Serine biosynthesis is a metabolic vulnerability in FLT3-ITD-driven acute myeloid leukaemia.

Abstract:

:Internal tandem duplication of the FMS-like tyrosine kinase 3 gene (FLT3-ITD) occurs in 30% of poor prognosis acute myeloid leukaemias (AMLs). 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 pharmacological 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, pharmacological inhibition of PHGDH sensitised 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.

journal_name

Cancer Discov

journal_title

Cancer discovery

authors

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

doi

10.1158/2159-8290.CD-20-0738

subject

Has Abstract

pub_date

2021-01-12 00:00:00

eissn

2159-8274

issn

2159-8290

pii

2159-8290.CD-20-0738

pub_type

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