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

作者：Birna Þorvaldsdóttir, Larry Mansouri, Lesley‐Ann Sutton, Ferran Nadeu, Manja Meggendorfer, Helen Parker, Christian Brieghel, Stamatia Laidou, Riccardo Moia, Davide Rossi, Jana Kotašková, Julio Delgado, Ana E. Rodríguez‐Vicente, Rocí­o Benito, Gian Matteo Rigolin, Silvia Bonfiglio, Lydia Scarfò, Mattias Mattsson, Zadie Davis, Panagiotis Baliakas, Inmaculada Rapado, Fátima Mirás, Joaquín Martínez‐López, Javier de la Serna, Jesús María Hernández‐Rivas, María José Larráyoz, Marı́a José Calasanz, Karin E. Smedby, Blanca Espinet, Anna Puiggros, Lars Bullinger, Francesc Bosch, Bárbara Tazón‐Vega, Fanny Baran‐Marszak, David Oscier, Florence Nguyen‐Khac, Thorsten Zenz, María José Terol, Antonio Cuneo, María Hernández‐Sánchez, Šárka Pospı́šilová, Gianluca Gaïdano, Carsten Utoft Niemann, Elı́as Campo, Jonathan C. Strefford, Paolo Ghia, Κώστας Σταματόπουλος, Richard Rosenquist · 发表于：Leukemia · 年份：2025 · DOI：10.1038/s41375-025-02615-5 · 被引用次数：5 · 研究领域：Chronic Lymphocytic Leukemia Research、Immunodeficiency and Autoimmune Disorders、Lymphoma Diagnosis and Treatment

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.