Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell-derived lymphomas
Angioimmunoblastic T-cell lymphoma (AITL) and other lymphomas derived from follicular T-helper cells (TFH) represent a large proportion of peripheral T-cell lymphomas (PTCLs) with poorly understood pathogenesis and unfavorable treatment results. We investigated a series of 85 patients with AITL (n = 72) or other TFH-derived PTCL (n = 13) by targeted deep sequencing of a gene panel enriched in T-cell receptor (TCR) signaling elements. RHOA mutations were identified in 51 of 85 cases (60%) consisting of the highly recurrent dominant negative G17V variant in most cases and a novel K18N in 3 cases, the latter showing activating properties in in vitro assays. Moreover, half of the patients carried virtually mutually exclusive mutations in other TCR-related genes, most frequently in PLCG1 (14.1%), CD28 (9.4%, exclusively in AITL), PI3K elements (7%), CTNNB1 (6%), and GTF2I (6%). Using in vitro assays in transfected cells, we demonstrated that 9 of 10 PLCG1 and 3 of 3 CARD11 variants induced MALT1 protease activity and increased transcription from NFAT or NF-κB response element reporters, respectively. Collectively, the vast majority of variants in TCR-related genes could be classified as gain-of-function. Accordingly, the samples with mutations in TCR-related genes other than RHOA had transcriptomic profiles enriched in signatures reflecting higher T-cell activation. Although no correlation with presenting clinical features nor significant impact on survival was observed, the presence of TCR-related mutations correlated with early disease progression. Thus, targeting of TCR-related events may hold promise for the treatment of TFH-derived lymphomas..
Medienart: |
Artikel |
---|
Erscheinungsjahr: |
2016 |
---|---|
Erschienen: |
2016 |
Enthalten in: |
Zur Gesamtaufnahme - volume:128 |
---|---|
Enthalten in: |
Blood - 128(2016), 11, Seite 1490 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Vallois, David [VerfasserIn] |
---|
Links: |
---|
RVK: |
---|
doi: |
10.1182/blood-2016-02-698977 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
OLC1985790734 |
---|
LEADER | 01000caa a2200265 4500 | ||
---|---|---|---|
001 | OLC1985790734 | ||
003 | DE-627 | ||
005 | 20230714231759.0 | ||
007 | tu | ||
008 | 161202s2016 xx ||||| 00| ||eng c | ||
024 | 7 | |a 10.1182/blood-2016-02-698977 |2 doi | |
028 | 5 | 2 | |a PQ20170206 |
035 | |a (DE-627)OLC1985790734 | ||
035 | |a (DE-599)GBVOLC1985790734 | ||
035 | |a (PRQ)c1047-b8b57cbcad71ac5c2c43d039eaaded3f2466e27d24de74137bf2a35e26105fd80 | ||
035 | |a (KEY)0186192120160000128001101490activatingmutationsingenesrelatedtotcrsignalingina | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
082 | 0 | 4 | |a 610 |q DNB |
084 | |a XA 33000 |q AVZ |2 rvk | ||
100 | 1 | |a Vallois, David |e verfasserin |4 aut | |
245 | 1 | 0 | |a Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell-derived lymphomas |
264 | 1 | |c 2016 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ohne Hilfsmittel zu benutzen |b n |2 rdamedia | ||
338 | |a Band |b nc |2 rdacarrier | ||
520 | |a Angioimmunoblastic T-cell lymphoma (AITL) and other lymphomas derived from follicular T-helper cells (TFH) represent a large proportion of peripheral T-cell lymphomas (PTCLs) with poorly understood pathogenesis and unfavorable treatment results. We investigated a series of 85 patients with AITL (n = 72) or other TFH-derived PTCL (n = 13) by targeted deep sequencing of a gene panel enriched in T-cell receptor (TCR) signaling elements. RHOA mutations were identified in 51 of 85 cases (60%) consisting of the highly recurrent dominant negative G17V variant in most cases and a novel K18N in 3 cases, the latter showing activating properties in in vitro assays. Moreover, half of the patients carried virtually mutually exclusive mutations in other TCR-related genes, most frequently in PLCG1 (14.1%), CD28 (9.4%, exclusively in AITL), PI3K elements (7%), CTNNB1 (6%), and GTF2I (6%). Using in vitro assays in transfected cells, we demonstrated that 9 of 10 PLCG1 and 3 of 3 CARD11 variants induced MALT1 protease activity and increased transcription from NFAT or NF-κB response element reporters, respectively. Collectively, the vast majority of variants in TCR-related genes could be classified as gain-of-function. Accordingly, the samples with mutations in TCR-related genes other than RHOA had transcriptomic profiles enriched in signatures reflecting higher T-cell activation. Although no correlation with presenting clinical features nor significant impact on survival was observed, the presence of TCR-related mutations correlated with early disease progression. Thus, targeting of TCR-related events may hold promise for the treatment of TFH-derived lymphomas. | ||
540 | |a Nutzungsrecht: © 2016 by The American Society of Hematology. | ||
700 | 1 | |a Dobay, Maria Pamela D |4 oth | |
700 | 1 | |a Morin, Ryan D |4 oth | |
700 | 1 | |a Lemonnier, François |4 oth | |
700 | 1 | |a Missiaglia, Edoardo |4 oth | |
700 | 1 | |a Juilland, Mélanie |4 oth | |
700 | 1 | |a Iwaszkiewicz, Justyna |4 oth | |
700 | 1 | |a Fataccioli, Virginie |4 oth | |
700 | 1 | |a Bisig, Bettina |4 oth | |
700 | 1 | |a Roberti, Annalisa |4 oth | |
700 | 1 | |a Grewal, Jasleen |4 oth | |
700 | 1 | |a Bruneau, Julie |4 oth | |
700 | 1 | |a Fabiani, Bettina |4 oth | |
700 | 1 | |a Martin, Antoine |4 oth | |
700 | 1 | |a Bonnet, Christophe |4 oth | |
700 | 1 | |a Michielin, Olivier |4 oth | |
700 | 1 | |a Jais, Jean-Philippe |4 oth | |
700 | 1 | |a Figeac, Martin |4 oth | |
700 | 1 | |a Bernard, Olivier A |4 oth | |
700 | 1 | |a Delorenzi, Mauro |4 oth | |
700 | 1 | |a Haioun, Corinne |4 oth | |
700 | 1 | |a Tournilhac, Olivier |4 oth | |
700 | 1 | |a Thome, Margot |4 oth | |
700 | 1 | |a Gascoyne, Randy D |4 oth | |
700 | 1 | |a Gaulard, Philippe |4 oth | |
700 | 1 | |a de Leval, Laurence |4 oth | |
773 | 0 | 8 | |i Enthalten in |t Blood |d Washington, DC : American Society of Hematology, 1946 |g 128(2016), 11, Seite 1490 |w (DE-627)129268852 |w (DE-600)80069-7 |w (DE-576)014459280 |x 0006-4971 |7 nnns |
773 | 1 | 8 | |g volume:128 |g year:2016 |g number:11 |g pages:1490 |
856 | 4 | 1 | |u http://dx.doi.org/10.1182/blood-2016-02-698977 |3 Volltext |
856 | 4 | 2 | |u http://www.ncbi.nlm.nih.gov/pubmed/27369867 |
912 | |a GBV_USEFLAG_A | ||
912 | |a SYSFLAG_A | ||
912 | |a GBV_OLC | ||
912 | |a SSG-OLC-DE-84 | ||
912 | |a GBV_ILN_31 | ||
912 | |a GBV_ILN_65 | ||
912 | |a GBV_ILN_69 | ||
912 | |a GBV_ILN_290 | ||
912 | |a GBV_ILN_2004 | ||
912 | |a GBV_ILN_2006 | ||
912 | |a GBV_ILN_2008 | ||
912 | |a GBV_ILN_2219 | ||
912 | |a GBV_ILN_4012 | ||
912 | |a GBV_ILN_4125 | ||
912 | |a GBV_ILN_4219 | ||
912 | |a GBV_ILN_4305 | ||
912 | |a GBV_ILN_4310 | ||
936 | r | v | |a XA 33000 |
951 | |a AR | ||
952 | |d 128 |j 2016 |e 11 |h 1490 |