Integration of CRISPR‐Cas9 screens and multi‐omics profiling reveals chromodomain helicase DNA binding protein 7‐angiopoietin‐1 as a novel multidrug resistance axis in acute myeloid leukemia

Abstract Acute myeloid leukemia (AML) is a devastating hematological malignancy and one of the most prevalent forms of leukemia in adults. Despite recent advancements and approval of novel targeted therapies, drug resistance remains a formidable clinical challenge. In this study, we conducted an unbiased CRISPR‐Cas9 knockout screen in AML cells to uncover novel mediators of resistance to the clinically approved FLT3 inhibitor gilteritinib. This screen identified chromodomain helicase DNA binding protein 7 (CHD7) as a new regulator of drug resistance. Strikingly, CHD7 loss not only conferred resistance to FLT3 inhibitors but also extended resistance to a broad range of therapeutics, including venetoclax and daunorubicin (DNR). Mechanistic investigations integrating transcriptomic and proteomic data revealed that CHD7 deletion upregulates angiopoietin‐1 (ANGPT1), which drives resistance by activating the PI3K/AKT and MAPK/ERK signaling pathways. Significantly, genetic knockdown of ANGPT1 or pharmacological inhibition of its receptor TIE2 partially restored drug sensitivity in CHD7‐deficient cells. Together, these findings identify the CHD7‐ANGPT1 axis as a novel mechanism of multi‐drug resistance in AML. Preclinical studies further suggest that combining targeted therapies with TIE2 inhibitors offers a promising strategy to overcome drug resistance in AML.