Hung Trinh, Senior VP of Operations at Seneca Therapeutics, shared a post on LinkedIn:
“Penn Medicine, University of Pennsylvania Health System and Children’s Hospital of Philadelphia Philadelphia launch first CRISPR–based platform to pinpoint drivers of acute myeloid leukemia in patient cells.
A new toolkit allows researchers to test potential cancer targets directly in patient-leukemia cells.
A new CRISPR-based tool that is directly used on patients’ cancer cells can identify genes and regulatory elements driving acute myeloid leukemia (AML), an aggressive blood cancer affecting the bone marrow and blood.
This first-of-its-kind approach reveals how individual patient cells respond to genetic changes and makes it easier to identify drug targets and understand why some cancers stop responding to treatment. The findings were published today in Molecular Cell, by researchers from Penn Medicine and Children’s Hospital of Philadelphia (CHOP).
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.
We also developed a Perturb-seq pipeline targeting 39 known AML-related therapeutic genes in patient samples, revealing distinct regulatory networks in supporting AML. From targeted screens encompassing 39 AML-related genes and 197 chromatin regulatory domains, we identified differential dependencies on chromatin regulators among patient samples.
Collectively, this study establishes a general framework for leveraging CRISPR functional genomics to dissect cancer vulnerabilities and cellular heterogeneity in primary AML patient samples.”
Title: CRISPR-based functional genomics for dissecting therapeutic dependency in primary acute myeloid leukemia samples
Authors: Zhendong Cao, Sixiang Yu, Jacqueline Peng, Declan R. Barrett, Yuqiao Liu, Jonathan H. Sussman, Changya Chen, Anusha Thadi, Li Liu, Fatemeh Alikarami, Jason Xu, Martin P. Carroll, Kai Tan, Kathrin M. Bernt
Read The Full Article
Other articles about AML on OncoDaily.