Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma.
Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma.
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DOI：
10.1038/s41467-021-25405-w
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发表时间：
2021-08-31
影响因子：
16.6
通讯作者：
Lenz G
中科院分区：
文献类型：
--
作者：
Frontzek F;Staiger AM;Zapukhlyak M;Xu W;Bonzheim I;Borgmann V;Sander P;Baptista MJ;Heming JN;Berning P;Wullenkord R;Erdmann T;Lutz M;Veratti P;Ehrenfeld S;Wienand K;Horn H;Goodlad JR;Wilson MR;Anagnostopoulos I;Lamping M;Gonzalez-Barca E;Climent F;Salar A;Castellvi J;Abrisqueta P;Menarguez J;Aldamiz T;Richter J;Klapper W;Tzankov A;Dirnhofer S;Rosenwald A;Mate JL;Tapia G;Lenz P;Miething C;Hartmann W;Chapuy B;Fend F;Ott G;Navarro JT;Grau M;Lenz G
浆母细胞淋巴瘤（PBL）是一种罕见的侵袭性淋巴瘤亚型，经常与免疫抑制有关。临床上，PBL患者的特征是预后差。目前的分子发病机制的理解是有限的。PBL的一个标志是其浆细胞分化，B细胞标志物丢失，在60%的病例中，其与EB病毒（EBV）相关。大约50%的PBL具有MYC易位。在这里，我们提供了一个全面的综合基因组分析，使用全外显子组测序（WES）和全基因组拷贝数测定在一个大的队列的96个主要PBL样本。我们确定了激活RAS-RAF、JAK-STAT和NOTCH通路的改变，以及MCL 1和IRF 4中频繁的高水平扩增。在PBL模型中使用无偏的shRNA筛选来评估这些改变的功能影响。这些分析将IRF 4和JAK-STAT途径确定为改善PBL患者结局的有希望的分子靶点。浆母细胞性淋巴瘤（PBL）是一种侵袭性淋巴瘤亚型，其特征是预后差，但对该疾病的分子认识有限。在这里，作者对主要样品进行了全外显子组测序和拷贝数测定，突出了IRF 4和JAK-STAT途径作为PBL的治疗靶点。
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. Plasmablastic lymphoma (PBL) is an aggressive lymphoma subtype characterized by poor prognosis but the molecular knowledge of the disease is limited. Here, the authors perform whole exome sequencing and copy number determination of primary samples highlighting IRF4 and JAK-STAT pathways as therapeutic targets for PBL.
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影响因子：
10.1
作者：
Garcia-Reyero J;Martinez Magunacelaya N;Gonzalez de Villambrosia S;Loghavi S;Gomez Mediavilla A;Tonda R;Beltran S;Gut M;Pereña Gonzalez A;d'Ámore E;Visco C;Khoury JD;Montes-Moreno S
通讯作者：
Montes-Moreno S
影响因子：
4
作者：
Hobbs, G. Aaron;Der, Channing J.;Rossman, Kent L.
通讯作者：
Rossman, Kent L.
影响因子：
50.3
作者：
Bai, Longchuan;Zhou, Haibin;Wang, Shaomeng
通讯作者：
Wang, Shaomeng
影响因子：
6.2
作者：
Castillo, Jorge J.;Furman, Michael;Vose, Julie M.
通讯作者：
Vose, Julie M.
影响因子：
64.8
作者：
Biankin, Andrew V.;Waddell, Nicola;Kassahn, Karin S.;Gingras, Marie-Claude;Muthuswamy, Lakshmi B.;Johns, Amber L.;Miller, David K.;Wilson, Peter J.;Patch, Ann-Marie;Wu, Jianmin;Chang, David K.;Cowley, Mark J.;Gardiner, Brooke B.;Song, Sarah;Harliwong, Ivon;Idrisoglu, Senel;Nourse, Craig;Nourbakhsh, Ehsan;Manning, Suzanne;Wani, Shivangi;Gongora, Milena;Pajic, Marina;Scarlett, Christopher J.;Gill, Anthony J.;Pinho, Andreia V.;Rooman, Ilse;Anderson, Matthew;Holmes, Oliver;Leonard, Conrad;Taylor, Darrin;Wood, Scott;Xu, Qinying;Nones, Katia;Fink, J. Lynn;Christ, Angelika;Bruxner, Tim;Cloonan, Nicole;Kolle, Gabriel;Newell, Felicity;Pinese, Mark;Mead, R. Scott;Humphris, Jeremy L.;Kaplan, Warren;Jones, Marc D.;Colvin, Emily K.;Nagrial, Adnan M.;Humphrey, Emily S.;Chou, Angela;Chin, Venessa T.;Chantrill, Lorraine A.;Mawson, Amanda;Samra, Jaswinder S.;Kench, James G.;Lovell, Jessica A.;Daly, Roger J.;Merrett, Neil D.;Toon, Christopher;Epari, Krishna;Nguyen, Nam Q.;Barbour, Andrew;Zeps, Nikolajs;Kakkar, Nipun;Zhao, Fengmei;Wu, Yuan Qing;Wang, Min;Muzny, Donna M.;Fisher, William E.;Brunicardi, F. Charles;Hodges, Sally E.;Reid, Jeffrey G.;Drummond, Jennifer;Chang, Kyle;Han, Yi;Lewis, Lora R.;Dinh, Huyen;Buhay, Christian J.;Beck, Timothy;Timms, Lee;Sam, Michelle;Begley, Kimberly;Brown, Andrew;Pai, Deepa;Panchal, Ami;Buchner, Nicholas;De Borja, Richard;Denroche, Robert E.;Yung, Christina K.;Serra, Stefano;Onetto, Nicole;Mukhopadhyay, Debabrata;Tsao, Ming-Sound;Shaw, Patricia A.;Petersen, Gloria M.;Gallinger, Steven;Hruban, Ralph H.;Maitra, Anirban;Iacobuzio-Donahue, Christine A.;Schulick, Richard D.;Wolfgang, Christopher L.;Morgan, Richard A.;Lawlor, Rita T.;Capelli, Paola;Corbo, Vincenzo;Scardoni, Maria;Tortora, Giampaolo;Tempero, Margaret A.;Mann, Karen M.;Jenkins, Nancy A.;Perez-Mancera, Pedro A.;Adams, David J.;Largaespada, David A.;Wessels, Lodewyk F. A.;Rust, Alistair G.;Stein, Lincoln D.;Tuveson, David A.;Copeland, Neal G.;Musgrove, Elizabeth A.;Scarpa, Aldo;Eshleman, James R.;Hudson, Thomas J.;Sutherland, Robert L.;Wheeler, David A.;Pearson, John V.;McPherson, John D.;Gibbs, Richard A.;Grimmond, Sean M.
通讯作者：
Grimmond, Sean M.