Clinical Relevance of Ubiquitin-Proteasome System Profiling in Acute Leukemias.

Abstract 2633

Poster Board II-609

The ubiquitin-proteasome system (UPS) plays a major role in the homeostasis of cellular proteins: chymotrypsin-like (Ch-L), caspase-like (Cas-L), and trypsin-like (Tr-L). The UPS system is involved in most critical cellular processes and its role in oncogenesis is well established. Here we compared UPS protein levels (proteasome and ubiquitin) and proteasome enzymatic activities in peripheral blood plasma from newly diagnosed patients with acute myeloid leukemia (AML; n=147), acute lymphoblastic leukemia (ALL; n=34?), or myelodysplastic syndrome (MDS ; n=27), and 99 apparently healthy control subjects. Proteasome and ubiquitin were measured using immunoassays based on electro-chemiluminescence technology. The proteasome enzymatic activities were measure using a standard enzymatic assay utilizing fluorogenic peptide-AMC substrate. By normalizing these enzymatic activities to the levels of proteasome protein in plasma, we also determined specific proteasome enzyme activities (Ch-L/p, Cas-L/p, and Tr-L, respectively). AML, ALL, and MDS patients all had high levels of proteasome protein, ubiquitin, and enzymatic activities relative to control subjects. However, each specific enzyme activity in general was lower in all 3 disease groups than in control subjects, which suggests that each proteasome has lower enzymatic activity in blast cells but we cannot rule out that the number of proteasomes might be increased. Despite these similarities, AML, ALL, and MDS each exhibited a specific profile of UPS protein and enzymatic activities . Proteasome protein levels and enzymatic activities also correlated with clinical behavior. In AML, proteasome protein level was a strong predictor of survival as a both a continuous (P<0.00001) and a dichotomous (P=0.04) variable, independent of cytogenetics, performance status, and age. In ALL, Ch-L/p showed a significant negative correlation with survival (P=0.0015). In conclusion, these data demonstrate that each disease has a unique UPS profile and confirm that the UPS system plays a major role in the leukemic process. In addition, profiling the UPS in leukemias using plasma provides valuable biomarkers that can be used to help predict clinical behavior and may ultimately help manage disease.