Page 187 - 2021_06-Haematologica-web
P. 187
Myelodysplastic Syndromes
Co-occurrence of cohesin complex and Ras signaling mutations during progression from myelodysplastic syndromes to secondary acute myeloid leukemia
Ferrata Storti Foundation
Haematologica 2021 Volume 106(8):2215-2223
Marta Martín-Izquierdo,1* María Abáigar,1* Jesús M. Hernández-Sánchez,1 David Tamborero,2,3 Félix López-Cadenas,4 Fernando Ramos,5 Eva Lumbreras,1 Andrés Madinaveitia-Ochoa,6 Marta Megido,7 Jorge Labrador,8 Javier Sánchez- Real,5 Carmen Olivier,9 Julio Dávila,10 Carlos Aguilar,11 Juan N. Rodríguez,12 Guillermo Martín-Nuñez,13 Sandra Santos-Mínguez,1 Cristina Miguel-García,1 Rocío Benito,1 María Díez-Campelo4* and Jesús M. Hernández-Rivas1,4#
1Institute of Biomedical Research of Salamanca (IBSAL), Cytogenetics-Molecular Genetics in Oncohematology, Cancer Research Center-University of Salamanca (IBMCC, USAL-CSIC), Salamanca, Spain; 2Research Program on Biomedical Informatics, Hospital del Mar Medical Research Institute (IMIM), Universitat Pompeu Fabra, Barcelona, Spain; 3Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden; 4University of Salamanca, IBSAL, Hematology, Hospital Clínico Universitario, Salamanca, Spain; 5Hematology, Hospital Universitario de León, Institute of Biomedicine (IBIOMED)-University of León, León, Spain; 6Hematology, Hospital Universitario Miguel Servet, Zaragoza, Spain; 7Hematology, Hospital del Bierzo, Ponferrada, León, Spain; 8Hematology, Hospital Universitario de Burgos, Burgos, Spain; 9Hematology, Hospital General de Segovia, Segovia, Spain; 10Hematology, Hospital Nuestra Señora de Sónsoles, Ávila, Spain; 11Hematology, Hospital Santa Bárbara, Soria, Spain; 12Hematology, Hospital Juan Ramón Jiménez, Huelva, Spain and 13Hematology, Hospital Virgen del Puerto, Plasencia, Spain
*MA and MMI contributed equally as co-first authors. #MDC and JMHR contributed equally as co-senior authors.
ABSTRACT
Myelodysplastic syndromes (MDS) are hematological disorders at high risk of progression to secondary acute myeloid leukemia (sAML). However, the mutational dynamics and clonal evolu- tion underlying disease progression are poorly understood at present. In order to elucidate the mutational dynamics of pathways and genes occurring during the evolution to sAML, next-generation sequencing was performed on 84 serially paired samples of MDS patients who developed sAML (discovery cohort) and 14 paired samples from MDS patients who did not progress to sAML during follow-up (control cohort). Results were validated in an independent series of 388 MDS patients (validation cohort). We used an integrative analysis to identify how mutations, alone or in combination, contribute to leukemic trans- formation. The study showed that MDS progression to sAML is charac- terized by greater genomic instability and the presence of several types of mutational dynamics, highlighting increasing (STAG2) and newly- acquired (NRAS and FLT3) mutations. Moreover, we observed co-opera- tion between genes involved in the cohesin and Ras pathways in 15-20% of MDS patients who evolved to sAML, as well as a high proportion of newly acquired or increasing mutations in the chromatin-modifier genes in MDS patients receiving a disease-modifying therapy before their pro- gression to sAML.
Introduction
Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by peripheral blood (PB) cytopenia with dys- plastic bone marrow (BM) morphology and an increased risk of progression to sec- ondary acute myeloid leukemia (sAML).1-3 Approximately one third of patients diag-
Correspondence:
JESÚS M HERNÁNDEZ-RIVAS
jmhr@usal.es
Received: February 3, 2020. Accepted: July 14, 2020. Pre-published: July 16, 2020.
https://doi.org/10.3324/haematol.2020.248807
©2021 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
haematologica | 2021; 106(8)
2215
ARTICLE
