In Vivo Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target.
Journal
Blood cancer discovery
ISSN: 2643-3249
Titre abrégé: Blood Cancer Discov
Pays: United States
ID NLM: 101764786
Informations de publication
Date de publication:
01 05 2023
01 05 2023
Historique:
received:
17
05
2022
revised:
30
11
2022
accepted:
06
02
2023
medline:
2
5
2023
pubmed:
11
2
2023
entrez:
10
2
2023
Statut:
ppublish
Résumé
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 in vivo two-step CRISPR-Cas9 screen to assay stem cell functionality, we found 32 RBPs essential for LSCs in MLL-AF9;NrasG12D AML. Loss-of-function approaches targeting key hit RBP ELAVL1 compromised LSC-driven in vivo 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 in vivo CRISPR screen, this work demonstrates pervasive reliance on RBPs as regulators of LSCs and highlights their potential as therapeutic targets in AML. LSC-targeted therapies remain a significant unmet need in AML. We developed a stem-cell-adapted in vivo 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. This article is highlighted in the In This Issue feature, p. 171.
Identifiants
pubmed: 36763002
pii: 716497
doi: 10.1158/2643-3230.BCD-22-0086
pmc: PMC10150294
doi:
Substances chimiques
RNA-Binding Proteins
0
TOMM34 protein, human
0
Mitochondrial Precursor Protein Import Complex Proteins
0
ELAVL1 protein, human
0
ELAV-Like Protein 1
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
180-207Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL137223
Pays : United States
Informations de copyright
©2023 The Authors; Published by the American Association for Cancer Research.
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