Recurrent somatic mutations of FAT family cadherins induce an
aggressive phenotype and poor prognosis in anaplastic large
cell lymphoma

J 2024

Recurrent somatic mutations of FAT family cadherins induce an aggressive phenotype and poor prognosis in anaplastic large cell lymphoma

VILLA, Matteo; Geeta G SHARMA; Federica MALIGHETTI; Mario MAURI; Giulia AROSIO et al.

Základní údaje

Originální název

Recurrent somatic mutations of FAT family cadherins induce an aggressive phenotype and poor prognosis in anaplastic large cell lymphoma

Autoři

Vydání

British journal of cancer, LONDON, NATURE PUBLISHING GROUP, 2024, 0007-0920

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30205 Hematology

Stát vydavatele

Velká Británie a Severní Irsko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 6.800

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14110/24:00137749

Organizační jednotka

Lékařská fakulta

Klíčová slova anglicky

FAT cadherins; somatic mutations; anaplastic large cell lymphoma; aggressive phenotype; poor prognosis

Štítky

14110212, 14110323, podil, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 22. 4. 2025 12:32, Mgr. Tereza Miškechová

Anotace

V originále

BackgroundAnaplastic Large Cell Lymphoma (ALCL) is a rare and aggressive T-cell lymphoma, classified into ALK-positive and ALK-negative subtypes, based on the presence of chromosomal translocations involving the ALK gene. The current standard of treatment for ALCL is polychemotherapy, with a high overall survival rate. However, a subset of patients does not respond to or develops resistance to these therapies, posing a serious challenge for clinicians. Recent targeted treatments such as ALK kinase inhibitors and anti-CD30 antibody-drug conjugates have shown promise but, for a fraction of patients, the prognosis is still unsatisfactory.MethodsWe investigated the genetic landscape of ALK + ALCL by whole-exome sequencing; recurring mutations were characterized in vitro and in vivo using transduced ALCL cellular models.ResultsRecurrent mutations in FAT family genes and the transcription factor RUNX1T1 were found. These mutations induced changes in ALCL cells morphology, growth, and migration, shedding light on potential factors contributing to treatment resistance. In particular, FAT4 silencing in ALCL cells activated the beta-catenin and YAP1 pathways, which play crucial roles in tumor growth, and conferred resistance to chemotherapy. Furthermore, STAT1 and STAT3 were hyper-activated in these cells. Gene expression profiling showed global changes in pathways related to cell adhesion, cytoskeletal organization, and oncogenic signaling. Notably, FAT mutations associated with poor outcome in patients.ConclusionsThese findings provide novel insights into the molecular portrait of ALCL, that could help improve treatment strategies and the prognosis for ALCL patients.

Návaznosti

LX22NPO5102, projekt VaV

Název: Národní ústav pro výzkum rakoviny (Akronym: NÚVR)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Národní ústav pro výzkum rakoviny, 5.1 EXCELES

Přiložené soubory

Recurrent_somatic_mutations_of_FAT_family_cadherins_induce_an_aggressive_phenotype_and_poor_prognosis_in_anaplastic_large_cell_lymphoma.pdf

Citovat

VILLA, Matteo; Geeta G SHARMA; Federica MALIGHETTI; Mario MAURI; Giulia AROSIO; Nicoletta CORDANI; Cosimo LOBELLO; Hugo LAROSE; Alessandra PIROLA; Deborah D'ALIBERTI; Luca MASSIMINO; Lucrezia CRISCUOLO; Lisa PAGANI; Clizia CHINELLO; Cristina MASTINI; Diletta FONTANA; Silvia BOMBELLI; Raffaella MENEVERI; Federica LOVISA; Lara MUSSOLIN; Andrea JANÍKOVÁ; Šárka POSPÍŠILOVÁ; Suzanne Dawn TURNER; Giorgio INGHIRAMI; Fulvio MAGNI; Mario URSO; Fabio PAGNI; Daniele RAMAZZOTTI; Rocco PIAZZA; Roberto CHIARLE; Carlo GAMBACORTI-PASSERINI a Luca MOLOGNI. Recurrent somatic mutations of FAT family cadherins induce an aggressive phenotype and poor prognosis in anaplastic large cell lymphoma. British journal of cancer. LONDON: NATURE PUBLISHING GROUP, 2024, roč. 131, č. 11, s. 1781-1795. ISSN 0007-0920. Dostupné z: https://doi.org/10.1038/s41416-024-02881-7.

@article{2454743,
   author = {Villa, Matteo and Sharma, Geeta G and Malighetti, Federica and Mauri, Mario and Arosio, Giulia and Cordani, Nicoletta and Lobello, Cosimo and Larose, Hugo and Pirola, Alessandra and D'Aliberti, Deborah and Massimino, Luca and Criscuolo, Lucrezia and Pagani, Lisa and Chinello, Clizia and Mastini, Cristina and Fontana, Diletta and Bombelli, Silvia and Meneveri, Raffaella and Lovisa, Federica and Mussolin, Lara and Janíková, Andrea and Pospíšilová, Šárka and Turner, Suzanne Dawn and Inghirami, Giorgio and Magni, Fulvio and Urso, Mario and Pagni, Fabio and Ramazzotti, Daniele and Piazza, Rocco and Chiarle, Roberto and GambacortiandPasserini, Carlo and Mologni, Luca},
   article_location = {LONDON},
   article_number = {11},
   doi = {https://doi.org/10.1038/s41416-024-02881-7},
   keywords = {FAT cadherins; somatic mutations; anaplastic large cell lymphoma; aggressive phenotype; poor prognosis},
   language = {eng},
   issn = {0007-0920},
   journal = {British journal of cancer},
   title = {Recurrent somatic mutations of FAT family cadherins induce an aggressive phenotype and poor prognosis in anaplastic large cell lymphoma},
   url = {https://www.nature.com/articles/s41416-024-02881-7},
   volume = {131},
   year = {2024}
}

TY  - JOUR
ID  - 2454743
AU  - Villa, Matteo - Sharma, Geeta G - Malighetti, Federica - Mauri, Mario - Arosio, Giulia - Cordani, Nicoletta - Lobello, Cosimo - Larose, Hugo - Pirola, Alessandra - D'Aliberti, Deborah - Massimino, Luca - Criscuolo, Lucrezia - Pagani, Lisa - Chinello, Clizia - Mastini, Cristina - Fontana, Diletta - Bombelli, Silvia - Meneveri, Raffaella - Lovisa, Federica - Mussolin, Lara - Janíková, Andrea - Pospíšilová, Šárka - Turner, Suzanne Dawn - Inghirami, Giorgio - Magni, Fulvio - Urso, Mario - Pagni, Fabio - Ramazzotti, Daniele - Piazza, Rocco - Chiarle, Roberto - Gambacorti-Passerini, Carlo - Mologni, Luca
PY  - 2024
TI  - Recurrent somatic mutations of FAT family cadherins induce an aggressive phenotype and poor prognosis in anaplastic large cell lymphoma
JF  - British journal of cancer
VL  - 131
IS  - 11
SP  - 1781-1795
EP  - 1781-1795
PB  - NATURE PUBLISHING GROUP
SN  - 00070920
KW  - FAT cadherins
KW  - somatic mutations
KW  - anaplastic large cell lymphoma
KW  - aggressive phenotype
KW  - poor prognosis
UR  - https://www.nature.com/articles/s41416-024-02881-7
N2  - BackgroundAnaplastic Large Cell Lymphoma (ALCL) is a rare and aggressive T-cell lymphoma, classified into ALK-positive and ALK-negative subtypes, based on the presence of chromosomal translocations involving the ALK gene. The current standard of treatment for ALCL is polychemotherapy, with a high overall survival rate. However, a subset of patients does not respond to or develops resistance to these therapies, posing a serious challenge for clinicians. Recent targeted treatments such as ALK kinase inhibitors and anti-CD30 antibody-drug conjugates have shown promise but, for a fraction of patients, the prognosis is still unsatisfactory.MethodsWe investigated the genetic landscape of ALK + ALCL by whole-exome sequencing; recurring mutations were characterized in vitro and in vivo using transduced ALCL cellular models.ResultsRecurrent mutations in FAT family genes and the transcription factor RUNX1T1 were found. These mutations induced changes in ALCL cells morphology, growth, and migration, shedding light on potential factors contributing to treatment resistance. In particular, FAT4 silencing in ALCL cells activated the beta-catenin and YAP1 pathways, which play crucial roles in tumor growth, and conferred resistance to chemotherapy. Furthermore, STAT1 and STAT3 were hyper-activated in these cells. Gene expression profiling showed global changes in pathways related to cell adhesion, cytoskeletal organization, and oncogenic signaling. Notably, FAT mutations associated with poor outcome in patients.ConclusionsThese findings provide novel insights into the molecular portrait of ALCL, that could help improve treatment strategies and the prognosis for ALCL patients.
ER  -

VILLA, Matteo; Geeta G SHARMA; Federica MALIGHETTI; Mario MAURI; Giulia AROSIO; Nicoletta CORDANI; Cosimo LOBELLO; Hugo LAROSE; Alessandra PIROLA; Deborah D'ALIBERTI; Luca MASSIMINO; Lucrezia CRISCUOLO; Lisa PAGANI; Clizia CHINELLO; Cristina MASTINI; Diletta FONTANA; Silvia BOMBELLI; Raffaella MENEVERI; Federica LOVISA; Lara MUSSOLIN; Andrea JANÍKOVÁ; Šárka POSPÍŠILOVÁ; Suzanne Dawn TURNER; Giorgio INGHIRAMI; Fulvio MAGNI; Mario URSO; Fabio PAGNI; Daniele RAMAZZOTTI; Rocco PIAZZA; Roberto CHIARLE; Carlo GAMBACORTI-PASSERINI a Luca MOLOGNI. Recurrent somatic mutations of FAT family cadherins induce an aggressive phenotype and poor prognosis in anaplastic large cell lymphoma. \textit{British journal of cancer}. LONDON: NATURE PUBLISHING GROUP, 2024, roč.~131, č.~11, s.~1781-1795. ISSN~0007-0920. Dostupné z: https://doi.org/10.1038/s41416-024-02881-7.

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