Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents
Abstract
The cytidine analogues azacytidine and 5-aza-2’-deoxycytidine (decitabine) are commonly used to treat myelodysplastic syndromes, with or without a myeloproliferative component. It remains unclear whether the response to these hypomethylating agents results from a cytotoxic or an epigenetic effect. In this study, we address this question in chronic myelomonocytic leukaemia. We describe a comprehensive analysis of the mutational landscape of these tumours, combining whole-exome and whole-genome sequencing. We identify an average of 14 ± 5 somatic mutations in coding sequences of sorted monocyte DNA and the signatures of three mutational processes. Serial sequencing demonstrates that the response to hypomethylating agents is associated with changes in DNA methylation and gene expression, without any decrease in the mutation allele burden, nor prevention of new genetic alteration occurence. Lastly, our findings indicate that cytosine analogues restore a balanced haematopoiesis without decreasing the size of the mutated clone, arguing for a predominantly epigenetic effect.
- Authors:
-
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- INSERM U1170, Villejuif (France); Gustave Roussy Cancer Center, Villejuif (France)
- INSERM U1170, Villejuif (France); Gustave Roussy Cancer Center, Villejuif (France); INSERM US23, Villejuif (France)
- Univ. of Michigan Medical School, Ann Arbor, MI (United States)
- Kyoto Univ., Kyoto (Japan)
- Univ. Lyon 1, UMR CNRS 5558, Univ. Claude Bernard, Lyon (France)
- Centre Leon Berard, INSERM U1052, CNRS UMR5286, Lyon (France)
- Hopital Saint-Louis, Paris (France)
- Hopital Avicenne, Bobigny (France)
- Cancer Research Institute de Lille, INSERM U837, Lille (France)
- INSERM U1040, Univ. de Montpellier, Montpellier (France)
- Centre Hospitalier Univ. de Nimes, Univ. Montpellier-Nimes, Nimes (France)
- INSERM US23, Villejuif (France)
- Kinghor Center for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst New South Wales (Australia)
- Centre National de Genotypage, Evry (France)
- Wellcome Trust Sanger Institute, Cambridgeshire (United Kingdom)
- Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Wellcome Trust Sanger Institute, Cambridgeshire (United Kingdom)
- H. Lee Moffitt Cancer Center, Tampa, FL (United States)
- Gustave Roussy Cancer Center, Villejuif (France)
- INSERM U1170, Villejuif (France); Gustave Roussy Cancer Center, Villejuif (France); Univ. Paris-Sud, Le Kremlin-Bicetre (France)
- Publication Date:
- Research Org.:
- Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1246362
- Report Number(s):
- LA-UR-15-24070
Journal ID: ISSN 2041-1723; ncomms10767
- Grant/Contract Number:
- AC52-06NA25396
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Communications
- Additional Journal Information:
- Journal Volume: 7; Journal ID: ISSN 2041-1723
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; biological sciences; cancer; genetics
Citation Formats
Merlevede, Jane, Droin, Nathalie, Qin, Tingting, Meldi, Kristen, Yoshida, Kenichi, Morabito, Margot, Chautard, Emilie, Auboeuf, Didier, Fenaux, Pierre, Braun, Thorsten, Itzykson, Raphael, de Botton, Stephane, Quesnel, Bruno, Commes, Therese, Jourdan, Eric, Vainchenker, William, Bernard, Olivier, Pata-Merci, Noemie, Solier, Stephanie, Gayevskiy, Velimir, Dinger, Marcel E., Cowley, Mark J., Selimoglu-Buet, Dorothee, Meyer, Vincent, Artiguenave, Francois, Deleuze, Jean -Francois, Preudhomme, Claude, Stratton, Michael R., Alexandrov, Ludmil B., Padron, Eric, Ogawa, Seishi, Koscielny, Serge, Figueroa, Maria, and Solary, Eric. Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents. United States: N. p., 2016.
Web. doi:10.1038/ncomms10767.
Merlevede, Jane, Droin, Nathalie, Qin, Tingting, Meldi, Kristen, Yoshida, Kenichi, Morabito, Margot, Chautard, Emilie, Auboeuf, Didier, Fenaux, Pierre, Braun, Thorsten, Itzykson, Raphael, de Botton, Stephane, Quesnel, Bruno, Commes, Therese, Jourdan, Eric, Vainchenker, William, Bernard, Olivier, Pata-Merci, Noemie, Solier, Stephanie, Gayevskiy, Velimir, Dinger, Marcel E., Cowley, Mark J., Selimoglu-Buet, Dorothee, Meyer, Vincent, Artiguenave, Francois, Deleuze, Jean -Francois, Preudhomme, Claude, Stratton, Michael R., Alexandrov, Ludmil B., Padron, Eric, Ogawa, Seishi, Koscielny, Serge, Figueroa, Maria, & Solary, Eric. Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents. United States. https://doi.org/10.1038/ncomms10767
Merlevede, Jane, Droin, Nathalie, Qin, Tingting, Meldi, Kristen, Yoshida, Kenichi, Morabito, Margot, Chautard, Emilie, Auboeuf, Didier, Fenaux, Pierre, Braun, Thorsten, Itzykson, Raphael, de Botton, Stephane, Quesnel, Bruno, Commes, Therese, Jourdan, Eric, Vainchenker, William, Bernard, Olivier, Pata-Merci, Noemie, Solier, Stephanie, Gayevskiy, Velimir, Dinger, Marcel E., Cowley, Mark J., Selimoglu-Buet, Dorothee, Meyer, Vincent, Artiguenave, Francois, Deleuze, Jean -Francois, Preudhomme, Claude, Stratton, Michael R., Alexandrov, Ludmil B., Padron, Eric, Ogawa, Seishi, Koscielny, Serge, Figueroa, Maria, and Solary, Eric. Wed .
"Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents". United States. https://doi.org/10.1038/ncomms10767. https://www.osti.gov/servlets/purl/1246362.
@article{osti_1246362,
title = {Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents},
author = {Merlevede, Jane and Droin, Nathalie and Qin, Tingting and Meldi, Kristen and Yoshida, Kenichi and Morabito, Margot and Chautard, Emilie and Auboeuf, Didier and Fenaux, Pierre and Braun, Thorsten and Itzykson, Raphael and de Botton, Stephane and Quesnel, Bruno and Commes, Therese and Jourdan, Eric and Vainchenker, William and Bernard, Olivier and Pata-Merci, Noemie and Solier, Stephanie and Gayevskiy, Velimir and Dinger, Marcel E. and Cowley, Mark J. and Selimoglu-Buet, Dorothee and Meyer, Vincent and Artiguenave, Francois and Deleuze, Jean -Francois and Preudhomme, Claude and Stratton, Michael R. and Alexandrov, Ludmil B. and Padron, Eric and Ogawa, Seishi and Koscielny, Serge and Figueroa, Maria and Solary, Eric},
abstractNote = {The cytidine analogues azacytidine and 5-aza-2’-deoxycytidine (decitabine) are commonly used to treat myelodysplastic syndromes, with or without a myeloproliferative component. It remains unclear whether the response to these hypomethylating agents results from a cytotoxic or an epigenetic effect. In this study, we address this question in chronic myelomonocytic leukaemia. We describe a comprehensive analysis of the mutational landscape of these tumours, combining whole-exome and whole-genome sequencing. We identify an average of 14 ± 5 somatic mutations in coding sequences of sorted monocyte DNA and the signatures of three mutational processes. Serial sequencing demonstrates that the response to hypomethylating agents is associated with changes in DNA methylation and gene expression, without any decrease in the mutation allele burden, nor prevention of new genetic alteration occurence. Lastly, our findings indicate that cytosine analogues restore a balanced haematopoiesis without decreasing the size of the mutated clone, arguing for a predominantly epigenetic effect.},
doi = {10.1038/ncomms10767},
journal = {Nature Communications},
number = ,
volume = 7,
place = {United States},
year = {Wed Feb 24 00:00:00 EST 2016},
month = {Wed Feb 24 00:00:00 EST 2016}
}
Web of Science
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