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Cancer Discovery
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Research Article

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

Stefan Bjelosevic, Emily Gruber, Andrea Newbold, Carolyn Shembrey, Jennifer R. Devlin, Simon J Hogg, Lev Kats, Izabela Todorovski, Zheng Fan, Thomas C. Abrehart, Giovanna Pomilio, Andrew Wei, Gareth P. Gregory, Stephin J Vervoort, Kristin K Brown and Ricky W. Johnstone
Stefan Bjelosevic
1Research Division, Peter MacCallum Cancer Centre
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Emily Gruber
2Cancer Immunology Program, Peter MacCallum Cancer Research Centre
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Andrea Newbold
3Gene Regulation Laboratory, Cancer Therapeutics Program, Peter MacCallum Cancer Centre
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Carolyn Shembrey
4Clinical Pathology, University of Melbourne
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Jennifer R. Devlin
5Division of Research, Peter MacCallum Cancer Centre
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Simon J Hogg
3Gene Regulation Laboratory, Cancer Therapeutics Program, Peter MacCallum Cancer Centre
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Lev Kats
6Translational Haematology Program, Peter MacCallum Cancer Centre
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Izabela Todorovski
2Cancer Immunology Program, Peter MacCallum Cancer Research Centre
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Zheng Fan
7Gene Regulation Laboratory, Peter MacCallum Cancer Centre
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Thomas C. Abrehart
7Gene Regulation Laboratory, Peter MacCallum Cancer Centre
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Giovanna Pomilio
8And the Australian Centre for blood diseases, Monash University, The Alfred Hospital
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Andrew Wei
9Clinical Hematology, The Alfred Hospital
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Gareth P. Gregory
3Gene Regulation Laboratory, Cancer Therapeutics Program, Peter MacCallum Cancer Centre
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Stephin J Vervoort
3Gene Regulation Laboratory, Cancer Therapeutics Program, Peter MacCallum Cancer Centre
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Kristin K Brown
10Cancer Research, Peter MacCallum Cancer Centre
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Ricky W. Johnstone
7Gene Regulation Laboratory, Peter MacCallum Cancer Centre
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  • For correspondence: ricky.johnstone@petermac.org
DOI: 10.1158/2159-8290.CD-20-0738
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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.

  • Received May 23, 2020.
  • Revision received November 29, 2020.
  • Accepted January 6, 2021.
  • Copyright ©2021, American Association for Cancer Research.

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This OnlineFirst version was published on January 12, 2021
doi: 10.1158/2159-8290.CD-20-0738

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Serine biosynthesis is a metabolic vulnerability in FLT3-ITD-driven acute myeloid leukaemia
Stefan Bjelosevic, Emily Gruber, Andrea Newbold, Carolyn Shembrey, Jennifer R. Devlin, Simon J Hogg, Lev Kats, Izabela Todorovski, Zheng Fan, Thomas C. Abrehart, Giovanna Pomilio, Andrew Wei, Gareth P. Gregory, Stephin J Vervoort, Kristin K Brown and Ricky W. Johnstone
Cancer Discov January 12 2021 DOI: 10.1158/2159-8290.CD-20-0738

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Serine biosynthesis is a metabolic vulnerability in FLT3-ITD-driven acute myeloid leukaemia
Stefan Bjelosevic, Emily Gruber, Andrea Newbold, Carolyn Shembrey, Jennifer R. Devlin, Simon J Hogg, Lev Kats, Izabela Todorovski, Zheng Fan, Thomas C. Abrehart, Giovanna Pomilio, Andrew Wei, Gareth P. Gregory, Stephin J Vervoort, Kristin K Brown and Ricky W. Johnstone
Cancer Discov January 12 2021 DOI: 10.1158/2159-8290.CD-20-0738
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