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 Discovjournal_title
Cancer discoveryauthors
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 RWdoi
10.1158/2159-8290.CD-20-0738subject
Has Abstractpub_date
2021-01-12 00:00:00eissn
2159-8274issn
2159-8290pii
2159-8290.CD-20-0738pub_type
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