Cancer Biology Commons^™

Targeting Neddylation Induces Dna Damage And Checkpoint Activation And Sensitizes Chronic Lymphocytic Leukemia B Cells To Alkylating Agents, C Paiva, J C. Godbersen, A Berger, J R. Brown, A V. Danilov

Dartmouth Scholarship

Microenvironment-mediated upregulation of the B-cell receptor (BCR) and nuclear factor-κB (NF-κB) signaling in CLL cells resident in the lymph node and bone marrow promotes apoptosis evasion and clonal expansion. We recently reported that MLN4924 (pevonedistat), an investigational agent that inhibits the NEDD8-activating enzyme (NAE), abrogates stromal-mediated NF-κB pathway activity and CLL cell survival. However, the NAE pathway also assists degradation of multiple other substrates. MLN4924 has been shown to induce DNA damage and cell cycle arrest, but the importance of this mechanism in primary neoplastic B cells has not been studied. Here we mimicked the lymph node microenvironment using CD40 …