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

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.

Cancer Biogenesis in Ribosomopathies

“…In particular, combined transcriptome and translatome analysis revealed that one of the key enzymes in serine synthesis—phosphoserine phosphatase (PSPH)—is more efficiently transcribed and translated in RPL10-R98S (uL16-R98S) mutant cells. The resulting elevated serine is converted to glycine, a reaction in which one carbon is released and converted into formate, which in turn sustains nucleotide synthesis [85]. Similarly, fibroblasts of DBA patients present elevated levels of serine/glycine synthesis enzymes phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and the mitochondrial serine hydroxymethyltransferase 2 (SHMT2) [86].…”

Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer

“…Consequently, FIR families, PUF60, FIR, and FIRΔexon2, potentially link among epigenetic modification, transcription, post-transcription, and alternative splicing in gene regulation. Recently, the ribosomal RPL10 R98S mutation was associated with T-cell type acute lymphocytic leukemia (T-ALL) pathogenesis [24][25][26] . Notably, FIR +/− TP53 −/− generated T-ALL 27 , indicating that FIRΔexon2 modifies ribosomal protein synthesis in cancers.…”

1H-NMR Based Serum Metabolomics Highlights Different Specific Biomarkers between Early and Advanced Hepatocellular Carcinoma Stages

“…Glycine plays a key role in regulating the methylation status of cancer cells and for DNA and RNA synthesis [36]. Recently, it has been reported that a high level of blood serine/glycine might form a protective niche for the maintenance of leukemia cells in xenografted mice [37], and that a downregulation of the glycine decarboxylase, an enzyme involved in glycine catabolism, enhances HCC progression and intrahepatic metastasis [38]. Based on this knowledge, the increased serum glycine level observed in ADV vs EAR HCC patients could be seen as a result of a reduced glycine catabolism in the advanced HCC stage.…”