Inhibition of NEDDylation enhances the cytostatic effect of Rohinitib on chronic lymphocytic leukemia cells.

Abstract

Chronic lymphocytic leukemia (CLL) is an incurable hematologic neoplasm that primarily affects elderly individuals. Its treatment consumes a significant amount of clinical resources, a demand expected to grow due to increasing life expectancy in our society. Two characteristics of B-CLL lymphocytes that have been scarcely explored as therapeutic targets are their high RNA translation and increased ubiquitin-like post-translational modifications (UBL-PTM). Previous studies have analyzed the effects of inhibiting these two processes in B-CLL cells separately, yielding promising results. Here we present data demonstrating that the combined inhibition of both processes using the compounds Rohinitib and MLN4924/Pevonedistat synergistically enhances the individual effects of each through the induction of apoptosis. This effect appears to be specific to CLL, as it is not significantly relevant in healthy lymphocytes or in other prevalent hematologic neoplasms, such as multiple myeloma. A molecular characterization of this synergistic effect was conducted, revealing RNA translation dysregulation of NAE1 and UBE2M, as well as kinases involved in BCR signaling, in CLL tumor cells. Additionally, a cooperative regulation of BCL2 and TP53 expression was observed. These preclinical observations support future studies for their therapeutical application in CLL.