Reprogramming of serine metabolism is an actionable vulnerability inFLT3-ITDdriven acute myeloid leukaemia

Abstract

Activating FMS-like tyrosine kinase 3 (FLT3) mutations occur in approximately 30% of all acute myeloid leukaemias (AMLs) and are associated with poor prognosis. The limited clinical efficacy of FLT3 inhibitor monotherapy has highlighted the need for alternative therapeutic targets and treatments for FLT3-mutant AML. Using human and murine models of MLL-rearranged AML harbouring FLT3 internal tandem duplication (FLT3-ITD) and primary patient samples, we have demonstrated 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 in FLT3-mutant AML is dependent on the mTORC1-ATF4 axis, that drives RNA-Pol II occupancy at PHGDH, PSAT1, SLC1A4 and SLC1A5. Genetic or pharmacological inhibition of the de novo serine synthesis pathway selectively inhibited the proliferation of FLT3-ITD AML cells, and this was potentiated by withdrawal of exogenous serine. Purine supplementation effectively rescued the antiproliferative effect of inhibiting de novo serine synthesis, consistent with the idea that serine fuels purine nucleotide synthesis in FLT3-mutant AML. Pharmacological inhibition of the de novo serine synthesis pathway, using the PHGDH inhibitor WQ-2101, sensitises FLT3-mutant AML cells to the standard of care chemotherapy agent cytarabine via exacerbation of DNA damage. Collectively, these data reveal new insights as to how FLT3 mutations reprogram metabolism in AML, and reveal a combination therapy strategy to improve the treatment of FLT3-mutant AML.Statement of SignificanceFLT3 mutations are common in AML and are associated with poor prognosis. We show that FLT3-ITD stimulates serine metabolism, thereby rendering FLT3-ITD leukemias dependent on serine for proliferation and survival. This metabolic dependency can be exploited pharmacologically to sensitize FLT3-mutant AML to chemotherapy.

Targeting Amino Acid Metabolic Vulnerabilities in Myeloid Malignancies

“…Blocking PHGDH activity in leukemic cells grown in fructose and glucose containing conditions markedly reduced their cell growth ( 75 ). AML bearing internal tandem duplications of FLT3 also have elevated expression of PHGDH ( 77 ). The transamination of 3-PP by PSAT is anaplerotic to the TCA and requires glutamine as the amino acid donor.…”

The SCP4-STK35/PDIK1L complex is a dual phospho-catalytic signaling dependency in acute myeloid leukemia

“…One of the most deficient amino acids was proline, which could be related to the decrease in PYCR1 expression, encoding the ratelimiting enzyme for proline biosynthesis (Xiao et al, 2020) (Figure S7A). Since amino acid biosynthesis and transport are known to be deregulated to support the rapid growth of AML cells (Bertuccio et al, 2017;Willems et al, 2013;Bjelosevic et al, 2021;Kreitz et al, 2019), these results lead us to propose that SCP4-STK35/PDIK1L signaling supports the aberrant metabolic state of this malignancy (Figure 7E).…”

The Role of Metabolism in the Development of Personalized Therapies in Acute Myeloid Leukemia

“…The group of patients that could most likely benefit from metabolic modulations are patients resistant to available therapies. As already mentioned, resistance to both cytarabine ( 47 )⁠ and venetoclax ( 44 , 45 )⁠ are mediated by increased OxPhos and metabolic switch to FAO, while resistance to FLT3 inhibitors is mediated through alterations in metabolism of glutamine ( 27 )⁠ and serine ( 26 ), as well as glycolysis ( 69 ). During intensive chemotherapy, AML cells appear to pass through a form of metabolic bottleneck producing resistant cells with a distinctive metabolic signature consisting of a switch in glutamine utilization primarily for nucleotide synthesis and gluthatione production and a modification of pyrimidine synthesis pathway to a higher dependency from extracellular aspartate provided by the bone marrow stroma ( 81 ).…”

“…The inhibition of this enzyme and the use of compounds that increase mitochondrial ROS, like phenformin, greatly increased the sensitivity to FLT3-inhibition ( 70 ). In addition, it was recently described that patients with FLT3-ITD mutation present with dysregulated serine metabolism and inhibition of de novo serine synthesis, most likely through decrease in purine synthesis for which serine is a physiological precursor, decreases proliferation of FLT3-ITD mutated AML cells and increases their sensitivity to cytarabine ( 26 ).…”

“…Rewired metabolism has emerged as a new hallmark of cancer ( 24 ) and recently there has been increasing evidence supporting its role in AML initiation and maintenance ( 25 ). Perhaps more importantly, unique metabolic rewirings have been shown to develop in specific AML subtypes ( 26 ), in response to therapy ( 27 ) or in specific AML cell populations including LSC ( 28 ). Metabolic reactions are carried out by specific enzymes which are targetable with small molecules and many metabolic inhibitors are already in clinical use or clinical development ( 29 ).…”