The T-cell leukemia-associated ribosomal RPL10 R98S mutation enhances JAK-STAT signaling

Area of Science:

• Molecular Biology
• Oncology
• Genetics

Background:

• Somatic ribosome defects are implicated in cancer, but their oncogenic roles are unclear.
• The JAK-STAT signaling pathway is crucial for cell growth and survival and is often dysregulated in cancers.

Purpose of the Study:

• To investigate the pathogenic role of the RPL10 R98S mutation in T-cell acute lymphoblastic leukemia (T-ALL).
• To elucidate the molecular mechanisms by which RPL10 R98S contributes to leukemogenesis.

Main Methods:

• Proteome screening of engineered RPL10 R98S mouse lymphoid cells.
• Confirmation in hematopoietic cells from transgenic mice and T-ALL xenografts.
• Analysis of JAK-STAT pathway activation, mutation patterns in T-ALL patients, ribosomal frameshifting, protein degradation, and proteasome activity.

Main Results:

• RPL10 R98S expression led to JAK-STAT pathway hyper-activation and increased sensitivity to JAK-STAT inhibitors.
• A mutually exclusive mutation pattern suggests RPL10 R98S mimics JAK-STAT activation in T-ALL.
• RPL10 R98S reduced ribosomal frameshifting in JAK-STAT genes, decreased Jak1 degradation, and impaired proteasome activity.

Conclusions:

• RPL10 R98S promotes cancer by modulating the JAK-STAT cascade, a novel mechanism for ribosomal mutations.
• The findings highlight the JAK-STAT pathway's expanded relevance in leukemia and suggest therapeutic potential for proteasome inhibitors.