volasertib and Precursor-B-Cell-Lymphoblastic-Leukemia-Lymphoma

In B-cell acute lymphoblastic leukemia (B-ALL), activation of Notch signaling leads to cell-cycle arrest and apoptosis. We aimed to harness knowledge acquired by understanding a mechanism of Notch-induced cell death to elucidate a therapeutically viable target in B-ALL. To this end, we identified that Notch activation suppresses Polo-like kinase 1 (PLK1) in a B-ALL-specific manner. We identified that PLK1 is expressed in all subsets of B-ALL and is highest in Philadelphia-like (Ph-like) ALL, a high-risk subtype of disease. We biochemically delineated a mechanism of Notch-induced PLK1 downregulation that elucidated stark regulation of p53 in this setting. Our findings identified a novel posttranslational cascade initiated by Notch in which CHFR was activated via PARP1-mediated PARylation, resulting in ubiquitination and degradation of PLK1. This led to hypophosphorylation of MDM2

Topics: Animals; Cell Cycle Proteins; Cell Line; Cell Line, Tumor; Humans; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Oncogenes; Polo-Like Kinase 1; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pteridines; Receptors, Notch; RNA Interference; Xenograft Model Antitumor Assays