Integrated Genomic, Functional, and Prognostic Characterization of Atypical Chronic Myeloid Leukemia
Autor: | Emilio Usala, Giovanni Caocci, Daniele Ramazzotti, Alessandra Pirola, Leonardo Campiotti, Alessandro Morotti, Fabio Stagno, Roberto A. Perego, Silvia Bungaro, Cristina Mastini, Fabio Pagni, Silvia Bombelli, Fabio Ciceri, Vera Magistroni, Bruno Martino, Michele Merli, Antonio Niro, Sara Redaelli, Delphine Rea, Luca Mologni, Rocco Piazza, Diletta Fontana, Virginia Brambilla, Elena Maria Elli, Andrea Aroldi, Carlo Gambacorti-Passerini, Marco Bregni, Luca Massimino, Monica Fumagalli, Francesco Onida |
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Přispěvatelé: | Fontana, D, Ramazzotti, D, Aroldi, A, Redaelli, S, Magistroni, V, Pirola, A, Niro, A, Massimino, L, Mastini, C, Brambilla, V, Bombelli, S, Bungaro, S, Morotti, A, Rea, D, Stagno, F, Martino, B, Campiotti, L, Caocci, G, Usala, E, Merli, M, Onida, F, Bregni, M, Elli, E, Fumagalli, M, Ciceri, F, Perego, R, Pagni, F, Mologni, L, Piazza, R, Gambacorti-Passerini, C |
Rok vydání: | 2020 |
Předmět: |
Genetics
lcsh:RC633-647.5 Somatic cell Genetic heterogeneity SETBP1 Whole exome sequencing lcsh:Diseases of the blood and blood-forming organs Hematology Disease ASXL1 Biology medicine.disease Somatic evolution in cancer MED/15 - MALATTIE DEL SANGUE In vivo Gene expression Atypical chronic myeloid leukemia medicine Original Article ETNK1 Gene Atypical Chronic Myeloid Leukemia |
Zdroj: | HemaSphere HemaSphere, Vol 4, Iss 6, p e497 (2020) |
ISSN: | 2572-9241 |
Popis: | Supplemental Digital Content is available for this article. Atypical chronic myeloid leukemia (aCML) is a BCR-ABL1-negative clonal disorder, which belongs to the myelodysplastic/myeloproliferative group. This disease is characterized by recurrent somatic mutations in SETBP1, ASXL1 and ETNK1 genes, as well as high genetic heterogeneity, thus posing a great therapeutic challenge. To provide a comprehensive genomic characterization of aCML we applied a high-throughput sequencing strategy to 43 aCML samples, including both whole-exome and RNA-sequencing data. Our dataset identifies ASXL1, SETBP1, and ETNK1 as the most frequently mutated genes with a total of 43.2%, 29.7 and 16.2%, respectively. We characterized the clonal architecture of 7 aCML patients by means of colony assays and targeted resequencing. The results indicate that ETNK1 variants occur early in the clonal evolution history of aCML, while SETBP1 mutations often represent a late event. The presence of actionable mutations conferred both ex vivo and in vivo sensitivity to specific inhibitors with evidence of strong in vitro synergism in case of multiple targeting. In one patient, a clinical response was obtained. Stratification based on RNA-sequencing identified two different populations in terms of overall survival, and differential gene expression analysis identified 38 significantly overexpressed genes in the worse outcome group. Three genes correctly classified patients for overall survival. |
Databáze: | OpenAIRE |
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