Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma

Fabian Frontzek; Annette M. Staiger; Myroslav Zapukhlyak; Wendan Xu; Irina Bonzheim; Vanessa Borgmann; Philip Sander; Maria Joao Baptista; Jan-Niklas Heming; Philipp Berning; Ramona Wullenkord; Tabea Erdmann; Mathias Lutz; Pia Veratti; Sophia Ehrenfeld; Kirsty Wienand; Heike Horn; John R. Goodlad; Matthew R. Wilson; Ioannis Anagnostopoulos; Mario Lamping; Eva González Barca; Fina Climent; Antonio Salar; Josep Castellvi; Pau Abrisqueta; Javier Menarguez; T Aldámiz-Echevarría; Julia Richter; Wolfram Klapper; Alexander Tzankov; Stefan Dirnhofer; Andreas Rosenwald; Jose Luís Mate Sanz; Gustavo Tapia; Peter Lenz; C. Miething; Wolfgang Hartmann; Björn Chapuy; Falko Fend; Gustav Ott; José-Tomás Navarro; Michael Grau; Georg Lenz

doi:10.1038/s41467-021-25405-w

Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma

Fabian Frontzek, Annette M. Staiger, Myroslav Zapukhlyak, Wendan Xu, Irina Bonzheim, Vanessa Borgmann, Philip Sander, Maria Joao Baptista, Jan-Niklas Heming, Philipp Berning, Ramona Wullenkord, Tabea Erdmann, Mathias Lutz, Pia Veratti, Sophia Ehrenfeld, Kirsty Wienand, Heike Horn, John R. Goodlad, Matthew R. Wilson, Ioannis AnagnostopoulosMario Lamping, Eva González Barca, Fina Climent, Antonio Salar, Josep Castellvi, Pau Abrisqueta, Javier Menarguez, T Aldámiz-Echevarría, Julia Richter, Wolfram Klapper, Alexander Tzankov, Stefan Dirnhofer, Andreas Rosenwald, Jose Luís Mate Sanz, Gustavo Tapia, Peter Lenz, C. Miething, Wolfgang Hartmann, Björn Chapuy, Falko Fend, Gustav Ott, José-Tomás Navarro, Michael Grau, Georg Lenz

Research output: Contribution to journal › Article › Research › peer-review

29 Citations (Scopus)

Abstract

Plasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and, in 60% of cases, its association with Epstein-Barr virus (EBV). Roughly 50% of PBLs harbor a MYC translocation. Here, we provide a comprehensive integrated genomic analysis using whole exome sequencing (WES) and genome-wide copy number determination in a large cohort of 96 primary PBL samples. We identify alterations activating the RAS-RAF, JAK-STAT, and NOTCH pathways as well as frequent high-level amplifications in MCL1 and IRF4. The functional impact of these alterations is assessed using an unbiased shRNA screen in a PBL model. These analyses identify the IRF4 and JAK-STAT pathways as promising molecular targets to improve outcome of PBL patients.

Original language	English
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-25405-w
Publication status	Published - 2021

Keywords

Adolescent
Adult
Aged
Aged, 80 and over
Cohort Studies
Female
Gene Amplification
Gene Dosage
Gene Expression Profiling
Humans
Interferon Regulatory Factors
Janus Kinases
Male
Middle Aged
Molecular Targeted Therapy
Plasmablastic Lymphoma
STAT Transcription Factors
Translocation, Genetic
Whole Exome Sequencing
Young Adult

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Frontzek, F., Staiger, A. M., Zapukhlyak, M., Xu, W., Bonzheim, I., Borgmann, V., Sander, P., Baptista, M. J., Heming, J.-N., Berning, P., Wullenkord, R., Erdmann, T., Lutz, M., Veratti, P., Ehrenfeld, S., Wienand, K., Horn, H., Goodlad, J. R., Wilson, M. R., ... Lenz, G. (2021). Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma. Nature Communications, 12(1). https://doi.org/10.1038/s41467-021-25405-w

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title = "Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma",

abstract = "Plasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and, in 60% of cases, its association with Epstein-Barr virus (EBV). Roughly 50% of PBLs harbor a MYC translocation. Here, we provide a comprehensive integrated genomic analysis using whole exome sequencing (WES) and genome-wide copy number determination in a large cohort of 96 primary PBL samples. We identify alterations activating the RAS-RAF, JAK-STAT, and NOTCH pathways as well as frequent high-level amplifications in MCL1 and IRF4. The functional impact of these alterations is assessed using an unbiased shRNA screen in a PBL model. These analyses identify the IRF4 and JAK-STAT pathways as promising molecular targets to improve outcome of PBL patients.",

keywords = "Adolescent, Adult, Aged, Aged, 80 and over, Cohort Studies, Female, Gene Amplification, Gene Dosage, Gene Expression Profiling, Humans, Interferon Regulatory Factors, Janus Kinases, Male, Middle Aged, Molecular Targeted Therapy, Plasmablastic Lymphoma, STAT Transcription Factors, Translocation, Genetic, Whole Exome Sequencing, Young Adult",

author = "Fabian Frontzek and Staiger, {Annette M.} and Myroslav Zapukhlyak and Wendan Xu and Irina Bonzheim and Vanessa Borgmann and Philip Sander and Baptista, {Maria Joao} and Jan-Niklas Heming and Philipp Berning and Ramona Wullenkord and Tabea Erdmann and Mathias Lutz and Pia Veratti and Sophia Ehrenfeld and Kirsty Wienand and Heike Horn and Goodlad, {John R.} and Wilson, {Matthew R.} and Ioannis Anagnostopoulos and Mario Lamping and {Gonz{\'a}lez Barca}, Eva and Fina Climent and Antonio Salar and Josep Castellvi and Pau Abrisqueta and Javier Menarguez and T Ald{\'a}miz-Echevarr{\'i}a and Julia Richter and Wolfram Klapper and Alexander Tzankov and Stefan Dirnhofer and Andreas Rosenwald and {Mate Sanz}, {Jose Lu{\'i}s} and Gustavo Tapia and Peter Lenz and C. Miething and Wolfgang Hartmann and Bj{\"o}rn Chapuy and Falko Fend and Gustav Ott and Jos{\'e}-Tom{\'a}s Navarro and Michael Grau and Georg Lenz",

year = "2021",

doi = "10.1038/s41467-021-25405-w",

language = "English",

volume = "12",

number = "1",

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Frontzek, F, Staiger, AM, Zapukhlyak, M, Xu, W, Bonzheim, I, Borgmann, V, Sander, P, Baptista, MJ, Heming, J-N, Berning, P, Wullenkord, R, Erdmann, T, Lutz, M, Veratti, P, Ehrenfeld, S, Wienand, K, Horn, H, Goodlad, JR, Wilson, MR, Anagnostopoulos, I, Lamping, M, González Barca, E, Climent, F, Salar, A, Castellvi, J , Abrisqueta, P, Menarguez, J, Aldámiz-Echevarría, T, Richter, J, Klapper, W, Tzankov, A, Dirnhofer, S, Rosenwald, A, Mate Sanz, JL , Tapia, G, Lenz, P, Miething, C, Hartmann, W, Chapuy, B, Fend, F, Ott, G, Navarro, J-T, Grau, M & Lenz, G 2021, 'Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma', Nature Communications, vol. 12, no. 1. https://doi.org/10.1038/s41467-021-25405-w

TY - JOUR

T1 - Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma

AU - Frontzek, Fabian

AU - Staiger, Annette M.

AU - Zapukhlyak, Myroslav

AU - Xu, Wendan

AU - Bonzheim, Irina

AU - Borgmann, Vanessa

AU - Sander, Philip

AU - Baptista, Maria Joao

AU - Heming, Jan-Niklas

AU - Berning, Philipp

AU - Wullenkord, Ramona

AU - Erdmann, Tabea

AU - Lutz, Mathias

AU - Veratti, Pia

AU - Ehrenfeld, Sophia

AU - Wienand, Kirsty

AU - Horn, Heike

AU - Goodlad, John R.

AU - Wilson, Matthew R.

AU - Anagnostopoulos, Ioannis

AU - Lamping, Mario

AU - González Barca, Eva

AU - Climent, Fina

AU - Salar, Antonio

AU - Castellvi, Josep

AU - Abrisqueta, Pau

AU - Menarguez, Javier

AU - Aldámiz-Echevarría, T

AU - Richter, Julia

AU - Klapper, Wolfram

AU - Tzankov, Alexander

AU - Dirnhofer, Stefan

AU - Rosenwald, Andreas

AU - Mate Sanz, Jose Luís

AU - Tapia, Gustavo

AU - Lenz, Peter

AU - Miething, C.

AU - Hartmann, Wolfgang

AU - Chapuy, Björn

AU - Fend, Falko

AU - Ott, Gustav

AU - Navarro, José-Tomás

AU - Grau, Michael

AU - Lenz, Georg

PY - 2021

Y1 - 2021

N2 - Plasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and, in 60% of cases, its association with Epstein-Barr virus (EBV). Roughly 50% of PBLs harbor a MYC translocation. Here, we provide a comprehensive integrated genomic analysis using whole exome sequencing (WES) and genome-wide copy number determination in a large cohort of 96 primary PBL samples. We identify alterations activating the RAS-RAF, JAK-STAT, and NOTCH pathways as well as frequent high-level amplifications in MCL1 and IRF4. The functional impact of these alterations is assessed using an unbiased shRNA screen in a PBL model. These analyses identify the IRF4 and JAK-STAT pathways as promising molecular targets to improve outcome of PBL patients.

AB - Plasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and, in 60% of cases, its association with Epstein-Barr virus (EBV). Roughly 50% of PBLs harbor a MYC translocation. Here, we provide a comprehensive integrated genomic analysis using whole exome sequencing (WES) and genome-wide copy number determination in a large cohort of 96 primary PBL samples. We identify alterations activating the RAS-RAF, JAK-STAT, and NOTCH pathways as well as frequent high-level amplifications in MCL1 and IRF4. The functional impact of these alterations is assessed using an unbiased shRNA screen in a PBL model. These analyses identify the IRF4 and JAK-STAT pathways as promising molecular targets to improve outcome of PBL patients.

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Cohort Studies

KW - Female

KW - Gene Amplification

KW - Gene Dosage

KW - Gene Expression Profiling

KW - Humans

KW - Interferon Regulatory Factors

KW - Janus Kinases

KW - Male

KW - Middle Aged

KW - Molecular Targeted Therapy

KW - Plasmablastic Lymphoma

KW - STAT Transcription Factors

KW - Translocation, Genetic

KW - Whole Exome Sequencing

KW - Young Adult

U2 - 10.1038/s41467-021-25405-w

DO - 10.1038/s41467-021-25405-w

M3 - Article

C2 - 34465776

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma

Abstract

Keywords

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