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

Area of Science:

• Molecular Biology
• Cancer Research
• Genetics

Background:

• Somatic mutations in ribosomal proteins are emerging in cancer.
• Their precise impact on cellular transcription and translation is not well understood.
• T-cell acute lymphoblastic leukemia (T-ALL) is a significant hematological malignancy.

Purpose of the Study:

• To investigate the functional consequences of the RPL10 R98S mutation in T-ALL.
• To elucidate the mechanisms by which ribosomal mutations affect protein and gene expression.
• To identify potential therapeutic vulnerabilities in T-ALL related to ribosomal mutations.

Main Methods:

• Integration of multi-omics datasets: mRNA sequencing, ribosome footprinting, polysomal RNA sequencing, and mass spectrometry.
• Utilized a mouse lymphoid cell model for T-ALL.
• Analysis of T-ALL patient samples and xenograft mouse models.

Main Results:

• The RPL10 R98S mutation primarily impacts protein levels through transcriptional changes, not translational efficiency.
• Phosphoserine phosphatase (PSPH) was identified as a key upregulated gene, leading to protein overexpression.
• PSPH upregulation is prevalent in T-ALL patient samples and linked to elevated serine/glycine levels.
• Reduced PSPH expression inhibited T-ALL cell proliferation and in vivo expansion.

Conclusions:

• Ribosomal mutations can drive metabolic alterations, specifically serine biosynthesis, in T-ALL.
• T-ALL cells exhibit a dependence on phosphoserine phosphatase (PSPH) for proliferation and survival.
• Targeting serine biosynthesis represents a potential therapeutic strategy for T-ALL.