Quijada‐álamo, Miguel, Pérez‐carretero, Claudia, Hernández‐sánchez, María, Rodríguez‐vicente, Ana‐eugenia, Herrero, Ana‐belén, Hernández‐sánchez, Jesús‐maría, Martín‐izquierdo, Marta, Santos‐mínguez, Sandra, Del Rey, Mónica, González, Teresa, Rubio‐martínez, Araceli, García De Coca, Alfonso, Dávila‐valls, Julio, Hernández‐rivas, José‐ángel, Parker, Helen, Strefford, Jonathan C., Benito, Rocío, Ordóñez, José‐luis and Hernández‐rivas, Jesús‐maría (2021) Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia. Clinical and Translational Medicine, 11 (2), e304, [e304]. (doi:10.1002/ctm2.304).
Abstract
Background: Several genetic alterations have been identified as driver events
in chronic lymphocytic leukemia (CLL) pathogenesis and oncogenic evolution.
Concurrent driver alterations usually coexist within the same tumoral clone,
but how the cooperation of multiple genomic abnormalities contributes to disease
progression remains poorly understood. Specifically, the biological and clinical
consequences of concurrent high-risk alterations such as del(11q)/ATMmutations
and del(17p)/TP53-mutations have not been established.
Methods:We integrated next-generation sequencing (NGS) and clustered regularly
interspaced short palindromic repeats (CRISPR)/Cas9 techniques to characterize
the in vitro and in vivo effects of concurrent monoallelic or biallelic
ATM and/or TP53 alterations in CLL prognosis, clonal evolution, and therapy
response.
Results: Targeted sequencing analysis of the co-occurrence of high-risk alterations
in 271 CLLs revealed that biallelic inactivation of both ATM and TP53 was
mutually exclusive, whereas monoallelic del(11q) and TP53 alterations significantly
co-occurred in a subset of CLL patients with a highly adverse clinical outcome.
We determined the biological effects of combined del(11q), ATM and/or
TP53 mutations in CRISPR/Cas9-edited CLL cell lines. Our results showed that
the combination of monoallelic del(11q) and TP53 mutations in CLL cells led
to a clonal advantage in vitro and in in vivo clonal competition experiments,
whereas CLL cells harboring biallelic ATM and TP53 loss failed to compete in
in vivo xenotransplants. Furthermore, we demonstrated that CLL cell lines harboring
del(11q) and TP53 mutations show only partial responses to B cell receptor
signaling inhibitors, but may potentially benefit from ATR inhibition.
Conclusions: Ourwork highlights that combinedmonoallelic del(11q) and TP53
alterations coordinately contribute to clonal advantage and shorter overall survival
in CLL.
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