Targeting 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.