TY - JOUR
T1 - Myc-induced SUMOylation is a therapeutic vulnerability for B-cell lymphoma
AU - Hoellein, Alexander
AU - Fallahi, Mohammad
AU - Schoeffmann, Stephanie
AU - Steidle, Sabine
AU - Schaub, Franz X
AU - Rudelius, Martina
AU - Laitinen, Iina
AU - Nilsson, Lisa
AU - Goga, Andrei
AU - Peschel, Christian
AU - Nilsson, Jonas A
AU - Cleveland, John L
AU - Keller, Ulrich
PY - 2014/9/25
Y1 - 2014/9/25
N2 - Myc oncogenic transcription factors (c-Myc, N-Myc, and L-Myc) coordinate the control of cell growth, division, and metabolism. In cancer, Myc overexpression is often associated with aggressive disease, which is in part due to the destruction of select targets by the ubiquitin-proteasome system (eg, SCF(Skp2)-directed destruction of the Cdk inhibitor p27(Kip1)). We reasoned that Myc would also regulate SUMOylation, a related means of posttranslational modification of proteins, and that this circuit would play essential roles in Myc-dependent tumorigenesis. Here, we report marked increases in the expression of genes that encode regulators and components of the SUMOylation machinery in mouse and human Myc-driven lymphomas, resulting in hyper-SUMOylation in these tumors. Further, inhibition of SUMOylation by genetic means disables Myc-induced proliferation, triggering G2/M cell-cycle arrest, polyploidy, and apoptosis. Using genetically defined cell models and conditional expression systems, this response was shown to be Myc specific. Finally, in vivo loss-of-function and pharmacologic studies demonstrated that inhibition of SUMOylation provokes rapid regression of Myc-driven lymphoma. Thus, targeting SUMOylation represents an attractive therapeutic option for lymphomas with MYC involvement.
AB - Myc oncogenic transcription factors (c-Myc, N-Myc, and L-Myc) coordinate the control of cell growth, division, and metabolism. In cancer, Myc overexpression is often associated with aggressive disease, which is in part due to the destruction of select targets by the ubiquitin-proteasome system (eg, SCF(Skp2)-directed destruction of the Cdk inhibitor p27(Kip1)). We reasoned that Myc would also regulate SUMOylation, a related means of posttranslational modification of proteins, and that this circuit would play essential roles in Myc-dependent tumorigenesis. Here, we report marked increases in the expression of genes that encode regulators and components of the SUMOylation machinery in mouse and human Myc-driven lymphomas, resulting in hyper-SUMOylation in these tumors. Further, inhibition of SUMOylation by genetic means disables Myc-induced proliferation, triggering G2/M cell-cycle arrest, polyploidy, and apoptosis. Using genetically defined cell models and conditional expression systems, this response was shown to be Myc specific. Finally, in vivo loss-of-function and pharmacologic studies demonstrated that inhibition of SUMOylation provokes rapid regression of Myc-driven lymphoma. Thus, targeting SUMOylation represents an attractive therapeutic option for lymphomas with MYC involvement.
KW - Anacardic Acids/pharmacology
KW - Animals
KW - Cell Cycle Checkpoints/genetics
KW - Cell Line, Tumor
KW - Cell Proliferation
KW - Cell Transformation, Neoplastic/drug effects
KW - Cluster Analysis
KW - Disease Models, Animal
KW - Gene Expression Profiling
KW - Gene Expression Regulation, Neoplastic
KW - Humans
KW - Lymphoma, B-Cell/genetics
KW - Mice
KW - Mice, Transgenic
KW - Polyploidy
KW - Proto-Oncogene Proteins c-myc/genetics
KW - Signal Transduction
KW - Sumoylation/drug effects
KW - Transcription, Genetic
KW - Ubiquitin-Activating Enzymes/genetics
U2 - 10.1182/blood-2014-06-584524
DO - 10.1182/blood-2014-06-584524
M3 - Article
C2 - 25143484
SN - 0006-4971
VL - 124
SP - 2081
EP - 2090
JO - Blood
JF - Blood
IS - 13
ER -