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

Birna Thorvaldsdottir; 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-Vicente; Rocío Benito; Gian Matteo Rigolin; Silvia Bonfiglio; Lydia Scarfò; Mattias Mattsson; Zadie Davis; Panagiotis Baliakas; Inmaculada Rapado; Fatima Miras; Joaquín Martinez-Lopez; Javier de la Serna; Jesús María Hernández Rivas; 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-Sánchez; Sarka Pospisilova; Gianluca Gaidano; Carsten U. Niemann; Elias Campo; Jonathan C. Strefford; Paolo Ghia; Kostas Stamatopoulos; Richard Rosenquist

doi:10.1038/s41375-025-02615-5

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

Birna Thorvaldsdottir
, 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-Vicente
, Rocío Benito
, Gian Matteo Rigolin
, Silvia Bonfiglio
, Lydia Scarfò
, Mattias Mattsson
, Zadie Davis
, Panagiotis Baliakas

Inmaculada Rapado, Fatima Miras, Joaquín Martinez-Lopez, Javier de la Serna, Jesús María Hernández Rivas, 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-Sánchez, Sarka Pospisilova, Gianluca Gaidano, Carsten U. Niemann, Elias Campo, Jonathan C. Strefford, Paolo Ghia, Kostas Stamatopoulos, Richard Rosenquist

Dipartimento di Medicina Traslazionale

Risultato della ricerca: Contributo su rivista › Articolo in rivista › peer review

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.

Lingua originale	Inglese
pagine (da-a)	1650-1660
Numero di pagine	11
Rivista	Leukemia
Volume	39
Numero di pubblicazione	7
DOI	https://doi.org/10.1038/s41375-025-02615-5
Stato di pubblicazione	Pubblicato - lug 2025

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Thorvaldsdottir, B., Mansouri, L., Sutton, L. A., Nadeu, F., Meggendorfer, M., Parker, H., Brieghel, C., Laidou, S., Moia, R., Rossi, D., Kotaskova, J., Delgado, J., Rodríguez-Vicente, A. E., Benito, R., Rigolin, G. M., Bonfiglio, S., Scarfò, L., Mattsson, M., Davis, Z., ... Rosenquist, R. (2025). ATM aberrations in chronic lymphocytic leukemia: del(11q) rather than ATM mutations is an adverse-prognostic biomarker. Leukemia, 39(7), 1650-1660. https://doi.org/10.1038/s41375-025-02615-5

@article{454afb971c744c2d8a409214f1ebdfb0,

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

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.",

author = "Birna Thorvaldsdottir and Larry Mansouri and Sutton, \{Lesley Ann\} and Ferran Nadeu and Manja Meggendorfer and Helen Parker and Christian Brieghel and Stamatia Laidou and Riccardo Moia and Davide Rossi and Jana Kotaskova and Julio Delgado and Rodr{\'i}guez-Vicente, \{Ana E.\} and Roc{\'i}o Benito and Rigolin, \{Gian Matteo\} and Silvia Bonfiglio and Lydia Scarf{\`o} and Mattias Mattsson and Zadie Davis and Panagiotis Baliakas and Inmaculada Rapado and Fatima Miras and Joaqu{\'i}n Martinez-Lopez and \{de la Serna\}, Javier and \{Hern{\'a}ndez Rivas\}, \{Jes{\'u}s Mar{\'i}a\} and Larr{\'a}yoz, \{Mar{\'i}a Jos{\'e}\} and Calasanz, \{Mar{\'i}a Jos{\'e}\} and Smedby, \{Karin E.\} and Blanca Espinet and Anna Puiggros and Lars Bullinger and Francesc Bosch and B{\'a}rbara Taz{\'o}n-Vega and Fanny Baran-Marszak and David Oscier and Florence Nguyen-Khac and Thorsten Zenz and Terol, \{Maria Jose\} and Antonio Cuneo and Mar{\'i}a Hern{\'a}ndez-S{\'a}nchez and Sarka Pospisilova and Gianluca Gaidano and Niemann, \{Carsten U.\} and Elias Campo and Strefford, \{Jonathan C.\} and Paolo Ghia and Kostas Stamatopoulos and Richard Rosenquist",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = jul,

doi = "10.1038/s41375-025-02615-5",

language = "English",

volume = "39",

pages = "1650--1660",

journal = "Leukemia",

issn = "0887-6924",

publisher = "Springer Nature",

number = "7",

}

Thorvaldsdottir, B, Mansouri, L, Sutton, LA, Nadeu, F, Meggendorfer, M, Parker, H, Brieghel, C, Laidou, S, Moia, R, Rossi, D, Kotaskova, J, Delgado, J, Rodríguez-Vicente, AE, Benito, R, Rigolin, GM, Bonfiglio, S, Scarfò, L, Mattsson, M, Davis, Z, Baliakas, P, Rapado, I, Miras, F, Martinez-Lopez, J, de la Serna, J, Hernández Rivas, JM, Larráyoz, MJ, Calasanz, MJ, Smedby, KE, Espinet, B, Puiggros, A, Bullinger, L, Bosch, F, Tazón-Vega, B, Baran-Marszak, F, Oscier, D, Nguyen-Khac, F, Zenz, T, Terol, MJ, Cuneo, A, Hernández-Sánchez, M, Pospisilova, S, Gaidano, G, Niemann, CU, Campo, E, Strefford, JC, Ghia, P, Stamatopoulos, K & Rosenquist, R 2025, 'ATM aberrations in chronic lymphocytic leukemia: del(11q) rather than ATM mutations is an adverse-prognostic biomarker', Leukemia, vol. 39, n. 7, pagg. 1650-1660. https://doi.org/10.1038/s41375-025-02615-5

TY - JOUR

T1 - ATM aberrations in chronic lymphocytic leukemia

T2 - del(11q) rather than ATM mutations is an adverse-prognostic biomarker

AU - Thorvaldsdottir, Birna

AU - Mansouri, Larry

AU - Sutton, Lesley Ann

AU - Nadeu, Ferran

AU - Meggendorfer, Manja

AU - Parker, Helen

AU - Brieghel, Christian

AU - Laidou, Stamatia

AU - Moia, Riccardo

AU - Rossi, Davide

AU - Kotaskova, Jana

AU - Delgado, Julio

AU - Rodríguez-Vicente, Ana E.

AU - Benito, Rocío

AU - Rigolin, Gian Matteo

AU - Bonfiglio, Silvia

AU - Scarfò, Lydia

AU - Mattsson, Mattias

AU - Davis, Zadie

AU - Baliakas, Panagiotis

AU - Rapado, Inmaculada

AU - Miras, Fatima

AU - Martinez-Lopez, Joaquín

AU - de la Serna, Javier

AU - Hernández Rivas, Jesús María

AU - Larráyoz, María José

AU - Calasanz, María José

AU - Smedby, Karin E.

AU - Espinet, Blanca

AU - Puiggros, Anna

AU - Bullinger, Lars

AU - Bosch, Francesc

AU - Tazón-Vega, Bárbara

AU - Baran-Marszak, Fanny

AU - Oscier, David

AU - Nguyen-Khac, Florence

AU - Zenz, Thorsten

AU - Terol, Maria Jose

AU - Cuneo, Antonio

AU - Hernández-Sánchez, María

AU - Pospisilova, Sarka

AU - Gaidano, Gianluca

AU - Niemann, Carsten U.

AU - Campo, Elias

AU - Strefford, Jonathan C.

AU - Ghia, Paolo

AU - Stamatopoulos, Kostas

AU - Rosenquist, Richard

PY - 2025/7

Y1 - 2025/7

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105003449208

U2 - 10.1038/s41375-025-02615-5

DO - 10.1038/s41375-025-02615-5

M3 - Article

SN - 0887-6924

VL - 39

SP - 1650

EP - 1660

JO - Leukemia

JF - Leukemia

IS - 7

ER -

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

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