Journal article

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

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, Ricky W Johnstone

CANCER DISCOVERY | AMER ASSOC CANCER RESEARCH | Published : 2021

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,..

View full abstract

Grants

Awarded by Victorian Cancer Agency Early Career Seed Grant


Awarded by Rubicon Fellowship from the Netherlands Organization for Scientific Research (NWO)


Awarded by NHMRC EL1 Fellowship


Awarded by NHMRC


Awarded by VCA Mid-Career Research Fellowship


Awarded by Susan G. Komen Career Catalyst Research Grant


Funding Acknowledgements

S. Bjelosevic was supported by an Australian Government Research Training Program Scholarship, the Peter MacCallum Cancer Foundation, and the Picchi Brothers Foundation; E. Gruber, C. Shembrey, I. Todorovski, and Z. Fan by an Australian Government Research Training Program Scholarship; J.R. Devlin by a Victorian Cancer Agency Early Career Seed Grant (ECSG17018); S.J. Hogg by a National Health and Medical Research Council of Australia (NHMRC) Investigator Grant; L. Kats by a Victorian Cancer Agency (VCA) Mid-Career Research Fellowship and grants from the Cancer Council of Victoria (CCV) and National Health and Medical Research Council (NHMRC); S.J. Vervoort was supported by a Rubicon Fellowship from the Netherlands Organization for Scientific Research (NWO; 019.161LW.017), an NHMRC EL1 Fellowship (GNT1178339), and a Peter MacCallum Cancer Foundation Grant; K.K. Brown by an NHMRC Project Grant (GNT1146642), a VCA Mid-Career Research Fellowship (MCRF17020), and a Susan G. Komen Career Catalyst Research Grant (CCR18548354); R.W. Johnstone by a Project Grant from CCV, a Project Grant and Program Grant (grant 454569) from the NHMRC, an NHMRC Senior Principal Research Fellowship, and a grant from The Kids' Cancer Project (to R.W. Johnstone and S.J. Vervoort). We acknowledge support from the Peter MacCallum Cancer Centre Foundation and the Australian Cancer Research Foundation. This research used National Collaborative Research Infrastructure Strategy (NCRIS)-enabled Metabolomics Australia infrastructure at the University of Melbourne, funded through BioPlatforms Australia. We also extend our thanks to the Peter MacCallum Cancer Centre Core Facilities and their staff who provided support for this work, namely, the Flow Cytometry, Molecular Genomics, and Animal Core Facilities. We especially thank Eva Vidacs, Lauren Matthews, Lena Ly, Mark Sheehan, Michael Durrant, and Stephanie Le for their invaluable technical expertise for in vivo experiments.