CRISPR screening reveals ZNF217 as a vulnerability in high-risk B-cell acute lymphoblastic leukemia

作者：Xi Qin, Keren Zhou, Lei Dong, Yang Lü, Wei Li, Zhenhua Chen, Chao Shen, Han Li, Yangchan Li, Anthony Chan, Sheela Pangeni Pokharel, Ying Qing, Meiling Chen, Kitty Wang, Keith Sai Kit Leung, Lillian Sau, Chun-Wei Chen, Xiaolan Deng, Rui Su, Jianjun Chen · 发表于：Theranostics · 年份：2025 · DOI：10.7150/thno.100295 · 被引用次数：6 · 研究领域：Acute Lymphoblastic Leukemia research、CRISPR and Genetic Engineering、Chronic Lymphocytic Leukemia Research

Rationale: Despite substantial advancement in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), it remains a leading cause of cancer mortality in children due to the high relapse rate.Moreover, the long-term survival rates for adult B-ALL patients are still less than 40%.The B-ALL patients carrying MLL rearrangements or BCR-ABL fusion represent high-risk B-ALL subtypes that face particularly dismal prognoses.This study aims to identify innovative therapeutic vulnerability for high-risk B-ALL.Methods: The CRISPR-Cas9 screen was conducted to pinpoint genes essential for high-risk B-ALL cell survival/growth.Both in vitro and in vivo models were then employed to investigate the pathological role of ZNF217 in high-risk B-ALL.To characterize the downstream functionally essential targets of ZNF217, we performed RNA-seq and CUT&RUN-seq, followed by integrative bioinformatics analysis and experimental validation.Results: Through the focused CRISPR-Cas9 screening, ZNF217 emerged as the most essential gene for the cell survival/growth of B-ALL driven by MLL rearrangement or BCR-ABL.Through in vitro gain-and loss-of-function assays, we demonstrated that ZNF217 is indeed required for B-ALL cell survival/growth.Moreover, we established the B-ALL xenograft model and patient-derived xenograft (PDX) model and demonstrated that ZNF217 depletion significantly suppressed B-ALL progression and substantially extended the survival of recipient mice.Through integrative multiple-omics ana...