Molecular cellFeb 27, 2026

Using gene editing to identify treatment weaknesses in primary acute myeloid leukemia samples

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Feb 28, 2026

Abstract

An optimized CRISPR-based platform was developed for functional genomics in primary acute myeloid leukemia (AML) samples.

Direct interrogation of primary tumors could identify therapeutic targets and uncover mechanisms of cancer resistance.
CRISPR-Cas9 knockout and CRISPR interference screens validated known AML targets and discovered essential cis-regulatory elements.
Integrating CRISPR perturbations with single-cell RNA sequencing revealed changes in regulatory networks and cell cycle states.
The approach may facilitate understanding of cellular hierarchies in heterogeneous AML patient samples.

Simplified

Cancer functional genomics enables high-throughput target discovery and mechanistic investigation, yet its application has remained largely confined to mouse models and established human cancer cell lines. Direct functional interrogation of heterogeneous primary tumors offers a powerful opportunity to evaluate therapeutic targets and uncover cancer dependencies or resistance mechanisms. Here, we developed an optimized CRISPR-based platform for functional genomics in patient-derived xenograft and primary acute myeloid leukemia (AML) samples harboring diverse pathogenic mutations. Integrated in vitro and in vivo CRISPR-Cas9 knockout and CRISPR interference (CRISPRi) dropout screens validated known AML-biased targets and identified cis-regulatory elements essential for leukemic growth. Coupling pooled CRISPR perturbations with single-cell RNA sequencing (Perturb-seq) further resolved the perturbation-induced alterations in regulatory networks, cell cycle states, and cellular hierarchies in primary AML samples. Together, these studies establish a general and robust framework for leveraging CRISPR-based functional genomics to directly dissect cancer dependencies and cellular heterogeneity in primary AML patient samples.

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Funding

Competing interests

Declaration of interests K.M.B. has previously received research funding from Syndax. J.S. has previously provided scientific consulting for Treeline Biosciences.

PubMed

Using gene editing to identify treatment weaknesses in primary acute myeloid leukemia samples

Abstract

Full Text

Funding

Competing interests

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