The Cks1/Cks2 axis fine-tunes Mll1 expression and is crucial for MLL-rearranged leukaemia cell viability |
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| Authors: | William Grey Adam Ivey Thomas A Milne Torsten Haferlach David Grimwade Frank Uhlmann Edwige Voisset Veronica Yu |
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| Institution: | 1. Department of Medical and Molecular Genetics, King''s College London, Faculty of Life Sciences and Medicine, London, UK;2. MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, UK;3. MLL Munich Leukemia Laboratory, Munich, Germany;4. Chromosome Segregation Laboratory, The Francis Crick Institute, London, UK |
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| Abstract: | 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. |
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| Keywords: | MLL1 Wnt MLL-fusion proteins SKP2/CKS1 inhibitor |
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