Mutant ribosomal protein RPS15 drives B cell malignancy through oxidative stress and genomic instability

Area of Science:

• Molecular Biology
• Cancer Research
• Genetics

Background:

• Ribosomal protein mutations are linked to cancer risk and p53 activation.
• Understanding how these mutations drive tumorigenesis is crucial.

Purpose of the Study:

• To investigate the role of the RPS15-S138F mutation in chronic lymphocytic leukemia development.
• To elucidate the mechanisms by which ribosomal mutations overcome p53-mediated tumor suppression.

Main Methods:

• Generation of an in vivo mouse model for the RPS15-S138F mutation.
• Analysis of pre-leukemic and leukemic stages, including ribosome biogenesis, translation, oxidative stress, DNA damage, and cell proliferation.
• Assessment of p53 and Myc activity, and TP53 deletion acquisition.

Main Results:

• The RPS15-S138F mutation caused ribosome defects, oxidative stress, and DNA damage, initially inducing p53-dependent hypo-proliferation.
• A subset of aged mice developed B-cell leukemia with increased Myc activity (37% penetrance).
• Mutant RPS15 promoted both hypo- and hyper-proliferative signals, ultimately leading to genomic instability and acquisition of TP53 deletion.

Conclusions:

• Mutant RPS15 initially triggers cell cycle arrest but promotes tumorigenesis through translational rewiring, DNA damage response defects, and genomic instability.
• The RPS15-S138F mutation facilitates the acquisition of secondary mutations, like TP53 deletion, enabling leukemia development.
• This study provides insights into the complex interplay between ribosomal protein mutations, p53, and cancer progression.