An In Vivo Genome-Wide CRISPR Screen Identifies the RNA-Binding Protein Staufen2 as a Key Regulator of Myeloid Leukemia

Authors

Jeevisha Bajaj
Michael Hamilton
Yutaka Shima
Kendall Chambers
Kyle Spinler
Eric L Van Nostrand
Brian A Yee
Steven M Blue
Michael Chen
David Rizzeri
Charles Chuah
Vivian G Oehler
H Elizabeth Broome
Roman Sasik
James Scott-Browne
Anjana Rao
Gene W Yeo
Tannishtha Reya

Publication Date

4-1-2020

Journal

Nature Cancer

DOI

10.1038/s43018-020-0054-2

PMID

34109316

PMCID

PMC8186448

PubMedCentral® Posted Date

6-8-2021

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, Blast Crisis, Clustered Regularly Interspaced Short Palindromic Repeats, Genome, Leukemia, Myeloid, Acute, Mice, Nerve Tissue Proteins, RNA-Binding Proteins

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.

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