GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE328nnn/GSE328416/primaryOK200GenomicsHomo sapiensGenome binding/occupancy profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE328416GEOGSEfalseCBFA2T3-GLIS2 fusion-mediated mSWI/SNF chromatin remodeler disruption generates cancer-specific dependencies in AMKL [Cut & Run]Transcription factor (TF) fusion oncoproteins are frequently associated with poor prognosis and remain challenging therapeutic targets. Here we show that the CBFA2T3-GLIS2 (C/G) fusion oncoprotein present in lethal pediatric acute megakaryocytic leukemias (AMKLs) co-opts mSWI/SNF chromatin remodeling complexes, reprogramming regulatory element architecture to sustain aberrant cell cycle progression. The C/G fusion binds to and redistributes mSWI/SNF complexes via the SMARCD1 SWIFT domain and targets complexes to oncogenic enhancers including those bound by ETS family TFs and the G1 cyclin CCND2, a C/G AML-specific dependency. Pharmacologic inhibition of mSWI/SNF-mediated G1 cell cycle phasing via FHD-286 suppresses C/G-driven gene expression programs, induces G1 arrest and apoptosis in cells, and reduces leukemic burden and extends survival in aggressive C/G AML in vivo. These findings define an oncogenic mSWI/SNF–G1 axis in C/G AML and establish a therapeutic framework for targeting chromatin dysfunction-mediated cell cycle aberrancy in high-risk pediatric leukemias.2026/04/22GSE328416GSM9682479GSM9682468GSM9682469GSM9682477GSM9682478GSM9682486GSM9682475GSM9682476GSM9682473GSM9682484GSM9682485GSM9682474GSM9682482GSM9682471GSM9682483GSM9682472GSM9682480GSM9682470GSM96824812467634281328416Homo sapiens