摘要：Post-transcriptional gene regulation, including that by RNA binding proteins (RBPs), has recently been described as an important mechanism in cancer. We had previously identified a set of RBPs that were highly dysregulated in B-cell acute lymphoblastic leukemia (B-ALL) with
MLL translocations, which carry a poor prognosis. Here, we sought to functionally characterize these dysregulated RBP genes by performing a focused CRISPR dropout screen in B-ALL cell lines, finding dependencies on several genes including
EIF3E,
EPRS and
USO1. Validating our findings, CRISPR/Cas9-mediated disruption of
USO1 in
MLL-translocated B-ALL cells reduced cell growth, promoted cell death, and altered the cell cycle. Transcriptomic analysis of
USO1-deficient cells revealed alterations in pathways related to mTOR signaling, RNA metabolism, and targets of MYC. In addition, USO1-regulated genes from these experimental samples were significantly and concordantly correlated with
USO1 expression in primary samples collected from B-ALL patients. Lastly, we found that loss of
Uso1 inhibited colony formation of
MLL-transformed in primary bone marrow cells from
Cas9-EGFP mice. Together, our findings demonstrate an approach to performing focused sub-genomic CRISPR screens and highlight a putative RBP vulnerability in
MLL-translocated B-ALL, thus identifying potential therapeutic targets in this disease.
