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

• DOI: 10.1038/s41375-025-02615-5
• Publication Date: 2025-04-24T09:30:53Z
• Authors: Birna Thorvaldsdo...; Larry Mansouri; Lesley-Ann Sutton; Ferran Nadeu; Manja Meggendorfer; Helen Parker; Christian Brieghel; Stamatia Laidou; Riccardo Moia; Davide Rossi; Jana Kotaskova; Julio Delgado; Ana E. Rodríguez-...; Rocío Benito; Gian Matteo Rigolin; Silvia Bonfiglio; Lydia Scarfò; Mattias Mattsson; Zadie Davis; Panagiotis Baliakas; Inmaculada Rapado; Fatima Miras; Joaquín Martinez-...; Javier de la Serna; Jesús María Herná...; María José Larráyoz; María 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; Maria Jose Terol; Antonio Cuneo; María Hernández-S...; Sarka Pospisilova; Gianluca Gaidano; Carsten U. Niemann; Elias Campo; Jonathan C. Stref...; Paolo Ghia; Kostas Stamatopoulos; Richard Rosenquist

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.