Translatome analysis reveals altered serine and glycine metabolism in T-cell acute lymphoblastic leukemia cells

Kim R. Kampen, Laura Fancello, Tiziana Girardi, Gianmarco Rinaldi, Mélanie Planque, Sergey O. Sulima, Fabricio Loayza-Puch, Benno Verbelen, Stijn Vereecke, Jelle Verbeeck, Joyce Op de Beeck, Jonathan Royaert, Pieter Vermeersch, David Cassiman, Jan Cools, Reuven Agami, Mark Fiers, Sarah-Maria Fendt and Kim De Keersmaecker ()
Additional contact information
Kim R. Kampen: KU Leuven and Leuven Cancer Institute (LKI)
Laura Fancello: KU Leuven and Leuven Cancer Institute (LKI)
Tiziana Girardi: KU Leuven and Leuven Cancer Institute (LKI)
Gianmarco Rinaldi: VIB-KU Leuven Center for Cancer Biology
Mélanie Planque: VIB-KU Leuven Center for Cancer Biology
Sergey O. Sulima: KU Leuven and Leuven Cancer Institute (LKI)
Fabricio Loayza-Puch: German Cancer Research Center (DKFZ)
Benno Verbelen: KU Leuven and Leuven Cancer Institute (LKI)
Stijn Vereecke: KU Leuven and Leuven Cancer Institute (LKI)
Jelle Verbeeck: KU Leuven and Leuven Cancer Institute (LKI)
Joyce Op de Beeck: KU Leuven and Leuven Cancer Institute (LKI)
Jonathan Royaert: KU Leuven and Leuven Cancer Institute (LKI)
Pieter Vermeersch: University Hospitals Leuven
David Cassiman: University Hospitals Leuven
Jan Cools: VIB-KU Leuven Center for Cancer Biology
Reuven Agami: Erasmus Medical Center
Mark Fiers: VIB-KU Leuven Center for Brain & Disease Research
Sarah-Maria Fendt: VIB-KU Leuven Center for Cancer Biology
Kim De Keersmaecker: KU Leuven and Leuven Cancer Institute (LKI)

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract Somatic ribosomal protein mutations have recently been described in cancer, yet their impact on cellular transcription and translation remains poorly understood. Here, we integrate mRNA sequencing, ribosome footprinting, polysomal RNA sequencing and mass spectrometry datasets from a mouse lymphoid cell model to characterize the T-cell acute lymphoblastic leukemia (T-ALL) associated ribosomal RPL10 R98S mutation. Surprisingly, RPL10 R98S induces changes in protein levels primarily through transcriptional rather than translation efficiency changes. Phosphoserine phosphatase (PSPH), encoding a key serine biosynthesis enzyme, was the only gene with elevated transcription and translation leading to protein overexpression. PSPH upregulation is a general phenomenon in T-ALL patient samples, associated with elevated serine and glycine levels in xenograft mice. Reduction of PSPH expression suppresses proliferation of T-ALL cell lines and their capacity to expand in mice. We identify ribosomal mutation driven induction of serine biosynthesis and provide evidence supporting dependence of T-ALL cells on PSPH.

Date: 2019
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DOI: 10.1038/s41467-019-10508-2

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