Targeting LMO2-induced autocrine FLT3 signalling to overcome chemoresistance in early T-cell precursor acute lymphoblastic leukemia

Abstract Early T-cell Precursor Acute Lymphoblastic Leukemia (ETP-ALL) is characterised by aberrant expression of the LMO2-LYL1 stem-cell transcription factor complex, activating mutations of cytokine receptor signalling and poor 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 chemoresistance linked to cellular quiescence. Here, analyses of Lmo2 transgenic mice, patient-derived xenografts and single-cell RNA-sequencing data from primary ETP-ALL identified a rare subpopulation of leukemic stem cells expressing high levels of the cytokine receptor FLT3. Despite a highly proliferative state, these FLT3-overexpressing cells had long-term self-renewal capacity and almost complete resistance to chemotherapy. We found that FLT3 and its ligand may be direct targets of the LMO2 stem-cell complex, thereby establishing an autocrine FLT3 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 ETP-ALL beyond activating mutations and a rationale for clinical trials of FLT3 inhibitors in ETP-ALL.