GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE264nnn/GSE264576/primaryOK200GenomicsHomo sapiensGenome binding/occupancy profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE264576GEOGSEfalseTargeting LMO2-induced autocrine FLT3 signalling to overcome chemoresistance in early T-cell precursor acute lymphoblastic leukemia [ChIP-seq]Early T-cell Precursor Acute Lymphoblastic Leukemia (ETP-ALL) is an immature subtype of T-cell acute lymphoblastic leukemia (T-ALL) characterised by aberrant expression of the LMO2-LYL1 stem cell transcription factor complex, activating mutations of cytokine receptor signalling and poor early response to intensive chemotherapy. Previously, studies of the Lmo2 transgenic mouse model of ETP-ALL identified a population of stem-like T-cell progenitors with long-term self-renewal capacity and intrinsic chemotherapy resistance linked to cellular quiescence. Here, analyses of Lmo2 transgenic mice, patient-derived xenografts and single cell RNA-seq data from primary ETP-ALL identified a rare subpopulation of leukemic stem cells co-expressing the cytokine receptors c-KIT and FLT3 (KF cells). Despite a highly proliferative state, these KF cells had long-term self-renewal capacity and almost complete resistance to chemotherapy. Chromatin immunoprecipitation and assay for transposase-accessible chromatin sequencing demonstrated FLT3 and its ligand may be direct targets of the LMO2 stem-cell complex. Media conditioned by Lmo2 transgenic thymocytes revealed an autocrine FLT3-dependent signalling loop that could be targeted by the FLT3 inhibitor Gilteritinib. Consequently, Gilteritinib impaired in vivo growth of ETP-ALL and improved the response to chemotherapy. Furthermore, Gilteritinib synergized with the BCL2 inhibitor Venetoclax, which may enable ‘chemo-free’ treatment of ETP-ALL. Together, these data provide a cellular and molecular explanation for enhanced cytokine signalling in LMO2-driven T-ALL beyond activating mutations and a rationale for clinical trials of FLT3 inhibitors in ETP-ALL.2026/04/30GSE264576GSM8222957GSM8222958GSM8222959GSM8222960GSM8222961GSM8222962GSM8222963GSM8222964GSM8222953GSM8222954GSM8222955GSM822295624676264576Homo sapiens