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. 2021 Jun;11(6):1582-1599.
doi: 10.1158/2159-8290.CD-20-0738. Epub 2021 Jan 12.

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

Stefan Bjelosevic  1   2 , Emily Gruber  1   2 , Andrea Newbold  1 , Carolyn Shembrey  3   4 , Jennifer R Devlin  1   2 , Simon J Hogg  5 , Lev Kats  1   2 , Izabela Todorovski  1   2 , Zheng Fan  1   2 , Thomas C Abrehart  1 , Giovanna Pomilio  6   7 , Andrew Wei  6   7   8 , Gareth P Gregory  1   9 , Stephin J Vervoort  1   2 , Kristin K Brown #  10   2   11 , Ricky W Johnstone #  10   2
Affiliations

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

Stefan Bjelosevic et al. Cancer Discov. 2021 Jun.

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.

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