Purpose Despite the encouraging results of bortezomib (BTZ) in hematologic malignancies to date, resistance to BTZ may be a limiting factor to its efficacy. Hence, parameters that may identify responsiveness to BTZ-containing therapy will be of clinical interest. Recently, we reported that higher ratios of immunoproteasome over constitutive proteasome protein expression in pediatric ALL and AML leukemia cells at diagnosis were an accountable factor for ex vivo sensitivity to proteasome inhibitors (Niewerth et al, Haematologica 2013). Here we explored whether this parameter was associated with response to BTZ in first relapsed and refractory pediatric acute leukemia patients treated in phase II clinical trials of BTZ combined with re-induction chemotherapy for pediatric ALL (COG-AALL07P1) and pediatric AML (COG-AAML07P1). Methods Protein expression levels of constitutive- β5 and β1, and immunoproteasome subunits β5i and β1i were determined by Western blot analysis in 61 acute leukemia patient samples (ALL n=47, AML n=14) obtained before BTZ-containing reinduction therapy. In addition, β5 and β5i proteasome catalytic activities were measured in 14 ALL and 13 AML samples prior to treatment. Lastly, NF-ΚB activity was determined by p65 ELISA in nuclear extracts of PBMCs before and 24h after BTZ treatment. Results In pre-treatment samples, expression ratios of both β5i/β5 and β1i/β1 were significantly higher in ALL cells than in AML cells (P=0.049 and P=0.002, respectively). Ratios of both β5i/β5 and β1i/β1 were significantly higher in patients that reached complete remission (CR; n=39) compared to patients that did not reach CR (n=22) (P=0.009 for β5i/β5, P=0.025 for β1i/β1). Moreover, increased ratios of β5i/β5 catalytic activity were observed in pre-treatment ALL+AML samples that reached CR compared to those that did not reach CR (P=0.078). Proteasome activity ratios correlated significantly with proteasome expression ratios (R=0.55 P=0.005). Notably, NF-ΚB activity was similar in both groups and was suppressed after BTZ treatment, being most pronounced in the pre-B ALL patients that achieved CR (average decrease: 47% p=0.05). Conclusion These results suggest that a higher ratio of immuno/constitutive proteasome in pretreatment ALL and AML cells is an accountable factor for the clinical response to BTZ. These results warrant further investigation to establish a biomarker that can be used for selecting relapsed pediatric acute leukemia patients eligible for BTZ-containing reinduction treatment.
|Publication status||Published - 2014|
Niewerth, D., Kaspers, G. J. L., Jansen, G., Van Meerloo, J., Zweegman, S., Jenkins, G., ... Horton, T. M. (2014). Ratios of immunoproteasome over constitutive proteasome expression are an indicator for sensitivity to bortezomib-containing reinduction chemotherapy in pediatric relapsed ALL and AML. Cancer Research, 74(19).