2021
DOI: 10.1038/s41598-021-92448-w
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Focused CRISPR-Cas9 genetic screening reveals USO1 as a vulnerability in B-cell acute lymphoblastic leukemia

Abstract: 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 E… Show more

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Cited by 11 publications
(14 citation statements)
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“…We first designed multiple single guide RNAs (sg) targeting Traf6 , and ultimately 2 guides (sgA, sgB) and one non-targeting control (sgNT) were selected after testing ( Supplement 5A ). SgRNAs were then cloned into MSCV-based retroviral vector containing RNA polymerase III U6 promoter driving expression of sgRNAs and scaffold sequence, with mCherry reporter cassette driven under a separate RNA polymerase II promoter to mark transduction, which we recently described ( 36 ). TRAF6 protein depletion was validated in a murine pre-B cell line, 70Z/3 ( Figure 5B , left).…”
Section: Resultsmentioning
confidence: 99%
“…We first designed multiple single guide RNAs (sg) targeting Traf6 , and ultimately 2 guides (sgA, sgB) and one non-targeting control (sgNT) were selected after testing ( Supplement 5A ). SgRNAs were then cloned into MSCV-based retroviral vector containing RNA polymerase III U6 promoter driving expression of sgRNAs and scaffold sequence, with mCherry reporter cassette driven under a separate RNA polymerase II promoter to mark transduction, which we recently described ( 36 ). TRAF6 protein depletion was validated in a murine pre-B cell line, 70Z/3 ( Figure 5B , left).…”
Section: Resultsmentioning
confidence: 99%
“…USO1 has been implicated in tumourigenesis in multiple cancers including gastric ( 10 ), colon ( 11 ), breast ( 12 ), liver cancer ( 13 ) as well as multiple myeloma ( 14 ) and leukaemia ( 38 ). Overexpression of USO1 has been shown to play a role in cell proliferation and cell cycle transition in these studies, and as such in general, one would expect high expression of USO1 to be associated with worse OS.…”
Section: Discussionmentioning
confidence: 99%
“…In the field of hematology, several custom libraries have been used to study specific molecular pathways or a particular set of genes that play a relevant role in the development of the disease or during treatment. Of note, a custom library containing sgRNAs targeting 36 highly regulated RNA-binding protein (RBP) genes in B-ALL was designed to identify which ones are essential in B-ALL [ 80 ]. Other libraries targeting only kinases or genes involved in DNA damage response have detected gene modulators whose disruption could enhance the sensitivity of drugs such as asparaginase or PARP inhibitors (PARPi), respectively [ 27 , 97 ].…”
Section: The Crispr Screening Libraries Used For the Study Of Hematol...mentioning
confidence: 99%
“…Specially, highly aggressive forms of B-ALL such as those harboring MLL-AF4 translocations need to be better characterized in order to outline potential therapeutic targets with a high specificity. Interestingly, CRISPR screening was performed to determine RNA-binding proteins as being specific essential genes for MLL-AF4-dependent leukemic cell growth, validating USO1 as a vulnerability in in vitro ALL models and primary murine cells [ 80 ].…”
Section: Hematologic Dependency Map Through Crispr Screens: Essential...mentioning
confidence: 99%
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