Portal de investigación
TRAF3 alterations are frequent in del-3 ' IGH chronic lymphocytic leukemia patients and define a specific subgroup with adverse clinical features
Fecha de publicación:
Fecha Ahead of Print:
Autores de IBSAL
Autores ajenos a IBSAL
- Perez-Carretero, C
- Hernandez-Sanchez, M
- Quijada-Alamo, M
- Martin-Izquierdo, M
- Miguel-Garcia, C
- Vidal, MJ
- Garcia-De-Coca, A
- Galende, J
- Pardal, E
- Aguilar, C
- Vargas-Pabon, M
- Davila, J
- Gascon-Y-Marin, I
- Rodriguez-Vicente, AE
Grupos
Abstract
Interstitial 14q32 deletions involving IGH gene are infrequent events in chronic lymphocytic leukemia (CLL), affecting less than 5% of patients. To date, little is known about their clinical impact and molecular underpinnings, and its mutational landscape is currently unknown. In this work, a total of 871 CLLs were tested for the IGH break-apart probe, and 54 (6.2%) had a 300 kb deletion of 3 ' IGH (del-3 ' IGH CLLs), which contributed to a shorter time to first treatment (TFT). The mutational analysis by next-generation sequencing of 317 untreated CLLs (54 del-3 ' IGH and 263 as the control group) showed high mutational frequencies of NOTCH1 (30%), ATM (20%), genes involved in the RAS signaling pathway (BRAF, KRAS, NRAS, and MAP2K1) (15%), and TRAF3 (13%) within del-3 ' IGH CLLs. Notably, the incidence of TRAF3 mutations was significantly higher in del-3 ' IGH CLLs than in the control group (p < .001). Copy number analysis also revealed that TRAF3 loss was highly enriched in CLLs with 14q deletion (p < .001), indicating a complete biallelic inactivation of this gene through deletion and mutation. Interestingly, the presence of mutations in the aforementioned genes negatively refined the prognosis of del-3 ' IGH CLLs in terms of overall survival (NOTCH1, ATM, and RAS signaling pathway genes) and TFT (TRAF3). Furthermore, TRAF3 biallelic inactivation constituted an independent risk factor for TFT in the entire CLL cohort. Altogether, our work demonstrates the distinct genetic landscape of del-3 ' IGH CLL with multiple molecular pathways affected, characterized by a TRAF3 biallelic inactivation that contributes to a marked poor outcome in this subgroup of patients.
Datos de la publicación
- ISSN/ISSNe:
- 0361-8609, 1096-8652
- Tipo:
- Article
- Páginas:
- 903-914
- DOI:
- 10.1002/ajh.26578
AMERICAN JOURNAL OF HEMATOLOGY WILEY-BLACKWELL
Citas Recibidas en Web of Science: 4
Documentos
- No hay documentos
Filiaciones
Financiación
Proyectos asociados
Red Temática de Investigación Cooperativa en Cáncer (RTICC)
Investigador Principal: Marcos González Díaz
RD12/0036/0069 . Instituto de Salud Carlos III . 2013
Estudio genómico y funcional de la concurrencia de alteraciones genéticas y de la resistencia a fármacos en pacientes de leucemia linfática crónica mediante modelos celulares y animales
Investigador Principal: Jesús María Hernández Rivas
PI18/01500 . Instituto de Salud Carlos III . 2019
Integration of multi-omic profiling and CRISPR/Cas9 screens for the assessment of therapeutic vulnerabilities and resistances in intermediate-high risk chronic lymphocytic leukemia
Investigador Principal: Jesús María Hernández Rivas
PI21/00983 . Instituto de Salud Carlos III . 2022
Identificación de pacientes con leucemia aguda linfoblástica B (LALB) con perfil Ph-like mediante secuenciación masiva de alto rendimiento. Nuevos retos en el manejo del enfermo
Investigador Principal: Jesús María Hernández Rivas
GRS2385/A/21 . Gerencia Regional de Salud de Castilla y León (GRS) . 2022
Cita
Perez C,Hernandez M,Gonzalez T,Quijada M,Martin M,Santos S,Miguel C,Vidal MJ,Garcia A,Galende J,Pardal E,Aguilar C,Vargas M,Davila J,Gascon I,Hernandez JA,Benito R,Hernandez JM,Rodriguez AE. TRAF3 alterations are frequent in del-3 ' IGH chronic lymphocytic leukemia patients and define a specific subgroup with adverse clinical features. Am J Hematol. 2022. 97. (7):p. 903-914. IF:12,800. (1).