Biallelic<i>ATM</i>alterations detected at diagnosis identify a subset of treatment-naïve chronic lymphocytic leukemia patients with reduced overall survival similar to patients with p53 deletion

Lozano-Santos, Carol; García-Vela, José Antonio; Pérez-Sanz, Nuria; Nova-Gurumeta, Sara; Fernández-Cuevas, Belén; Gómez‐Lozano, Natalia; Sánchez‐Beato, Margarita; Sánchez-Godoy, Pedro; Bueno, José Luis; García-Marco, José A.

doi:10.1080/10428194.2016.1213829

Cited by 8 publications

(6 citation statements)

References 37 publications

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“…15 Deleterious mutations in the remaining allele of ATM or gain-of-function SF3B1 mutations in del(11q) patients have been shown to drive CLL oncogenesis, being associated with a worse prognosis. [15][16][17][18][19] Nevertheless, these mutations only account for 30% or 20% of del(11q) cases, respectively, leaving more than half of del(11q) patients with unknown second driver of the disease. Another high-risk-associated cytogenetic feature in CLL is the deletion of chromosome 17p13.1 (del(17p)), which appears in 4-10% of CLL cases at diagnosis 20,21 and in up to 40% of relapsing cases to chemoimmunotherapy.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, it has been reported that monoallelic ATM deletion is not enough to cause a CLL‐like disease in mice 15 . Deleterious mutations in the remaining allele of ATM or gain‐of‐function SF3B1 mutations in del(11q) patients have been shown to drive CLL oncogenesis, being associated with a worse prognosis 15–19 . Nevertheless, these mutations only account for 30% or 20% of del(11q) cases, respectively, leaving more than half of del(11q) patients with unknown second driver of the disease.…”

Section: Introductionmentioning

confidence: 99%

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

Quijada‐Álamo

Pérez‐Carretero

Hernández‐Sánchez

et al. 2021

Clinical & Translational Med

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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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Quijada‐Álamo

Pérez‐Carretero

Hernández‐Sánchez

et al. 2021

Clinical & Translational Med

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“…Mutations in TP53, NOTCH1, SF3B1, and ATM and/or loss of ATM (11q22.3) in CLL/SLL have been reported to be associated with a worse prognosis. [27][28][29][30] The K1992T mutation in ATM in our patient has not been reported previously. As the K1992T ATM mutation seen in our patient occurs in the FAT domain, a critical regulator of ATM protein kinase activity, 31 it is possible that this alteration could alter ATM activity.…”

Section: Discussionmentioning

confidence: 49%

Chronic Myelogenous Leukemia Diagnosed in the Setting of Untreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

et al. 2019

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Chronic myeloid leukemia (CML) is rarely reported to occur in treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). In this article, we report a woman in her 70s, diagnosed with CLL/SLL in 2000, untreated, who subsequently presented 12 years later with de novo CML, BCR-ABL1+. Her IGHV mutated CLL/SLL based on the initial sample in our laboratory showed homozygous and heterozygous 13q14.3 deletions, whereas her CML, at presentation, showed a 46,XX,t(9;22)(q34;q11.2)[7]/46,XX[18] karyotype with a p190 BCR-ABL1 transcript. The tumor burden of each clone varied with treatment, including when treated with dasatinib, used to target both clones. In addition, the cytogenetic abnormalities evolved over time and treatments and included acquisition of an extra chromosome 8 in the CML clone and a novel K1992T ATM missense mutation (47% allele frequency) in the CLL/SLL clone. The patient’s last bone marrow biopsy, 5 years after her CML diagnosis and 17 years after the CLL/SLL diagnosis, showed residual CML with extensive involvement by CLL/SLL (80%). Cytogenetic studies showed a 46,XX karyotype, while FISH identified 13q14.3 deletion and the BCR-ABL1 translocation in the CLL/SLL and CML clones, respectively. To date, this is the fourth case of concurrent CML, BCR-ABL1+ arising in untreated CLL/SLL. Here we show dynamic variation in the size of the 2 clonal processes reflecting the variable responsiveness to specific therapies. In addition to the unusual BCR-ABL1+ p190 transcript in the patient’s CML, a novel ATM K1992T mutation was identified in the CLL/SLL population.

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“…Moreover, it is desirable to examine both alleles of the TP53 and ATM genes, representing adverse prognostic factors. 30,[47][48][49] Integrative targeted NGS testing in CLL can overcome the drawbacks of parallel genetic tests by simultaneous analysis of multiple genetic markers, resulting in faster and consolidated interpretation of results. 24,25 In summary, our data extend the previous reports on CLL evolution and dynamics of genomic defects during the pretreatment period of the disease.…”

Section: Discussionmentioning

confidence: 99%

Integrative NGS testing reveals clonal dynamics of adverse genomic defects contributing to a natural progression in treatment‐naïve CLL patients

Navrkalova,

Plevova,

Radova

et al. 2023

Br J Haematol

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SummaryLarge‐scale next‐generation sequencing (NGS) studies revealed extensive genetic heterogeneity, driving a highly variable clinical course of chronic lymphocytic leukaemia (CLL). The evolution of subclonal populations contributes to diverse therapy responses and disease refractoriness. Besides, the dynamics and impact of subpopulations before therapy initiation are not well understood. We examined changes in genomic defects in serial samples of 100 untreated CLL patients, spanning from indolent to aggressive disease. A comprehensive NGS panel LYNX, which provides targeted mutational analysis and genome‐wide chromosomal defect assessment, was employed. We observed dynamic changes in the composition and/or proportion of genomic aberrations in most patients (62%). Clonal evolution of gene variants prevailed over the chromosomal alterations. Unsupervised clustering based on aberration dynamics revealed four groups of patients with different clinical behaviour. An adverse cluster was associated with fast progression and early therapy need, characterized by the expansion of TP53 defects, ATM mutations, and 18p− alongside dynamic SF3B1 mutations. Our results show that clonal evolution is active even without therapy pressure and that repeated genetic testing can be clinically relevant during long‐term patient monitoring. Moreover, integrative NGS testing contributes to the consolidated evaluation of results and accurate assessment of individual patient prognosis.

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BiallelicATMalterations detected at diagnosis identify a subset of treatment-naïve chronic lymphocytic leukemia patients with reduced overall survival similar to patients with p53 deletion

Cited by 8 publications

References 37 publications

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

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

Chronic Myelogenous Leukemia Diagnosed in the Setting of Untreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Integrative NGS testing reveals clonal dynamics of adverse genomic defects contributing to a natural progression in treatment‐naïve CLL patients

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