<scp>TP53</scp> mutations at codon 234 are associated with chlorambucil treatment in chronic lymphocytic leukemia

Lazarian, Grégory; Theves, Floriane; Hormi, Myriam; Letestu, Rémi; Éclache, Virginie; Bidet, Audrey; Cornillet‐Lefèbvre, Pascale; Davi, Frédéric; Delabesse, Éric; Estienne, Marie-Hélène; Étancelin, Pascaline; Kosmider, Olivier; Laibe, Sophy; Lodé, Laurence; Müller, Marc; Nadal, Nathalie; Naguib, Dina; Pastoret, Cedric; Poulain, Stéphanie; Sujobert, Pierre; Véronèse, Lauren; Imache, Samia; Lefebvre, Valérie; Cymbalista, Florence; Baran‐Marszak, Fanny; Soussi, Thierry

doi:10.1002/ajh.26479

Cited by 3 publications

(6 citation statements)

References 19 publications

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“…This supplementary observation and the various large-scale analyses of the CLL genome strongly support the multiclonality of these tumors [6, 12-14, 16, 45]. As described in our previous study, the intratumoral genetic heterogeneity in CLL raises the question of the impact of treatment on the selection or acquisition of TP53 mutations [18]. Longitudinal studies have described the acquisition of TP53 abnormalities and complex 13 Human Mutation karyotypes in treated relapsed or refractory patients [37].…”

Section: Discussionsupporting

confidence: 63%

“…The first was located at codon 234 (NP_000537_p.Tyr234His, NM_000546_c.700T>C), which has a very low frequency of mutation in the majority of cancers (Supplementary Figure S4B). Our previous study on 336 patients showed that this nonfunctional TP53 variant is found mainly in patients treated with chlorambucil (CLB), an alkylating drug that had been widely used to treat CLL patients before the development of individualized therapy [18]. A survey of the literature and data from UMD_CLL also showed an excess of mutations at codon 234 in CLL compared to other cancer types (Supplementary Figure S4B).…”

Section: Resultsmentioning

confidence: 97%

“…The third CLL-specific variant is located at codon 234 with a high prevalence of tyrosine-to-cysteine substitution. This variant, found at very low frequency in all tumor types, has been shown to be specifically associated to CLB treatment [18]. It remains to be determined whether this variant results directly from a mutational event provoked by CLB or is specifically selected during the treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Any line of treatment significantly increased the number of mutations per patient, but some treatment types did so more than others. Any regimen including the continuous administration of the alkylating agent CLB, whether alone or with other subsequent treatments, dramatically increased the number of mutations per patient [18].…”

Section: Discussionmentioning

confidence: 99%

“…The clinical value of these minor clones is still under investigation [17]. In a previous study, using a dataset of 336 TP53-mutated CLL patients, we uncovered a novel TP53 mutation hotspot in codon 234 associated with chlorambucil treatment [18].…”

Section: Introductionmentioning

confidence: 98%

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The Broad Spectrum of TP53 Mutations in CLL: Evidence of Multiclonality and Novel Mutation Hotspots

et al. 2023

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TP53 aberrations are a major predictive factor of resistance to chemoimmunotherapy in chronic lymphocytic leukemia (CLL), and an assessment of them before each line of treatment is required for theranostic stratification. Acquisition of subclonal TP53 abnormalities underlies the evolution of CLL. To better characterize the distribution, combination, and impact of TP53 variants in CLL, 1,056 TP53 variants collected from 683 patients included in a multicenter collaborative study in France were analyzed and compared to UMD_CLL, a dataset built from published articles collectively providing 5,173 TP53 variants detected in 3,808 patients. Our analysis confirmed the presence of several CLL-specific hotspot mutations, including a two-base pair deletion in codon 209 and a missense variant at codon 234, the latter being associated with alkylating treatment. Our analysis also identified a novel CLL-specific variant in the splice acceptor signal of intron 6 leading to the use of a cryptic splice site, similarly utilized by TP53 to generate p53psi, a naturally truncated p53 isoform localized in the mitochondria. Examination of both UMD_CLL and several recently released large-scale genomic analyses of CLL patients confirmed that this splice variant is highly enriched in this disease when compared to other cancer types. Using a TP53-specific single-nucleotide polymorphism, we also confirmed that copy-neutral loss of heterozygosity is frequent in CLL. This event can lead to misinterpretation of TP53 status. Unlike other cancers, CLL displayed a high proportion of patients harboring multiple TP53 variants. Using both in silico analysis and single molecule smart sequencing, we demonstrated the coexistence of distinct subclones harboring mutations on distinct alleles. In summary, our study provides a detailed TP53 mutational architecture in CLL and gives insights into how treatments may shape the genetic landscape of CLL patients.

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Section: Discussionsupporting

confidence: 63%

Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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The Broad Spectrum of TP53 Mutations in CLL: Evidence of Multiclonality and Novel Mutation Hotspots

et al. 2023

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Improved efficacy and safety of zanubrutinib versus ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL) in China: a subgroup of ALPINE

Zhou,

Wang,

Pan

et al. 2024

Ann Hematol

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Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has different epidemiology in Chinese vs. Western patients, but there are few studies of CLL/SLL in large populations of Chinese patients. ALPINE is a global phase 3 trial investigating Bruton tyrosine kinase inhibitors zanubrutinib vs. ibrutinib to treat relapsed/refractory (R/R) CLL/SLL. Here we report results from the subgroup of Chinese patients. Adults with R/R CLL/SLL were randomized 1:1 to receive zanubrutinib (160 mg twice-daily) or ibrutinib (420 mg once-daily) until disease progression or unacceptable toxicity. Endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Data were analyzed descriptively. Ninety patients were randomized in China (zanubrutinib, n = 47; ibrutinib, n = 43). Baseline characteristics were balanced between groups, with fewer male patients in the zanubrutinib vs. ibrutinib group (55.3% vs. 69.8%). Median age was 60.5 years, 11% had del(17p) mutation, and 32% had tumor protein 53 (TP53) mutation. With median 25.3 months follow-up, ORR was 80.9% with zanubrutinib vs. 72.1% with ibrutinib. PFS was improved with zanubrutinib vs. ibrutinib (HR = 0.34 [95% CI, 0.15, 0.77]), and the HR for OS was 0.45 (95% CI, 0.14, 1.50). Rates of Grade ≥ 3 treatment-emergent adverse events (TEAEs; 64.4% vs. 72.1%), AEs leading to discontinuation (6.4% vs. 14.0%), and serious TEAEs (35.6% vs. 51.2%) were lower with zanubrutinib vs. ibrutinib. Zanubrutinib demonstrated improved ORR, PFS, and OS vs. ibrutinib and a more favorable safety profile in patients with R/R CLL/SLL in China. These results are consistent with the full global population of ALPINE. ClinicalTrials.gov: NCT03734016, registered November 7, 2018.

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Structural basis of p53 inactivation by cavity-creating cancer mutations and its implications for the development of mutant p53 reactivators

Balourdas,

Markl,

Krämer

et al. 2024

Cell Death Dis

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SummaryThe cavity-creating p53 cancer mutation Y220C is an ideal paradigm for developing small-molecule drugs based on protein stabilization. Here, we have systematically analyzed the structural and stability effects of all oncogenic Tyr-to-Cys mutations (Y126C, Y163C, Y205C, Y220C, Y234C, and Y236C) in the p53 DNA-binding domain (DBD). They were all highly destabilizing, drastically lowering the melting temperature of the protein by 8–17 °C. In contrast, two non-cancerous mutations, Y103C and Y107C, had only a moderate effect on protein stability. Differential stabilization of the mutants upon treatment with the anticancer agent arsenic trioxide and stibogluconate revealed an interesting proximity effect. Crystallographic studies complemented by MD simulations showed that two of the mutations, Y234C and Y236C, create internal cavities of different size and shape, whereas the others induce unique surface lesions. The mutation-induced pockets in the Y126C and Y205C mutant were, however, relatively small compared with that of the already druggable Y220C mutant. Intriguingly, our structural studies suggest a pronounced plasticity of the mutation-induced pocket in the frequently occurring Y163C mutant, which may be exploited for the development of small-molecule stabilizers. We point out general principles for reactivating thermolabile cancer mutants and highlight special cases where mutant-specific drugs are needed for the pharmacological rescue of p53 function in tumors.

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TP53 mutations at codon 234 are associated with chlorambucil treatment in chronic lymphocytic leukemia

Cited by 3 publications

References 19 publications

The Broad Spectrum of TP53 Mutations in CLL: Evidence of Multiclonality and Novel Mutation Hotspots

The Broad Spectrum of TP53 Mutations in CLL: Evidence of Multiclonality and Novel Mutation Hotspots

Improved efficacy and safety of zanubrutinib versus ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL) in China: a subgroup of ALPINE

Structural basis of p53 inactivation by cavity-creating cancer mutations and its implications for the development of mutant p53 reactivators

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