Ratios of immunoproteasome over constitutive proteasome expression are an indicator for sensitivity to bortezomib-containing reinduction chemotherapy in pediatric relapsed acute lymphocytic leukemia and acute myeloid leukemia

Ratios of immunoproteasome over constitutive proteasome expression are an indicator for sensitivity to bortezomib-containing reinduction chemotherapy in pediatric relapsed acute lymphocytic leukemia and acute myeloid leukemia Manuscript in preparation 8 152 ABSTRACT Bortezomib, a proteasome inhibitor, is in Phase 3 clinical trials for the treatment of pediatric acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). For optimal personalized treatment, identification of bortezomib-responders is of clinical interest. Here, we investigated whether ratios of immunoproteasome to constitutive proteasome protein correlate with clinical outcome in first relapsed and refractory pediatric acute leukemia. Patients were enrolled in two Children's Oncology Group (COG) phase 2 clinical trials of bortezomib with reinduction chemotherapy for pediatric acute ALL (COG-AALL07P1) and pediatric AML (COG-AAML07P1). Protein expression of proteasome subunits was examined in 58 acute leukemia patient samples (ALL n=46, AML n=12) obtained before bortezomib-containing reinduction therapy. AML myeloblasts showed significantly 3-fold higher constitutive β5 and β1 subunit expression in AML cells than ALL lymphoblasts (P=0.004 and P=0.026). Ratios of both β5i/β5 and β1i/β1 subunit expression were significantly 2.5-fold higher in ALL cells than in AML cells (P=0.013 and P=0.003). Upon stratification of patients by attainment of complete remission (CR) following induction, ratios of both β5i/β5 and β1i/β1 were significantly 2-fold higher in patients that attained a CR (N=37) compared to patients that did not (N=21; P=0.019 for β5i/β5, P=0.022 for β1i/β1). In addition to protein expression ratios, increased ratios of pre-treatment proteasome subunit-specific catalytic activity of β5i/β5 were observed in patients that reached CR (N=10) compared to those that did not (N=14; P=0.056). Together, these results suggest that higher ratios of immuno/constitutive proteasome in pretreatment acute leukemia can serve as a novel putative predictor for the clinical response to bortezomib-containing treatment.