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Co-occurrence of cohesin complex and Ras signaling mutations during progression from myelodysplastic syndromes to secondary acute myeloid leukemia

Authors :
Marta Martín-Izquierdo
María Abáigar
Jesús M Hernández-Sánchez
David Tamborero
Félix López-Cadenas
Fernando Ramos
Eva Lumbreras
Andrés Madinaveitia-Ochoa
Marta Megido
Jorge Labrador
Javier Sánchez-Real
Carmen Olivier
Julio Dávila
Carlos Aguilar
Juan N Rodríguez
Guillermo Martín-Nuñez
Sandra Santos-Mínguez
Cristina Miguel-García
Rocío Benito
María Díez-Campelo
Jesús M Hernández-Rivas
Source :
Haematologica, Vol 106, Iss 8 (2020)
Publication Year :
2020
Publisher :
Ferrata Storti Foundation, 2020.

Abstract

Myelodysplastic syndromes (MDS) are hematological disorders at high risk of progression to secondary acute myeloid leukemia (sAML). However, the mutational dynamics and clonal evolution underlying disease progression are poorly understood at present. 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 transformation. The study showed that MDS progression to sAML is characterized 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 cooperation 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 progression to sAML.

Details

Language :
English
ISSN :
03906078 and 15928721
Volume :
106
Issue :
8
Database :
Directory of Open Access Journals
Journal :
Haematologica
Publication Type :
Academic Journal
Accession number :
edsdoj.b5af1325c7414ed19ff05fb9bebee8d7
Document Type :
article
Full Text :
https://doi.org/10.3324/haematol.2020.248807