Whole exome sequencing reveals NOTCH1 mutations in anaplastic
large cell lymphoma and points to Notch both as a key pathway
and a potential therapeutic target

J 2021

Whole exome sequencing reveals NOTCH1 mutations in anaplastic large cell lymphoma and points to Notch both as a key pathway and a potential therapeutic target

LAROSE, H.; N. PROKOPH; J.D. MATTHEWS; M. SCHLEDERER; S. HOGLER et al.

Základní údaje

Originální název

Whole exome sequencing reveals NOTCH1 mutations in anaplastic large cell lymphoma and points to Notch both as a key pathway and a potential therapeutic target

Autoři

Vydání

haematologica, PAVIA, FERRATA STORTI FOUNDATION, 2021, 0390-6078

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30205 Hematology

Stát vydavatele

Itálie

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 11.049

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14740/21:00119067

Organizační jednotka

Středoevropský technologický institut

Klíčová slova anglicky

SECRETASE INHIBITOR PF-03084014; ALK; TUMOR; EXPRESSION; NPM; GLYCOSYLATION; ADOLESCENTS; CRIZOTINIB; SIGNATURES; CHILDREN

Štítky

rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 14. 7. 2021 11:23, Mgr. Pavla Foltynová, Ph.D.

Anotace

V originále

Patients diagnosed with anaplastic large cell lymphoma (ALCL) are still treated with toxic multi-agent chemotherapy and as many as 25-50% of patients relapse. To understand disease pathology and to uncover novel targets for therapy, we performed whole-exome sequencing of anaplastic lymphoma kinase (ALK)(+) ALCL, as well as gene-set enrichment analysis. This revealed that the T-cell receptor and Notch pathways were the most enriched in mutations. In particular, variant T349P of NOTCH1, which confers a growth advantage to cells in which it is expressed, was detected in 12% of ALK(+) and ALK(-) ALCL patients' samples. Furthermore, we demonstrated that NPM-ALK promotes NOTCH1 expression through binding of STAT3 upstream of NOTCH1. Moreover, inhibition of NOTCH1 with gamma-secretase inhibitors or silencing by short hairpin RNA leads to apoptosis; co-treatment in vitro with the ALK inhibitor crizotinib led to additive/synergistic antitumor activity suggesting that this may be an appropriate combination therapy for future use in the circumvention of ALK inhibitor resistance. Indeed, crizotinib-resistant and -sensitive ALCL were equally sensitive to gamma-secretase inhibitors. In conclusion, we show a variant in the extracellular domain of NOTCH1 that provides a growth advantage to cells and confirm the suitability of the Notch pathway as a second-line druggable target in ALK(+) ALCL.

Návaznosti

GJ19-23424Y, projekt VaV

Název: Imunogenika v sekvencování následující generace: Dešifrování patogenetických mechanismů u lymfoproliferativních poruch

Investor: Grantová agentura ČR, Immunogenetics in the Next Generation Sequencing era: Deciphering the pathogenetic mechanisms in lymphoproliferative disorders

LM2015064, projekt VaV

Název: Český národní uzel Evropské infrastruktury pro translační medicínu (Akronym: EATRIS-ERIC-CZ)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Involvement of Czech Translational Medicine Infrastructure to the European Advanced Translational Research Infrastructure in Medicine

LM2015091, projekt VaV

Název: Národní centrum lékařské genomiky (Akronym: NCLG)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Národní centrum lékařské genomiky

Citovat

LAROSE, H.; N. PROKOPH; J.D. MATTHEWS; M. SCHLEDERER; S. HOGLER; A.F. ALSULAMI; S.P. DUCRAY; E. NUGLOZEH; M.F. FAZALUDEEN; A. ELMOUNA; M. CECCON; L. MOLOGNI; C. GAMBACORTI-PASSERINI; G. HOEFLER; Cosimo LOBELLO; Šárka POSPÍŠILOVÁ; A. JANIKOVA; W. WOESSMANN; C. DAMM-WELK; M. ZIMMERMANN; A. FEDOROVA; A. MALONE; O. SMITH; M. WASIK; G. INGHIRAMI; L. LAMANT; T.L. BLUNDELL; W. KLAPPER; O. MERKEL; G.A.A. BURKE; S. MIAN; I. ASHANKYTY; L. KENNER a Suzanne Dawn TURNER. Whole exome sequencing reveals NOTCH1 mutations in anaplastic large cell lymphoma and points to Notch both as a key pathway and a potential therapeutic target. haematologica. PAVIA: FERRATA STORTI FOUNDATION, 2021, roč. 106, č. 6, s. 1693-1704. ISSN 0390-6078. Dostupné z: https://doi.org/10.3324/haematol.2019.238766.

@article{1782167,
   author = {Larose, H. and Prokoph, N. and Matthews, J.D. and Schlederer, M. and Hogler, S. and Alsulami, A.F. and Ducray, S.P. and Nuglozeh, E. and Fazaludeen, M.F. and Elmouna, A. and Ceccon, M. and Mologni, L. and GambacortiandPasserini, C. and Hoefler, G. and Lobello, Cosimo and Pospíšilová, Šárka and Janikova, A. and Woessmann, W. and DammandWelk, C. and Zimmermann, M. and Fedorova, A. and Malone, A. and Smith, O. and Wasik, M. and Inghirami, G. and Lamant, L. and Blundell, T.L. and Klapper, W. and Merkel, O. and Burke, G.A.A. and Mian, S. and Ashankyty, I. and Kenner, L. and Turner, Suzanne Dawn},
   article_location = {PAVIA},
   article_number = {6},
   doi = {https://doi.org/10.3324/haematol.2019.238766},
   keywords = {SECRETASE INHIBITOR PF-03084014; ALK; TUMOR; EXPRESSION; NPM; GLYCOSYLATION; ADOLESCENTS; CRIZOTINIB; SIGNATURES; CHILDREN},
   language = {eng},
   issn = {0390-6078},
   journal = {haematologica},
   title = {Whole exome sequencing reveals NOTCH1 mutations in anaplastic large cell lymphoma and points to Notch both as a key pathway and a potential therapeutic target},
   url = {https://haematologica.org/article/view/9725},
   volume = {106},
   year = {2021}
}

TY  - JOUR
ID  - 1782167
AU  - Larose, H. - Prokoph, N. - Matthews, J.D. - Schlederer, M. - Hogler, S. - Alsulami, A.F. - Ducray, S.P. - Nuglozeh, E. - Fazaludeen, M.F. - Elmouna, A. - Ceccon, M. - Mologni, L. - Gambacorti-Passerini, C. - Hoefler, G. - Lobello, Cosimo - Pospíšilová, Šárka - Janikova, A. - Woessmann, W. - Damm-Welk, C. - Zimmermann, M. - Fedorova, A. - Malone, A. - Smith, O. - Wasik, M. - Inghirami, G. - Lamant, L. - Blundell, T.L. - Klapper, W. - Merkel, O. - Burke, G.A.A. - Mian, S. - Ashankyty, I. - Kenner, L. - Turner, Suzanne Dawn
PY  - 2021
TI  - Whole exome sequencing reveals NOTCH1 mutations in anaplastic large cell lymphoma and points to Notch both as a key pathway and a potential therapeutic target
JF  - haematologica
VL  - 106
IS  - 6
SP  - 1693-1704
EP  - 1693-1704
PB  - FERRATA STORTI FOUNDATION
SN  - 03906078
KW  - SECRETASE INHIBITOR PF-03084014
KW  - ALK
KW  - TUMOR
KW  - EXPRESSION
KW  - NPM
KW  - GLYCOSYLATION
KW  - ADOLESCENTS
KW  - CRIZOTINIB
KW  - SIGNATURES
KW  - CHILDREN
UR  - https://haematologica.org/article/view/9725
N2  - Patients diagnosed with anaplastic large cell lymphoma (ALCL) are still treated with toxic multi-agent chemotherapy and as many as 25-50% of patients relapse. To understand disease pathology and to uncover novel targets for therapy, we performed whole-exome sequencing of anaplastic lymphoma kinase (ALK)(+) ALCL, as well as gene-set enrichment analysis. This revealed that the T-cell receptor and Notch pathways were the most enriched in mutations. In particular, variant T349P of NOTCH1, which confers a growth advantage to cells in which it is expressed, was detected in 12% of ALK(+) and ALK(-) ALCL patients' samples. Furthermore, we demonstrated that NPM-ALK promotes NOTCH1 expression through binding of STAT3 upstream of NOTCH1. Moreover, inhibition of NOTCH1 with gamma-secretase inhibitors or silencing by short hairpin RNA leads to apoptosis; co-treatment in vitro with the ALK inhibitor crizotinib led to additive/synergistic antitumor activity suggesting that this may be an appropriate combination therapy for future use in the circumvention of ALK inhibitor resistance. Indeed, crizotinib-resistant and -sensitive ALCL were equally sensitive to gamma-secretase inhibitors. In conclusion, we show a variant in the extracellular domain of NOTCH1 that provides a growth advantage to cells and confirm the suitability of the Notch pathway as a second-line druggable target in ALK(+) ALCL.
ER  -

LAROSE, H.; N. PROKOPH; J.D. MATTHEWS; M. SCHLEDERER; S. HOGLER; A.F. ALSULAMI; S.P. DUCRAY; E. NUGLOZEH; M.F. FAZALUDEEN; A. ELMOUNA; M. CECCON; L. MOLOGNI; C. GAMBACORTI-PASSERINI; G. HOEFLER; Cosimo LOBELLO; Šárka POSPÍŠILOVÁ; A. JANIKOVA; W. WOESSMANN; C. DAMM-WELK; M. ZIMMERMANN; A. FEDOROVA; A. MALONE; O. SMITH; M. WASIK; G. INGHIRAMI; L. LAMANT; T.L. BLUNDELL; W. KLAPPER; O. MERKEL; G.A.A. BURKE; S. MIAN; I. ASHANKYTY; L. KENNER a Suzanne Dawn TURNER. Whole exome sequencing reveals NOTCH1 mutations in anaplastic large cell lymphoma and points to Notch both as a key pathway and a potential therapeutic target. \textit{haematologica}. PAVIA: FERRATA STORTI FOUNDATION, 2021, roč.~106, č.~6, s.~1693-1704. ISSN~0390-6078. Dostupné z: https://doi.org/10.3324/haematol.2019.238766.

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