TY - JOUR
T1 - The Cks1/Cks2 axis fine-tunes Mll1 expression and is crucial for MLL-rearranged leukaemia cell viability
AU - Grey, William
AU - Ivey, Adam
AU - Milne, Thomas A
AU - Haferlach, Torsten
AU - Grimwade, David
AU - Uhlmann, Frank
AU - Voisset, Edwige
AU - Yu, Veronica
N1 - Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.
PY - 2018/1
Y1 - 2018/1
N2 - 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 SCF(Skp2) and APC(Cdc20). Notable targets controlled by Cks include p27 and Cyclin A. Here, we demonstrate that Cks1 and Cks2 proteins interact with both the Mll(N) and Mll(C) 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.
AB - 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 SCF(Skp2) and APC(Cdc20). Notable targets controlled by Cks include p27 and Cyclin A. Here, we demonstrate that Cks1 and Cks2 proteins interact with both the Mll(N) and Mll(C) 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.
KW - Journal Article
U2 - 10.1016/j.bbamcr.2017.09.009
DO - 10.1016/j.bbamcr.2017.09.009
M3 - Article
C2 - 28939057
SN - 0006-3002
VL - 1865
SP - 105
EP - 116
JO - Biochimica et Biophysica Acta
JF - Biochimica et Biophysica Acta
IS - 1
ER -