Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene occur in approximately 30% of all acute myeloid leukaemias (AMLs) and are associated with poor prognosis. The clinical utility of FLT3 inhibitor monotherapy has been limited by the rapid development of resistance, highlighting the need for identification of alternative therapeutic targets for the treatment of FLT3-mutant AML. Using a syngeneic murine model of AML harbouring FLT3 internal tandem duplication (FLT3-ITD), we demonstrate that FLT3-ITD promotes serine uptake and serine synthesis via transcriptional regulation of neutral amino acid transporters (SLC1A4 and SLC1A5) and genes in the de novo serine synthesis pathway (PHGDH and PSAT1). Mechanistically, dysregulation of serine metabolism was dependent on the mTORC1-ATF4 axis, which promoted RNA-Pol II occupancy at PHGDH, PSAT1, SLC1A4 and SLC1A5 in AML cells harbouring FLT3-ITD mutations. Genetic or pharmacological inhibition of the de novo serine synthesis pathway selectively inhibited the proliferation and viability of FLT3-ITD AML cells, and purine supplementation effectively rescued the apoptotic effects of inhibiting FLT3-ITD, consistent with the hypothesis that serine fuels purine nucleotide synthesis in FLT3-ITD AML cells. To exploit these findings in the context of standard-of-care therapy in AML, we show that pharmacological inhibition of the de novo serine synthesis pathway, using the PHGDH inhibitor WQ-2101, sensitises FLT3-ITD AML cells to the chemotherapy agent cytarabine by greatly exacerbating the DNA damage response in AML cell lines harbouring FLT3-ITD mutations, primary AML patient samples, and an aggressive PDX mouse model of FLT3-ITD-driven AML. Collectively, these data reveal new insights into FLT3-ITD-induced metabolic reprogramming in AML, and suggest a novel combinatorial therapeutic strategy for the treatment of FLT3-mutant AML.
