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Relapsed Acute Lymphoblastic Leukemia (ALL): Mutational Landscape

ABSTRACT: Relapsed Acute Lymphoblastic Leukemia (ALL): Mutational Landscape

PROVIDER: PRJNA597498 | ENA |

REPOSITORIES: ENA

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Relapsed Acute Lymphoblastic Leukemia (ALL): Mutational Landscape

Project description:Relapsed Acute Lymphoblastic Leukemia (ALL): Mutational Landscape

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Genomic Analysis of Relapsed Pediatric Acute Lymphoblastic Leukemia

Project description:<p>Although multi-agent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die due to chemo-refractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape and pattern of clonal evolution at relapse in pediatric ALL cases. These analyses showed that ALL relapses originate from a common ancestral precursor clone of the diagnosis and relapsed populations and frequently harbor mutations implicated in chemotherapy resistance. RAS-MAPK pathway activating mutations in NRAS, KRAS and PTPN11 were present in 24/55 (44%) cases in our series. Notably, while some cases showed emergence of RAS mutant clones at relapse, in others, RAS mutant clones present at diagnosis were replaced by RAS wild type populations. Mechanistically, functional dissection of mouse and human wild type Kras and mutant Kras (Kras G12D) isogenic leukemia cells demonstrated induction of methotrexate resistance, but also improved response to vincristine, in mutant Kras- expressing lymphoblasts. These results identify chemotherapy driven selection as a central mechanism of leukemia clonal evolution and pave the road for the development of tailored personalized therapies for the treatment of relapsed ALL. </p>

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Mutational landscape and patterns of clonal evolution in relapsed pediatric acute lymphoblastic leukemia.

Project description: Not available

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The Methylome Landscape of Infant B-cell precursor Acute Lymphoblastic Leukemia (iB-ALL)

Project description:B-cell acute lymphoblastic leukemia (B-ALL) is the most prevailing childhood cancer. As predicated by its prenatal origin, infant B-ALL (iB-ALL) show a silent mutational landscape irrespective of the MLL rearrangement/status, suggesting that other regulatory mechanisms might be impaired in the context of the disease. Here we used the most recent Illumina MethylationEPIC Beadchip platform to describe the genome-wide DNA methylation changes observed in a total of 69 de novo MLL-AF4+, MLL-AF9+ and non-rearranged MLL iB-ALL leukemias uniformly treated according to Interfant 99/06 protocol. Please note that samples X8 and X9 (pool of B cells and BCP) correspond to samples 200340580160_R08C01 and 200340580161_R07C01 from study E-MTAB-6315, respectively.

2021-03-12 | E-MTAB-8505 | biostudies-arrayexpress

Mutational Landscape of Pediatric Acute Lymphoblastic Leukemia.

Project description: Not available

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Relapsed Acute Lymphoblastic Leukemia (ALL): Genomic Analysis in Pediatric Patients

Project description:Relapsed Acute Lymphoblastic Leukemia (ALL): Genomic Analysis in Pediatric Patients

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Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia.

Project description: Not available

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Molecular genetics of pre-B acute lymphoblastic leukemia sister cell lines during disease progression - WES

Project description:Retaining the mutational pattern of tumors, immortalized cell lines represent excellent tools for the molecular study of genetic aberrations. Tumors can consist of subclones which develop under selective forces driven by mutational alterations. This explains why after therapy, relapsed clones can be genetically distinct from clones at diagnosis. We analyzed the mutational patterns of pairs of cell lines raised at early and late phases of development from patients with a hematopoietic tumor named pre-B acute lymphoblastic leukemia (ALL). All cell lines tested showed mutations that typically occur in this tumor. We also observed clonal differences in sister cell lines, genetic aberrations developing during disease progression. Especially noteworthy was the presence of two mutations which are hitherto undescribed in cell lines.

2021-12-02 | E-MTAB-11039 | biostudies-arrayexpress

Molecular genetics of pre-B acute lymphoblastic leukemia sister cell lines during disease progression - RNA-seq

2021-12-02 | E-MTAB-11038 | biostudies-arrayexpress

Mutational landscape and patterns of clonal evolution in relapsed pediatric acute lymphoblastic leukemia

Project description:Relapse of acute lymphoblastic leukemia (ALL) remains a leading cause of childhood death. Prior studies have shown clonal mutations at relapse often arise from relapse-fated subclones that exist at diagnosis. However, the genomic landscape, evolutionary trajectories and mutational mechanisms driving relapse are incompletely understood. In an analysis of 92 cases of relapsed childhood ALL, incorporating multimodal DNA and RNA sequencing, deep digital mutational tracking and xenografting to formally define clonal structure, we identify 50 significant targets of mutation with distinct patterns of mutational acquisition or enrichment. CREBBP, NOTCH1, and Ras signaling mutations rose from diagnosis subclones, whereas variants in NCOR2, USH2A and NT5C2 were exclusively observed at relapse. Evolutionary modeling and xenografting demonstrated that relapse-fated clones were minor (50%), major (27%) or multiclonal (18%) at diagnosis. Putative second leukemias, including those with lineage shift, were shown to most commonly represent relapse from an ancestral clone rather than a truly independent second primary leukemia. A subset of leukemias prone to repeated relapse exhibited hypermutation driven by at least three distinct mutational processes, resulting in heightened neoepitope burden and potential vulnerability to immunotherapy. Finally, relapse-driving sequence mutations were detected prior to relapse using deep digital PCR at levels comparable to orthogonal approaches to monitor levels of measurable residual disease. These results provide a genomic framework to anticipate and circumvent relapse by earlier detection and targeting of relapse-fated clones.

| EGAS00001003975 | EGA

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