ID
45799
Beschreibung
Principal Investigator: Adolfo Ferrando, MD, PhD, Columbia University, New York, NY, USA MeSH: Leukemia, Lymphoid,Lymphoblastic Leukemia, Acute, T-Cell,Precursor B-Cell Lymphoblastic Leukemia https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001072 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.
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Stichworte
Versionen (1)
- 23.06.23 23.06.23 - Chiara Middel
Rechteinhaber
Adolfo Ferrando, MD, PhD, Columbia University, New York, NY, USA
Hochgeladen am
23. Juni 2023
DOI
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Lizenz
Creative Commons BY 4.0
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dbGaP phs001072 Genomic Analysis of Relapsed Pediatric Acute Lymphoblastic Leukemia
This subject phenotype table contains subject ID, age and gender of participant.
- StudyEvent: SEV1
- The subject consent file includes subject IDs, consent information, subject aliases, and affection status for pediatric acute lymphoblastic leukemia.
- This data table contains a mapping of study subject IDs to sample IDs. Samples are the final preps submitted for genotyping, sequencing, and/or expression data. For example, if one patient (subject ID) gave one sample, and that sample was processed differently to generate 2 sequencing runs, there would be two rows, both using the same subject ID, but having 2 unique sample IDs. The data table also includes sample aliases and sample use.
- This subject phenotype table contains subject ID, age and gender of participant.
- This sample attributes table contains sample IDs, body site where sample was collected, analyte type, tumor status, histological type, primary or metastatic tumor, primary tumor location, and name of the center which conducted sequencing.
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This subject phenotype table contains subject ID, age and gender of participant.
- StudyEvent: SEV1
- The subject consent file includes subject IDs, consent information, subject aliases, and affection status for pediatric acute lymphoblastic leukemia.
- This data table contains a mapping of study subject IDs to sample IDs. Samples are the final preps submitted for genotyping, sequencing, and/or expression data. For example, if one patient (subject ID) gave one sample, and that sample was processed differently to generate 2 sequencing runs, there would be two rows, both using the same subject ID, but having 2 unique sample IDs. The data table also includes sample aliases and sample use.
- This subject phenotype table contains subject ID, age and gender of participant.
- This sample attributes table contains sample IDs, body site where sample was collected, analyte type, tumor status, histological type, primary or metastatic tumor, primary tumor location, and name of the center which conducted sequencing.
C2348585 (UMLS CUI [1,2])