The Cks1/Cks2 axis fine-tunes Mll1 expression and is crucial for MLL-rearranged leukemia cell viability
journal contributionposted on 05.08.2020, 16:29 authored by William Grey, Adam Ivey, Thomas A Milne, Torsten Haferlach, David Grimwade, Frank Uhlmann, Edwige Voisset, Veronica Yu
The Cdc28 protein kinase subunits, Cks1 and Cks2, play dual roles in Cdk-substrate specificity and Cdk-independent protein degradation, in concert with the E3 ubiquitin ligase complexes SCFSkp2 and APCCdc20. Notable targets controlled by Cks include p27 and Cyclin A. Here, we demonstrate that Cks1 and Cks2 proteins interact with both the MllN and MllC subunits of Mll1 (Mixed-lineage leukaemia 1), and together, the Cks proteins define Mll1 levels throughout the cell cycle. Overexpression of CKS1B and CKS2 is observed in multiple human cancers, including various MLL-rearranged (MLLr) AML subtypes. To explore the importance of MLL-Fusion Protein regulation by CKS1/2, we used small molecule inhibitors (MLN4924 and C1) to modulate their protein degradation functions. These inhibitors specifically reduced the proliferation of MLLr cell lines compared to primary controls. Altogether, this study uncovers a novel regulatory pathway for MLL1, which may open a new therapeutic approach to MLLr leukaemia.
CKS1BCKS2MLL-fusion proteinsMLL1SKP2/CKS1 inhibitorWntAnimalsCDC2-CDC28 KinasesCDC28 Protein Kinase, S cerevisiaeCarrier ProteinsCell Cycle ProteinsCell SurvivalCells, CulturedEmbryo, MammalianGene Expression Regulation, LeukemicGene RearrangementHistone-Lysine N-MethyltransferaseHumansLeukemiaMiceMyeloid-Lymphoid Leukemia ProteinOncogene Proteins, FusionSignal TransductionUhlmann FC00119806 Biological Sciences02 Physical Sciences