TY - JOUR
T1 - Loss of PRDM11 promotes MYC-driven lymphomagenesis
AU - Fog-Tonnesen, Cathrine Kolster
AU - Asmar, Fazila
AU - Côme, Christophe Roger Michel
AU - Jensen, Klaus Thorleif
AU - Johansen, Jens Vilstrup
AU - Bou Kheir, Tony
AU - Jacobsen, Linda
AU - Friis, Carsten
AU - Louw, Alison
AU - Rosgaard, Louise
AU - Øbro, Nina Friesgaard
AU - Marquart, Hanne Vibeke
AU - Anthonsen, Kristian
AU - Braat, Arie Koen
AU - van Lohuizen, Maarten
AU - Ralfkiaer, Elisabeth
AU - Grønbæk, Kirsten
AU - Lund, Anders Henrik
N1 - © 2015 by The American Society of Hematology.
PY - 2015/2/19
Y1 - 2015/2/19
N2 - The PR-domain (PRDM) family of genes encodes transcriptional regulators, several of which are deregulated in cancer. By using a functional screening approach, we sought to identify novel tumor suppressors among the PRDMs. Here we demonstrate oncogenic collaboration between depletion of the previously uncharacterized PR-domain family member Prdm11 and overexpression of MYC. Overexpression of PRDM11 inhibits proliferation and induces apoptosis. Prdm11 knockout mice are viable, and loss of Prdm11 accelerates MYC-driven lymphomagenesis in the Eµ-Myc mouse model. Moreover, we show that patients with PRDM11-deficient diffuse large B-cell lymphomas (DLBCLs) have poorer overall survival and belong to the nongerminal center B-cell-like subtype. Mechanistically, genome-wide mapping of PRDM11 binding sites coupled with transcriptome sequencing in human DLBCL cells evidenced that PRDM11 associates with transcriptional start sites of target genes and regulates important oncogenes such as FOS and JUN. Hence, we characterize PRDM11 as a putative novel tumor suppressor that controls the expression of key oncogenes, and we add new mechanistic insight into B-cell lymphomagenesis.
AB - The PR-domain (PRDM) family of genes encodes transcriptional regulators, several of which are deregulated in cancer. By using a functional screening approach, we sought to identify novel tumor suppressors among the PRDMs. Here we demonstrate oncogenic collaboration between depletion of the previously uncharacterized PR-domain family member Prdm11 and overexpression of MYC. Overexpression of PRDM11 inhibits proliferation and induces apoptosis. Prdm11 knockout mice are viable, and loss of Prdm11 accelerates MYC-driven lymphomagenesis in the Eµ-Myc mouse model. Moreover, we show that patients with PRDM11-deficient diffuse large B-cell lymphomas (DLBCLs) have poorer overall survival and belong to the nongerminal center B-cell-like subtype. Mechanistically, genome-wide mapping of PRDM11 binding sites coupled with transcriptome sequencing in human DLBCL cells evidenced that PRDM11 associates with transcriptional start sites of target genes and regulates important oncogenes such as FOS and JUN. Hence, we characterize PRDM11 as a putative novel tumor suppressor that controls the expression of key oncogenes, and we add new mechanistic insight into B-cell lymphomagenesis.
KW - Animals
KW - Carrier Proteins
KW - Cell Transformation, Neoplastic
KW - Cells, Cultured
KW - Embryo, Mammalian
KW - Gene Deletion
KW - Gene Expression Regulation, Neoplastic
KW - Gene Knockout Techniques
KW - HEK293 Cells
KW - HeLa Cells
KW - Humans
KW - Lymphoma
KW - Lymphoma, Large B-Cell, Diffuse
KW - Mice
KW - Molecular Sequence Data
KW - Proto-Oncogene Proteins c-myc
KW - Tumor Suppressor Proteins
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1182/blood-2014-03-560805
DO - 10.1182/blood-2014-03-560805
M3 - Journal article
C2 - 25499759
SN - 0006-4971
VL - 125
SP - 1272
EP - 1281
JO - Blood
JF - Blood
IS - 8
ER -
