Sensitizing hematopoietic malignancies to genotoxic treatment by targeting APOBEC3G

Highlights

• We have discovered that the human cellular cytidine deaminase APOBEC3G is required for repair of genomic DNA double strand breaks (DSBs) in lymphoid malignancies.
• We have discovered that a peptide derived from the HIV-1 Vif protein directly inhibits APOBEC3G catalytic activity.
• Inhibition of APOBEC3G catalytic activity with the Vif-derived peptide attenuated DSB repair in lymphoma cells following exposure to ionizing radiation (IR).

Our Innovation

 Sensitizing hematopoietic malignancies to genotoxic treatment by targeting APOBEC3G

Key Features

• APOBEC3G is expressed only in activated hematopoietic cells, representing a minor subset of the hematopoietic cell population.
• The level of APOBEC3G expression in lymphoid and myeloid malignant cell lines correlated with the cellular DSB repair efficiency and overall cell survival following genotoxic IR.
• In response to IR, APOBEC3G was recruited from the cytoplasm to nuclear DSB repair foci.
• ShRNA-mediated depletion of APOBEC3G in lymphoma cells resulted in attenuated DSB repair and cells death following treatment with a sub-lethal dose of IR.
• A 15-mer Vif-derived peptide that inhibits A3G activity when bound to single-stranded DNA (ssDNA) attenuated DSB repair in lymphoma cells following IR in µM concentrations.
• APOBEC3G multimers associate with ssDNA ends in vitro and promote ssDNA end joining.

Development Milestones

Increasing efficiency and stability of the Vif-derived inhibitor in lymphoid cell lines; Establishing feasibility and activity in malignant human lymphoid and myeloid explants; Establishing safety and activity in terminal lymphoma and myeloma patients.

The Opportunity

Targeted cancer therapy by neutralizing an antiviral enzyme with no known essential functions involving normal cell physiology, which is uniquely expressed in activated and malignant hematopoietic cells and required for DSB repair.