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• W4367603711 abstract "<div>Abstract<p>Acute myeloid leukemia (AML) is fueled by leukemic stem cells (LSC) whose determinants are challenging to discern from hematopoietic stem cells (HSC) or uncover by approaches focused on general cell properties. We have identified a set of RNA-binding proteins (RBP) selectively enriched in human AML LSCs. Using an <i>in vivo</i> two-step CRISPR-Cas9 screen to assay stem cell functionality, we found 32 RBPs essential for LSCs in MLL-AF9;Nras^G12D AML. Loss-of-function approaches targeting key hit RBP ELAVL1 compromised LSC-driven <i>in vivo</i> leukemic reconstitution, and selectively depleted primitive malignant versus healthy cells. Integrative multiomics revealed differentiation, splicing, and mitochondrial metabolism as key features defining the leukemic ELAVL1–mRNA interactome with mitochondrial import protein, TOMM34, being a direct ELAVL1-stabilized target whose repression impairs AML propagation. Altogether, using a stem cell–adapted <i>in vivo</i> CRISPR screen, this work demonstrates pervasive reliance on RBPs as regulators of LSCs and highlights their potential as therapeutic targets in AML.</p>Significance:<p>LSC-targeted therapies remain a significant unmet need in AML. We developed a stem-cell–adapted <i>in vivo</i> CRISPR screen to identify key LSC drivers. We uncover widespread RNA-binding protein dependencies in LSCs, including ELAVL1, which we identify as a novel therapeutic vulnerability through its regulation of mitochondrial metabolism.</p><p><i><a href=https://aacrjournals.org/bloodcancerdiscov/article/doi/10.1158/2643-3230.BCD-4-3-ITI target=_blank>This article is highlighted in the In This Issue feature, p. 171</a></i></p></div>" @default.
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• W4367603711 date "2023-05-01" @default.
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• W4367603711 title "Data from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target" @default.
• W4367603711 doi "https://doi.org/10.1158/2643-3230.c.6572000.v2" @default.
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