Dysregulated APOBEC3G causes DNA damage and promotes genomic instability in multiple myeloma

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Multiple myeloma (MM) is a cancer of plasma cells, characterized by genomic instability.
• Somatic mutations induced by AID/APOBEC deaminases are implicated in MM development.
• APOBEC/AID represents a significant mutational signature in MM at diagnosis and relapse.

Purpose of the Study:

• To investigate the role of APOBEC3G in multiple myeloma.
• To determine if APOBEC3G contributes to genomic instability and evolution in MM.

Main Methods:

• Analysis of APOBEC3 family gene expression in MM cell lines and patient samples.
• Loss-of- and gain-of-function studies to assess APOBEC3G's impact on DNA damage.
• Whole genome sequencing and SNP arrays to evaluate effects on genome stability.
• Assessment of homologous recombination activity.

Main Results:

• APOBEC3G (A3G) is highly expressed in MM cells and exhibits elevated deaminase activity.
• APOBEC3G significantly increases DNA damage, including abasic sites and DNA breaks.
• Elevated APOBEC3G promotes copy number alterations and mutations, contributing to genomic evolution.
• APOBEC3G enhances homologous recombination activity, facilitating genomic rearrangements.

Conclusions:

• APOBEC3G is a key driver of genomic instability and evolution in multiple myeloma.
• Targeting APOBEC3G may offer a novel therapeutic strategy for MM.
• Understanding APOBEC3G's role sheds light on MM pathogenesis and genomic alterations.