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

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...

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Published inHaematologica (Roma) Vol. 106; no. 8; pp. 2215 - 2223
Main Authors Martín-Izquierdo, Marta, Abáigar, María, Hernández-Sánchez, Jesús M, Tamborero, David, López-Cadenas, Félix, Ramos, Fernando, Lumbreras, Eva, Madinaveitia-Ochoa, Andrés, Megido, Marta, Labrador, Jorge, Sánchez-Real, Javier, Olivier, Carmen, Dávila, Julio, Aguilar, Carlos, Rodríguez, Juan N, Martín-Nuñez, Guillermo, Santos-Mínguez, Sandra, Miguel-García, Cristina, Benito, Rocío, Díez-Campelo, María, Hernández-Rivas, Jesús M
Format Journal Article
LanguageEnglish
Published Italy Fondazione Ferrata Storti 01.08.2021
Ferrata Storti Foundation
Subjects
Cell Cycle Proteins
Chromosomal Proteins, Non-Histone
Cohesins
Humans
Leukemia, Myeloid, Acute - genetics
Medicin och hälsovetenskap
Mutation
Myelodysplastic Syndromes - genetics
Neoplasms, Second Primary
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Summary: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.
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Disclosures
Contributions
MMI designed the experiments, performed targeted-deep sequencing experiments, analyzed the data and wrote the paper; MA designed the experiments, performed whole-exome sequencing experiments, contributed to interpret the results and wrote the paper; JMHS performed NGS data analysis and contributed to the experiment design; DT analyzed the wholeexome sequencing data; FLC, FR, EL, AMO, MM, JL, JSR, CO, JD, CA, JNR and GMN provided patient samples and clinical information and SSM and CMG contributed to perform the NGS experiments; RB contributed to data analysis, interpretation of the results and critically reviewed the manuscript and MDC and JMHR conceived the study, designed the experiments and wrote the manuscript. All authors discussed the results and revised the manuscript.
No conflicts of interest to disclose.
ISSN:0390-6078
1592-8721
1592-8721
DOI:10.3324/haematol.2020.248807