Genetic evolution and relapse‐associated mutations in adult T‐cell acute lymphoblastic leukemia patients treated in PETHEMA trials
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 <i>N/KRAS</i> mutations (20% relapsed cases) at diagnosis and at relapse (resistance profile). <i>N/KRAS</i> <sup><i>mut</i></sup> patients frequently relapse early during consolidation treatment. Relapse-specific mutations in <i>NT5C2, NR3C1</i>, <i>SMARCA4</i>, and <i>TP53</i> (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 <i>NT5C2</i> 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%).
Authors
- Pau Montesinos (ORCID: https://orcid.org/0000-0002-3275-5593)
- María Vidal (ORCID: https://orcid.org/0000-0003-1992-5727)
- Carolina Martínez‐Laperche (ORCID: https://orcid.org/0000-0001-6802-3485)
- Mar Tormo (ORCID: https://orcid.org/0000-0001-9622-1649)
- Manel Esteller (ORCID: https://orcid.org/0000-0003-4490-6093)
- Lourdes Hermosín
- Ana Torres (ORCID: https://orcid.org/0000-0001-9074-1897)
- María‐Paz Queipo
- Marta Cervera (ORCID: https://orcid.org/0000-0002-6806-8736)
- Mireia Morgades (ORCID: https://orcid.org/0000-0003-0295-2534)
- Rosa Coll (ORCID: https://orcid.org/0000-0003-0560-1254)
- Eulàlia Genescà (ORCID: https://orcid.org/0000-0002-5657-4842)
- Pere Barba (ORCID: https://orcid.org/0000-0001-7076-7969)
- Teresa Artola
- Carlos Rodríguez Medina
- Celia González‐Gil
- Ferran Vall‐Llovera (ORCID: https://orcid.org/0000-0002-0718-5955)
- Antònia Cladera
- Francisco Fuster‐Tormo (ORCID: https://orcid.org/0000-0002-1220-6183)
- Teresa González‐Martínez (ORCID: https://orcid.org/0000-0002-3793-4865)
- Manuel Fernández‐Delgado (ORCID: https://orcid.org/0000-0003-3684-2712)
- Marina Díaz‐Beyá (ORCID: https://orcid.org/0000-0001-9624-2597)
- Anna Bigas (ORCID: https://orcid.org/0000-0003-4801-6899)
- Gemma Azaceta (ORCID: https://orcid.org/0000-0001-5068-7355)
- Clara Maluquer (ORCID: https://orcid.org/0000-0002-1278-6413)
- Rosa María Ayala (ORCID: https://orcid.org/0000-0002-2699-8353)
- José González‐Campos (ORCID: https://orcid.org/0000-0002-4892-067X)
- Josep‐María Ribera (ORCID: https://orcid.org/0000-0003-1042-6024)
- Lurdes Zamora (ORCID: https://orcid.org/0000-0003-1713-7110)
- Anna Torrent (ORCID: https://orcid.org/0000-0002-3727-5716)
- Alberto Órfão (ORCID: https://orcid.org/0000-0002-0007-7230)
- Jesús Feliu (ORCID: https://orcid.org/0000-0002-9630-8813)
- Marı́a José Calasanz (ORCID: https://orcid.org/0000-0002-0374-3008)
- Jordi Ribera (ORCID: https://orcid.org/0000-0003-4796-6470)
- Pilar Martínez‐Sánchez
- Thaysa Lopes
- M.C. Mateos
- Cristina Gil‐Cortés
Institutions
- Universitat Autònoma de Barcelona (ES)
- Universidad de Salamanca (ES)
- Hospital General Universitario Gregorio Marañón (ES)
- Hospital Universitari i Politècnic La Fe (ES)
- Hospital General De Segovia (ES)
- Hospital Son Llatzer (ES)
- Hospital Clínico Universitario de Valencia (ES)
- University Hospital Mútua de Terrassa (ES)
- Complejo Hospitalario de Navarra (ES)
- Hospital Universitario de Gran Canaria Doctor Negrín (ES)
- Complejo Hospitalario de Salamanca (ES)
- Hospital Universitario 12 De Octubre (ES)
- Hospital Clínic de Barcelona (ES)
- Hospital General Universitari de Castelló (ES)
- Vall d'Hebron Hospital Universitari (ES)
- Clinica Universidad de Navarra (ES)
- Hospital Clínico Universitario Lozano Blesa (ES)
- Hospital General Universitario de Alicante Doctor Balmis (ES)
- Hospital San Pedro (ES)
- Centro de Investigación del Cáncer (ES)
- Donostiako Unibertsitate Ospitalea (ES)
- Duran i Reynals Hospital (ES)
- Fundación Josep Carreras Contra la Leucemia (ES)
- Hospital Universitari Joan XXIII de Tarragona (ES)
- Hospital Universitario Virgen del Rocío (ES)
- Hospital Universitari Germans Trias i Pujol (ES)
- Hospital Jerez Puerta del Sur (ES)
- Hospital Universitari de Girona Doctor Josep Trueta (ES)
- Hospital del Mar Research Institute (ES)
- Hospital Clínico Universitario Virgen de la Victoria (ES)
- INCLIVA Health Research Institute (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Hospital Universitario de León (ES)
Publication Details
- Journal
- HemaSphere
- Published
- 2025-05-01
- DOI
- https://doi.org/10.1002/hem3.70148
- Primary Topic
- Acute Lymphoblastic Leukemia research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Centres de Recerca de Catalunya
- Generalitat de Catalunya
- José Carreras Leukämie-Stiftung
- Instituto de Salud Carlos III
- European Regional Development Fund
- European Social Fund