Abstract P28: Immunoproteasome inhibitors for the treatment of ALL

Abstract The t(4;11)(q21;q23) chromosomal translocation that creates the MLL-AF4 fusion protein, confers a poor prognosis in infant acute lymphoblastic leukemia (ALL). This translocation also sensitizes cells to proteasome inhibitors bortezomib and carfilzomib, which are approved by the FDA for the treatment of multiple myeloma. Clinical activity of bortezomib in combination with standard chemotherapy has been documented in several clinical trials of ALL patients, and a case of a single-agent activity against relapsed leukemia driven by the MLL-AF4 translocation has been described. However, toxicities of bortezomib and carfilzomib linmit their use to treat to pediatric patients. We found that the overwhelming majority of proteasomes in this subtype of ALL are lymphoid tissue specific immunoproteasomes. Cells with MLL-AF4 translocations were sensitive to pharmacologically relevant concentrations of specific immunoproteasome inhibitors ONX-0914 and M3258. Furthermore, both compounds dramatically delayed growth of orthotopic xenograft tumors in mice, and improved responce to induction chemotherapy. Thus, immunoproteasomes are therapeutic targets in ALL and replacing bortezomib and carfilzomib with immunoproteasome inhibitors in ALL should reduce toxicities associated with inhibition of the proteasomes in non-lymphoid tissues. Citation Format: Alexei F Kisselev. Immunoproteasome inhibitors for the treatment of ALL [abstract]. In: Proceedings of the Blood Cancer Discovery Symposium; 2024 Mar 4-6; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(2_Suppl):Abstract nr P28.