GABARAP Loss Mediates Immune Escape in High Risk Multiple Myeloma

Proteasome inhibitor bortezomib (BTZ) has been shown to result in immunogenic cell death (ICD) and a viral mimicry state in MM cells, and ICD is thought to be associated with long-term response after BTZ treatment.

Annamaria Gulla, MD and colleagues hypothesized that genomic or transcriptomic alterations associated with shorter survival of patients with MM after BTZ treatment may impair activation of the ICD pathway. To test this, they performed a transcriptomic analysis of purified CD138+ cells from 360 newly diagnosed patients with MM and found that low levels of GABA Type A Receptor-Associated Protein (GABARAP) were associated with inferior clinical outcomes.

This finding was significant even when excluding patients with del17p, indicating that GABARAP is an independent predictor of clinical outcomes. Furthermore, treatment of GABARAPKO clones with BTZ failed to activate an efficient T cell response.