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HemaSphere - 2025 - González‐Gil - Genetic evolution and relapse‐associated mutations in adult T‐cell acute lymphoblastic.pdf (2.35 MB)

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2025-05-01

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cc by-nc-nd (c) González Gil, Celia et al, 2025
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/222138

Genetic evolution and relapse‐associated mutations in adult T‐cell acute lymphoblastic leukemia patients treated in PETHEMA trials

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https://doi.org/10.1002/hem3.70148

Resum

Relapse is the main cause of treatment failure in T-cell acute lymphoblastic leukemia (T-ALL). Despite this, data from adult T-ALL patients treated with specific chemotherapeutic regimens that examine predictive markers and describe relapse mechanisms are scarce. In this study, we studied 74 paired diagnosis-relapse samples from 37 patients homogeneously treated with three consecutive measurable residual disease-oriented trials to identify genetic determinants involved in relapse in adult T-ALL. Analysis of single-nucleotide variants and copy number alterations consistently found N/KRAS mutations (20% relapsed cases) at diagnosis and at relapse (resistance profile). N/KRASmut patients frequently relapse early during consolidation treatment. Relapse-specific mutations in NT5C2, NR3C1, SMARCA4, and TP53 (40% relapse cases) were not detected at diagnosis by conventional molecular techniques (relapse profile). However, single-cell-based analysis revealed a very minor clone containing the NT5C2(p.R367Q) variant at diagnosis. Patients with the NT5C2(p.R367Q) variant mostly relapse later during maintenance treatment. Tracking the NT5C2 variant by digital PCR confirm the expansion of the NT5C2 clone at maintenance treatment. Overall, our exploratory analysis suggests a role for these genetic events, most of which have already been described in pediatric cases, driving resistance associated to specific chemotherapeutic agents, contributing to the relapse of a high proportion of adult T-ALL patients (60%).

Matèries

Leucèmia, Teràpia cel·lular

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Leukemia, Cellular therapy

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Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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GONZÁLEZ GIL, Celia, LOPES, Thaysa, MORGADES, Mireia, FUSTER TORMO, Francisco, MONTESINOS, Pau, RODRÍGUEZ MEDINA, Carlos, HERMOSÍN, Lourdes, GONZÁLEZ MARTÍNEZ, Teresa, QUEIPO DE LLANO, María paz, GONZÁLEZ CAMPOS, José, MARTÍNEZ SÁNCHEZ, Pilar, DÍAZ BEYA, Marina, COLL, Rosa, MALUQUER, Clara, ZAMORA, Lurdes, ARTOLA, Teresa, VALL LLOVERA, Ferran, TORMO, Mar, TORRENT, Anna, MARTÍNEZ LAPERCHE, Carolina, GIL CORTÉS, Cristina, BARBA, Pere, CERVERA, Marta, RIBERA, Jordi, FERNÁNDEZ DELGADO, Manuel, AYALA, Rosa, CLADERA, Antonia, MATEOS, María carmen, VIDAL, María jesús, FELIU, Jesús, TORRES, Ana, AZACETA, Gemma, JOSÉ CALASANZ, María, BIGAS, Anna, ESTELLER, Manel, ORFAO, Alberto, RIBERA, Josep maria, GENESCÀ, Eulalia. Genetic evolution and relapse‐associated mutations in adult T‐cell acute lymphoblastic leukemia patients treated in PETHEMA trials. _HemaSphere_. 2025. Vol. 9, núm. 5. [consulta: 23 de gener de 2026]. ISSN: 2572-9241. [Disponible a: https://hdl.handle.net/2445/222138]

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