Loss of PRDM11 promotes MYC-driven lymphomagenesis

Cathrine Kolster Fog-Tonnesen; Fazila Asmar; Christophe Roger Michel Côme; Klaus Thorleif Jensen; Jens Vilstrup Johansen; Tony Bou Kheir; Linda Jacobsen; Carsten Friis; Alison Louw; Louise Rosgaard; Nina Friesgaard Øbro; Hanne Vibeke Marquart; Kristian Anthonsen; Arie Koen Braat; Maarten van Lohuizen; Elisabeth Ralfkiaer; Kirsten Grønbæk; Anders Henrik Lund

doi:10.1182/blood-2014-03-560805

Loss of PRDM11 promotes MYC-driven lymphomagenesis

Cathrine Kolster Fog-Tonnesen, Fazila Asmar, Christophe Roger Michel Côme, Klaus Thorleif Jensen, Jens Vilstrup Johansen, Tony Bou Kheir, Linda Jacobsen, Carsten Friis, Alison Louw, Louise Rosgaard, Nina Friesgaard Øbro, Hanne Vibeke Marquart, Kristian Anthonsen, Arie Koen Braat, Maarten van Lohuizen, Elisabeth Ralfkiaer, Kirsten Grønbæk, Anders Henrik Lund

13 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Blood
Volume	125
Issue number	8
Pages (from-to)	1272-81
Number of pages	10
ISSN	0006-4971
DOIs	https://doi.org/10.1182/blood-2014-03-560805
Publication status	Published - 19 Feb 2015

Keywords

Animals
Carrier Proteins
Cell Transformation, Neoplastic
Cells, Cultured
Embryo, Mammalian
Gene Deletion
Gene Expression Regulation, Neoplastic
Gene Knockout Techniques
HEK293 Cells
HeLa Cells
Humans
Lymphoma
Lymphoma, Large B-Cell, Diffuse
Mice
Molecular Sequence Data
Proto-Oncogene Proteins c-myc
Tumor Suppressor Proteins
Journal Article
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Fog-Tonnesen, C. K., Asmar, F., Côme, C. R. M., Jensen, K. T., Johansen, J. V., Bou Kheir, T., Jacobsen, L., Friis, C., Louw, A., Rosgaard, L., Øbro, N. F., Marquart, H. V., Anthonsen, K., Braat, A. K., van Lohuizen, M., Ralfkiaer, E., Grønbæk, K., & Lund, A. H. (2015). Loss of PRDM11 promotes MYC-driven lymphomagenesis. Blood, 125(8), 1272-81. https://doi.org/10.1182/blood-2014-03-560805

Fog-Tonnesen, CK, Asmar, F, Côme, CRM, Jensen, KT, Johansen, JV, Bou Kheir, T, Jacobsen, L, Friis, C, Louw, A, Rosgaard, L, Øbro, NF, Marquart, HV, Anthonsen, K, Braat, AK, van Lohuizen, M, Ralfkiaer, E, Grønbæk, K & Lund, AH 2015, 'Loss of PRDM11 promotes MYC-driven lymphomagenesis', Blood, vol. 125, no. 8, pp. 1272-81. https://doi.org/10.1182/blood-2014-03-560805

@article{0ed08b22293d4415b1081257e54068ee,

title = "Loss of PRDM11 promotes MYC-driven lymphomagenesis",

abstract = "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.",

keywords = "Animals, Carrier Proteins, Cell Transformation, Neoplastic, Cells, Cultured, Embryo, Mammalian, Gene Deletion, Gene Expression Regulation, Neoplastic, Gene Knockout Techniques, HEK293 Cells, HeLa Cells, Humans, Lymphoma, Lymphoma, Large B-Cell, Diffuse, Mice, Molecular Sequence Data, Proto-Oncogene Proteins c-myc, Tumor Suppressor Proteins, Journal Article, Research Support, Non-U.S. Gov't",

author = "Fog-Tonnesen, {Cathrine Kolster} and Fazila Asmar and C{\^o}me, {Christophe Roger Michel} and Jensen, {Klaus Thorleif} and Johansen, {Jens Vilstrup} and {Bou Kheir}, Tony and Linda Jacobsen and Carsten Friis and Alison Louw and Louise Rosgaard and {\O}bro, {Nina Friesgaard} and Marquart, {Hanne Vibeke} and Kristian Anthonsen and Braat, {Arie Koen} and {van Lohuizen}, Maarten and Elisabeth Ralfkiaer and Kirsten Gr{\o}nb{\ae}k and Lund, {Anders Henrik}",

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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

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 -

Loss of PRDM11 promotes MYC-driven lymphomagenesis

Abstract

Keywords

UN SDGs

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