Activation Of C-Abl Kinase Potentiates The Anti-myeloma Drug Lenalidomide By Promoting DDA1 Recruitment To The CRL4 Ubiquitin Ligase

Cullin Ring Ligase 4(CRL4),a complex of Cul4 and DDB1,regulates cell cycle,DNA damage repair,and chromatin replication by targeting a variety of substrates for ubiquitination.CRL4 is also hijacked by viral proteins or thalidomide-derived compounds to degrade host restriction factors.Lenalidomide hijacks the CRL4CRBN ubiquitin ligase to degrade essential lymphoid transcription factors IKZF1 and IKZF3 in multiple myeloma cells.Here we report that the c-Abl non-receptor kinase phosphorylates DDB1 at residue Y316 to recruit a small regulatory protein DDA1,leading to increased substrate ubiquitination.Pharmacological inhibition or genetic ablation of the Abl-DDB1-DDA1 axis decreases the ubiquitination of CRL4 substrates,including IKZF1 and IKZF3 in lenalidomide-treated multiple myeloma cells.Importantly,panobinostat,a recently approved anti-myeloma drug,and dexamethasone enhance lenalidomide-induced substrate degradation and cytotoxicity by activating c-Abl,therefore providing mechanism underlying their combination with lenalidomide to treat multiple myeloma.