Genome-wide CRISPR screen identifies AraC-Dauno-Eto (ADE) response modulators that predicts outcome in pediatric AML.

Autor:	Nguyen NH; University of Florida, Gainesville, Florida, United States., Rafiee R; University of Florida, GAINESVILLE, Florida, United States., Parcha PK; University of Florida, Gainesville, Florida, United States., Tagmount A; University of Florida, Gainesville, Florida, United States., Rubnitz J; St. Jude Children's Research Hospital, Memphis, Tennessee, United States., Ribeiro RC; St. Jude Children's Research Hospital, Memphis, Tennessee, United States., Cao X; University of Tennessee Health Science Center, Memphis, Tennessee, United States., Pounds SB; St. Jude Children's Research Hospital, Memphis, Tennessee, United States., Vulpe CD; UFL Gainesville, Gainesville, Florida, United States., Lamba JK; University of Florida, Gainesville, Florida, United States.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2024 Dec 23. Date of Electronic Publication: 2024 Dec 23.
DOI:	10.1182/bloodadvances.2024014157
Abstrakt:	Cytarabine, daunorubicin, and etoposide (ADE) have been the standard backbone of induction chemotherapy regimens for acute myeloid leukemia (AML) patients for over five decades. However, chemoresistance is still a major concern, and a significant proportion of AML becomes resistant to ADE treatment leading to relapse and poor survival. Therefore, there is a significant need to identify mechanisms mediating drug resistance to overcome chemoresistance. Herein, we performed genome-wide synthetic lethal CRISPR/Cas9 screens using araC, daunorubicin and etoposide. We further integrated significant findings from the CRISPR screen with outcome in pAML patients treated with standard ADE regimen on 3 independent clinical trials to identify drug response biomarkers of prognostic significance. We identified seveal mediators that would represent clinically and biologically significant genes for ADE treatment, such as BCL2, CLIP2, and VAV3, which are resistant genes with high expression associated with poor outcomes in pAML treated with ADE, and GRPEL1, HCFC1, and TAF10, which are sensitive genes with high expression showing beneficial outcomes. Notably, knockdowns of the BCL2, CLIP2, and VAV3 genes sensitize the ADE component in AML cell lines, suggesting that these genes should be further studied as potential therapeutic targets to overcome chemoresistance. (Copyright © 2024 American Society of Hematology.)
Databáze:	MEDLINE
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