GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE306nnn/GSE306460/primaryOK200OtherHomo sapiensOtherhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE306460GEOGSEfalseEvaluation of PTBP1 binding at transcripts in the human acute myeloid leukemia cell line MOLM-13RNA-modifying enzymes (RNAes) and RNA-binding proteins (RBPs) have emerged as critical gene regulators in both normal physiology and cancer. To systematically evaluate their necessity in cancer, we performed domain-focused CRISPR screens targeting RNAes and RBPs across a broad spectrum of cancer cell lines. These screens identified novel acute myeloid leukemia (AML) dependencies, including PTBP1, with a bias toward KMT2A-rearranged (KMT2A-r) AML, an aggressive subtype with poor clinical outcomes. Genetic and cellular validation confirmed all four RNA-binding domains in PTBP1 are required for KMT2A-r AML proliferation. PTBP1 loss led to cell cycle arrest, apoptosis, and induction of myeloid differentiation programs. Transcriptomic analyses revealed widespread dysregulation of gene expression and splicing. eCLIP-seq further showed PTBP1 binds to a subset of these transcripts critical for AML proliferation, including ACSL4, DPF2, and IKZF1. Our findings demonstrate that PTBP1 supports AML proliferation by fine-tuning the expression and splicing of AML-essential genes and provide a workflow for systematically annotating RNAe and RBP dependencies in cancer.2026/08/10GSE306460GSM9201763GSM9201765GSM920176418573306460Homo sapiens