ATM aberrations in chronic lymphocytic leukemia: del(11q) rather than ATM mutations is an adverse-prognostic biomarker

Despite the well-established adverse impact of del(11q) in chronic lymphocytic leukemia (CLL), the prognostic significance of somatic ATM mutations remains uncertain. We evaluated the effects of ATM aberrations (del(11q) and/or ATM mutations) on time-to-first-treatment (TTFT) in 3631 untreated patients with CLL, in the context of IGHV gene mutational status and mutations in nine CLL-related genes. ATM mutations were present in 246 cases (6.8%), frequently co-occurring with del(11q) (112/246 cases, 45.5%). ATM-mutated patients displayed a different spectrum of genetic abnormalities when comparing IGHV-mutated (M-CLL) and unmutated (U-CLL) cases: M-CLL was enriched for SF3B1 and NFKBIE mutations, whereas U-CLL showed mutual exclusivity with trisomy 12 and TP53 mutations. Isolated ATM mutations were rare, affecting 1.2% of Binet A patients and <1% of M-CLL cases. While univariable analysis revealed shorter TTFT for Binet A patients with any ATM aberration compared to ATM-wildtype, multivariable analysis identified only del(11q), trisomy 12, SF3B1, and EGR2 mutations as independent prognosticators of shorter TTFT among Binet A patients and within M-CLL and U-CLL subgroups. These findings highlight del(11q), and not ATM mutations, as a key biomarker of increased risk of early progression and need for therapy, particularly in otherwise indolent M-CLL, providing insights into risk-stratification and therapeutic decision-making.

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Journal
Leukemia
Published
2025-04-24
DOI
https://doi.org/10.1038/s41375-025-02615-5
Primary Topic
Chronic Lymphocytic Leukemia Research
Type
article
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article

ATM aberrations in chronic lymphocytic leukemia: del(11q) rather than ATM mutations is an adverse-prognostic biomarker

Thorsten Zenz, Ana E. Rodríguez‐Vicente, Julio Delgado, Fanny Baran‐Marszak et al.
Leukemia
Chronic Lymphocytic Leukemia Research
article

ATM aberrations in chronic lymphocytic leukemia: del(11q) rather than ATM mutations is an adverse-prognostic biomarker

Thorsten Zenz, Ana E. Rodríguez‐Vicente, Julio Delgado, Fanny Baran‐Marszak, Florence Nguyen‐Khac, Davide Rossi, Richard Rosenquist, Fátima Mirás, Mattias Mattsson, Inmaculada Rapado, Riccardo Moia, Stamatia Laidou, Christian Brieghel, Elı́as Campo, Lydia Scarfò, Joaquín Martínez‐López, Jesús María Hernández‐Rivas, Gian Matteo Rigolin, Silvia Bonfiglio, Panagiotis Baliakas, María José Larráyoz, Lars Bullinger, Manja Meggendorfer, Gianluca Gaïdano, Κώστας Σταματόπουλος, Jonathan C. Strefford, Bárbara Tazón‐Vega, María Hernández‐Sánchez, Zadie Davis, Larry Mansouri, Francesc Bosch, Ferran Nadeu, Blanca Espinet, Carsten Utoft Niemann, Helen Parker, María José Terol, Jana Kotašková, Šárka Pospı́šilová, Anna Puiggros, Rocí­o Benito, Javier de la Serna, Birna Þorvaldsdóttir, Paolo Ghia, Lesley‐Ann Sutton, Karin E. Smedby, Marı́a José Calasanz, David Oscier, Antonio Cuneo
article en

Abstract

Despite the well-established adverse impact of del(11q) in chronic lymphocytic leukemia (CLL), the prognostic significance of somatic ATM mutations remains uncertain. We evaluated the effects of ATM aberrations (del(11q) and/or ATM mutations) on time-to-first-treatment (TTFT) in 3631 untreated patients with CLL, in the context of IGHV gene mutational status and mutations in nine CLL-related genes. ATM mutations were present in 246 cases (6.8%), frequently co-occurring with del(11q) (112/246 cases, 45.5%). ATM-mutated patients displayed a different spectrum of genetic abnormalities when comparing IGHV-mutated (M-CLL) and unmutated (U-CLL) cases: M-CLL was enriched for SF3B1 and NFKBIE mutations, whereas U-CLL showed mutual exclusivity with trisomy 12 and TP53 mutations. Isolated ATM mutations were rare, affecting 1.2% of Binet A patients and <1% of M-CLL cases. While univariable analysis revealed shorter TTFT for Binet A patients with any ATM aberration compared to ATM-wildtype, multivariable analysis identified only del(11q), trisomy 12, SF3B1, and EGR2 mutations as independent prognosticators of shorter TTFT among Binet A patients and within M-CLL and U-CLL subgroups. These findings highlight del(11q), and not ATM mutations, as a key biomarker of increased risk of early progression and need for therapy, particularly in otherwise indolent M-CLL, providing insights into risk-stratification and therapeutic decision-making.

LeukemiaVol. 39(7)
Universidad Complutense de Madrid (ES), Universitat Autònoma de Barcelona (ES), Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT), Uppsala University (SE), University of Copenhagen (DK), Central European Institute of Technology (CZ), Karolinska University Hospital (SE), Vita-Salute San Raffaele University (IT), Universitat de València (ES), Universidad de Salamanca (ES), University of Ferrara (IT), University of Zurich (CH), Masaryk University (CZ), Copenhagen University Hospital (DK), Rigshospitalet (DK), Karolinska Institutet (SE), Humboldt-Universität zu Berlin (DE), Sorbonne Université (FR), Spanish National Cancer Research Centre (ES), Central European Institute of Technology – Masaryk University (CZ), Munich Leukemia Laboratory (Germany) (DE), Ente Ospedaliero Cantonale (CH), Assistance Publique – Hôpitaux de Paris (FR), University Hospital of Zurich (CH), Hospital Universitario 12 De Octubre (ES), University Hospital Brno (CZ), Navarre Institute of Health Research (ES), Hospital Clínic de Barcelona (ES), Vall d'Hebron Hospital Universitari (ES), Hôpital Avicenne (FR), Hospital Del Mar (ES), IRCCS Ospedale San Raffaele (IT), Instituto de Investigación Biomédica de Salamanca (ES), Centre for Research and Technology Hellas (GR), Centro de Investigación del Cáncer (ES), Danish Cancer Society (DK), INCLIVA Health Research Institute (ES), Centro de Investigación Biomédica en Red de Cáncer (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), University of Southampton (GB), Università della Svizzera italiana (CH), Universitat de Barcelona (ES), Universidad de Navarra (ES), Bournemouth University (GB)
American Association for Cancer Research, Amgen, Cancer Research UK, European Commission, Cancerfonden, Karolinska Institutet, Vetenskapsrådet, Associazione Italiana per la Ricerca sul Cancro, Università degli Studi di Ferrara, Radiumhemmets Forskningsfonder, Associazione Italiana Contro le Leucemie-Linfomi e Mieloma, Instituto de Salud Carlos III
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Chronic Lymphocytic Leukemia Research
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