.
Abstract
Aggressive myeloid leukemias such as blast crisis chronic myeloid leukemia and acute myeloid leukemia remain highly lethal. Here we report a genome-wide in vivo CRISPR screen to identify new dependencies in this disease. Among these, RNA-binding proteins (RBPs) in general, and the double-stranded RBP Staufen2 (Stau2) in particular, emerged as critical regulators of myeloid leukemia. In a newly developed knockout mouse, loss of Stau2 led to a profound decrease in leukemia growth and improved survival in mouse models of the disease. Further, Stau2 was required for growth of primary human blast crisis chronic myeloid leukemia and acute myeloid leukemia. Finally, integrated analysis of CRISPR, eCLIP and RNA-sequencing identified Stau2 as a regulator of chromatin-binding factors, driving global alterations in histone methylation. Collectively, these data show that in vivo CRISPR screening is an effective tool for defining new regulators of myeloid leukemia progression and identify the double-stranded RBP Stau2 as a critical dependency of myeloid malignancies.Entities:
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Year: 2020 PMID： 34109316 PMCID： PMC8186448 DOI： 10.1038/s43018-020-0054-2
Source DB: PubMed Journal: Nat Cancer ISSN： 2662-1347