Integrated Genomic, Functional, and Prognostic Characterization of Atypical Chronic Myeloid Leukemia
Abstract. 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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-12-01
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| Series: | HemaSphere |
| Online Access: | http://journals.lww.com/10.1097/HS9.0000000000000497 |
| _version_ | 1797284137671852032 |
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| author | Diletta Fontana Daniele Ramazzotti Andrea Aroldi Sara Redaelli Vera Magistroni Alessandra Pirola Antonio Niro Luca Massimino Cristina Mastini Virginia Brambilla Silvia Bombelli Silvia Bungaro Alessandro Morotti Delphine Rea Fabio Stagno Bruno Martino Leonardo Campiotti Giovanni Caocci Emilio Usala Michele Merli Francesco Onida Marco Bregni Elena Maria Elli Monica Fumagalli Fabio Ciceri Roberto A. Perego Fabio Pagni Luca Mologni Rocco Piazza Carlo Gambacorti-Passerini |
| author_facet | Diletta Fontana Daniele Ramazzotti Andrea Aroldi Sara Redaelli Vera Magistroni Alessandra Pirola Antonio Niro Luca Massimino Cristina Mastini Virginia Brambilla Silvia Bombelli Silvia Bungaro Alessandro Morotti Delphine Rea Fabio Stagno Bruno Martino Leonardo Campiotti Giovanni Caocci Emilio Usala Michele Merli Francesco Onida Marco Bregni Elena Maria Elli Monica Fumagalli Fabio Ciceri Roberto A. Perego Fabio Pagni Luca Mologni Rocco Piazza Carlo Gambacorti-Passerini |
| author_sort | Diletta Fontana |
| collection | DOAJ |
| description | Abstract. 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. |
| first_indexed | 2024-03-07T17:43:44Z |
| format | Article |
| id | doaj.art-3319347f08c04865829698754ec8c474 |
| institution | Directory Open Access Journal |
| issn | 2572-9241 |
| language | English |
| last_indexed | 2024-03-07T17:43:44Z |
| publishDate | 2020-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | HemaSphere |
| spelling | doaj.art-3319347f08c04865829698754ec8c4742024-03-02T15:23:24ZengWileyHemaSphere2572-92412020-12-0146e49710.1097/HS9.0000000000000497202012000-00010Integrated Genomic, Functional, and Prognostic Characterization of Atypical Chronic Myeloid LeukemiaDiletta FontanaDaniele RamazzottiAndrea AroldiSara RedaelliVera MagistroniAlessandra PirolaAntonio NiroLuca MassiminoCristina MastiniVirginia BrambillaSilvia BombelliSilvia BungaroAlessandro MorottiDelphine ReaFabio StagnoBruno MartinoLeonardo CampiottiGiovanni CaocciEmilio UsalaMichele MerliFrancesco OnidaMarco BregniElena Maria ElliMonica FumagalliFabio CiceriRoberto A. PeregoFabio PagniLuca MologniRocco PiazzaCarlo Gambacorti-PasseriniAbstract. 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.http://journals.lww.com/10.1097/HS9.0000000000000497 |
| spellingShingle | Diletta Fontana Daniele Ramazzotti Andrea Aroldi Sara Redaelli Vera Magistroni Alessandra Pirola Antonio Niro Luca Massimino Cristina Mastini Virginia Brambilla Silvia Bombelli Silvia Bungaro Alessandro Morotti Delphine Rea Fabio Stagno Bruno Martino Leonardo Campiotti Giovanni Caocci Emilio Usala Michele Merli Francesco Onida Marco Bregni Elena Maria Elli Monica Fumagalli Fabio Ciceri Roberto A. Perego Fabio Pagni Luca Mologni Rocco Piazza Carlo Gambacorti-Passerini Integrated Genomic, Functional, and Prognostic Characterization of Atypical Chronic Myeloid Leukemia HemaSphere |
| title | Integrated Genomic, Functional, and Prognostic Characterization of Atypical Chronic Myeloid Leukemia |
| title_full | Integrated Genomic, Functional, and Prognostic Characterization of Atypical Chronic Myeloid Leukemia |
| title_fullStr | Integrated Genomic, Functional, and Prognostic Characterization of Atypical Chronic Myeloid Leukemia |
| title_full_unstemmed | Integrated Genomic, Functional, and Prognostic Characterization of Atypical Chronic Myeloid Leukemia |
| title_short | Integrated Genomic, Functional, and Prognostic Characterization of Atypical Chronic Myeloid Leukemia |
| title_sort | integrated genomic functional and prognostic characterization of atypical chronic myeloid leukemia |
| url | http://journals.lww.com/10.1097/HS9.0000000000000497 |
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