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

VL - 125

SP - 1272

EP - 1281

JO - Blood

JF - Blood

SN - 0006-4971

IS - 8

ER -