Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia

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)/ATM‐mutations 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 Our work highlights that combined monoallelic del(11q) and TP53 alterations coordinately contribute to clonal advantage and shorter overall survival in CLL.

Utilization of CRISPR-Mediated Tools for Studying Functional Genomics in Hematological Malignancies: An Overview on the Current Perspectives, Challenges, and Clinical Implications

“…Further study also confirms the reliability of this method as TP53 and ATM mutation never co-occurred in patient with CLL (Quijada-Álamo et al, 2021a). Targeting of CLL with del (11q) and ATM mutation was also proven to be more effective with BCR or PARP inhibitors, thus further supporting that direct targeting of both TP53 and ATM is favorable in CLL aberration (Quijada-Álamo et al, 2020).…”

“…Furthermore, downstream identification of targets for leukemia treatment could also be streamlined with this strategy. This has been exemplified in the generation of a CLL line with complete biallelic loss of the ATM gene function to mimic this adverse prognosis state found in approximately 1/3 of patients (Quijada-Álamo et al, 2020). Furthermore, drug screening revealed a previously unknown susceptibility of del (11q)/ATM-mutant to inhibition of PARP and BCR.…”

The Evolving Landscape of Chronic Lymphocytic Leukemia on Diagnosis, Prognosis and Treatment

“…Unlike the TP53 -altered cases, a poor prognosis due to ATM alterations might be overcome by the administration of novel agents such as ibrutinib in treatment-naïve patients, as well as in CIT-relapsed/refractory patients [ 111 , 112 , 113 , 114 ]. Nonetheless, ibrutinib-relapsed/refractory patients with these alterations exhibit an inferior outcome, demonstrating the necessity of new combination therapies [ 115 , 116 , 117 , 118 ].…”

“…Associations between trisomy 12 and NOTCH1 mutations, as well as the deletion of 11q with SF3B1 or BIRC3 mutations, have been described, showing that these genetic mutations could further refine the prognosis of those cytogenetic subgroups [ 135 , 139 , 140 , 141 , 142 , 143 , 144 , 145 ]. Moreover, a recent study has shown that a subset of patients with a co-occurrence of 11q deletion and TP53 alterations had a highly adverse outcome [ 117 ]. By contrast, the mutations in MYD88 appeared in higher frequencies within 13q-deleted patients, being associated with a good prognosis and IGHV mutation [ 12 , 144 , 146 ].…”

Heterogeneity in BIRC3 and ATM Alterations in del(11q) Chronic Lymphocytic Leukemia

“…In addition, there are controversial results with respect to the relationship between del(11q) and del(17)(p13), where the TP53 (Tumor Protein P53) gene is located. Some authors found a low frequency of TP53 alterations in cases with del(11q) [12,14] while others have reported the co-occurrence of these anomalies in the same clone [15][16][17]. In this study, we have evaluated BIRC3 and ATM losses in CLL patients and their relation with adverse prognostic factors of the disease.…”