Serine Biosynthesis Is a Metabolic Vulnerability in FLT3-ITD-Driven Acute Myeloid Leukemia

Bjelosevic, S; Gruber, E; Newbold, A; Shembrey, C; Devlin, JR; Hogg, SJ; Kats, L; Todorovski, I; Fan, Z; Abrehart, TC; Pomilio, G; Wei, A; Gregory, GP; Vervoort, SJ; Brown, KK; Johnstone, RW

Author(s): Bjelosevic, S; Gruber, E; Newbold, A; Shembrey, C; Devlin, JR; Hogg, SJ; Kats, L; Todorovski, I; Fan, Z; Abrehart, TC; Pomilio, G; Wei, A; Gregory, GP; Vervoort, SJ; Brown, KK; Johnstone, RW;
Details: Publication Year 2021-06,Volume 11,Issue #6,Page 1582-1599
Journal Title: Cancer Discovery
Publication Type: Research article
Abstract: Internal tandem duplication of the FMS-like tyrosine kinase 3 gene (FLT3-ITD) occurs in 30% of all acute myeloid leukemias (AML). Limited clinical efficacy of FLT3 inhibitors highlights the need for alternative therapeutic modalities in this subset of disease. Using human and murine models of FLT3-ITD-driven AML, we demonstrate that FLT3-ITD promotes serine synthesis and uptake via ATF4-dependent transcriptional regulation of genes in the de novo serine biosynthesis pathway and neutral amino acid transport. Genetic or pharmacologic inhibition of PHGDH, the rate-limiting enzyme of de novo serine biosynthesis, selectively inhibited proliferation of FLT3-ITD AMLs in vitro and in vivo. Moreover, pharmacologic inhibition of PHGDH sensitized FLT3-ITD AMLs to the standard-of-care chemotherapeutic cytarabine. Collectively, these data reveal novel insights into FLT3-ITD-induced metabolic reprogramming and reveal a targetable vulnerability in FLT3-ITD AML. SIGNIFICANCE: FLT3-ITD mutations are common in AML and are associated with poor prognosis. We show that FLT3-ITD stimulates serine biosynthesis, thereby rendering FLT3-ITD-driven leukemias dependent upon serine for proliferation and survival. This metabolic dependency can be exploited pharmacologically to sensitize FLT3-ITD-driven AMLs to chemotherapy.This article is highlighted in the In This Issue feature, p. 1307.
Keywords: Animals; Cell Line, Tumor/metabolism; Disease Models, Animal; Humans; Leukemia, Myeloid, Acute/*metabolism; Mice; Protein Kinase Inhibitors; Serine/*metabolism; fms-Like Tyrosine Kinase 3/*metabolism
Department(s): Laboratory Research
PubMed ID: 33436370
Publisher's Version: https://doi.org/10.1158/2159-8290.CD-20-0738
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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