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PDX models recapitulate the genetic and epigenetic landscape of pediatric T-cell leukemia.

ABSTRACT: We compared 24 primary pediatric T-cell acute lymphoblastic leukemias (T-ALL) collected at the time of initial diagnosis and relapse from 12 patients and 24 matched patient-derived xenografts (PDXs). DNA methylation profile was preserved in PDX mice in 97.5% of the promoters (? = 0.99). Similarly, the genome-wide chromatin accessibility (ATAC-Seq) was preserved remarkably well (? = 0.96). Interestingly, both the ATAC regions, which showed a significant decrease in accessibility in PDXs and the regions hypermethylated in PDXs, were associated with immune response, which might reflect the immune deficiency of the mice and potentially the incomplete interaction between murine cytokines and human receptors. The longitudinal approach of this study allowed an observation that samples collected from patients who developed a type 1 relapse (clonal mutations maintained at relapse) preserved their genomic composition; whereas in patients who developed a type 2 relapse (subset of clonal mutations lost at relapse), the preservation of the leukemia's composition was more variable. In sum, this study underlines the remarkable genomic stability, and for the first time documents the preservation of the epigenomic landscape in T-ALL-derived PDX models.

SUBMITTER: Richter-Pechanska P

PROVIDER: S-EPMC6284381 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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PDX models recapitulate the genetic and epigenetic landscape of pediatric T-cell leukemia.

Richter-Pechańska Paulina P Kunz Joachim B JB Bornhauser Beat B von Knebel Doeberitz Caroline C Rausch Tobias T Erarslan-Uysal Büşra B Assenov Yassen Y Frismantas Viktoras V Marovca Blerim B Waszak Sebastian M SM Zimmermann Martin M Seemann Julia J Happich Margit M Stanulla Martin M Schrappe Martin M Cario Gunnar G Escherich Gabriele G Bakharevich Kseniya K Kirschner-Schwabe Renate R Eckert Cornelia C Muckenthaler Martina U MU Korbel Jan O JO Bourquin Jean-Pierre JP Kulozik Andreas E AE

EMBO molecular medicine 20181201 12

We compared 24 primary pediatric T-cell acute lymphoblastic leukemias (T-ALL) collected at the time of initial diagnosis and relapse from 12 patients and 24 matched patient-derived xenografts (PDXs). DNA methylation profile was preserved in PDX mice in 97.5% of the promoters (ρ = 0.99). Similarly, the genome-wide chromatin accessibility (ATAC-Seq) was preserved remarkably well (ρ = 0.96). Interestingly, both the ATAC regions, which showed a significant decrease in accessibility in PDXs and the r ...[more]

PMID: 30389682

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Project description:BackgroundMurine xenografts of pediatric leukemia accurately recapitulate genomic aberrations. How this translates to the functional capacity of cells remains unclear. Here, we studied global protein abundance, phosphorylation, and protein maturation by proteolytic processing in 11 pediatric B- and T- cell ALL patients and 19 corresponding xenografts.MethodsXenograft models were generated for each pediatric patient leukemia. Mass spectrometry-based methods were used to investigate global protein abundance, protein phosphorylation, and limited proteolysis in paired patient and xenografted pediatric acute B- and T- cell lymphocytic leukemia, as well as in pediatric leukemia cell lines. Targeted next-generation sequencing was utilized to examine genetic abnormalities in patients and in corresponding xenografts. Bioinformatic and statistical analysis were performed to identify functional mechanisms associated with proteins and protein post-translational modifications.ResultsOverall, we found xenograft proteomes to be most equivalent with their patient of origin. Protein level differences that stratified disease subtypes at diagnostic and relapse stages were largely recapitulated in xenografts. As expected, PDXs lacked multiple human leukocyte antigens and complement proteins. We found increased expression of cell cycle proteins indicating a high proliferative capacity of xenografted cells. Structural genomic changes and mutations were reflected at the protein level in patients. In contrast, the post-translational modification landscape was shaped by leukemia type and host and only to a limited degree by the patient of origin. Of 201 known pediatric oncogenic drivers and drug-targetable proteins, the KMT2 protein family showed consistently high variability between patient and corresponding xenografts. Comprehensive N terminomics revealed deregulated proteolytic processing in leukemic cells, in particular from caspase-driven cleavages found in patient cells.ConclusionGenomic and host factors shape protein and post-translational modification landscapes differently. This study highlights select areas of diverging biology while confirming murine patient-derived xenografts as a generally accurate model system.

Dataset Information

PDX models recapitulate the genetic and epigenetic landscape of pediatric T-cell leukemia.

Publications

PDX models recapitulate the genetic and epigenetic landscape of pediatric T-cell leukemia.

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