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Title: 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:
 [1];  [2];  [3];  [3];  [4];  [1]; ORCiD logo [5];  [6];  [7];  [8];  [7];  [1];  [9];  [10];  [11];  [1];  [1];  [12];  [1];  [13] more »; ORCiD logo [13];  [13];  [1];  [14];  [14];  [14];  [9];  [15];  [16];  [17];  [4];  [18];  [3];  [19] « less
  1. INSERM U1170, Villejuif (France); Gustave Roussy Cancer Center, Villejuif (France)
  2. INSERM U1170, Villejuif (France); Gustave Roussy Cancer Center, Villejuif (France); INSERM US23, Villejuif (France)
  3. Univ. of Michigan Medical School, Ann Arbor, MI (United States)
  4. Kyoto Univ., Kyoto (Japan)
  5. Univ. Lyon 1, UMR CNRS 5558, Univ. Claude Bernard, Lyon (France)
  6. Centre Leon Berard, INSERM U1052, CNRS UMR5286, Lyon (France)
  7. Hopital Saint-Louis, Paris (France)
  8. Hopital Avicenne, Bobigny (France)
  9. Cancer Research Institute de Lille, INSERM U837, Lille (France)
  10. INSERM U1040, Univ. de Montpellier, Montpellier (France)
  11. Centre Hospitalier Univ. de Nimes, Univ. Montpellier-Nimes, Nimes (France)
  12. INSERM US23, Villejuif (France)
  13. Kinghor Center for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst New South Wales (Australia)
  14. Centre National de Genotypage, Evry (France)
  15. Wellcome Trust Sanger Institute, Cambridgeshire (United Kingdom)
  16. Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Wellcome Trust Sanger Institute, Cambridgeshire (United Kingdom)
  17. H. Lee Moffitt Cancer Center, Tampa, FL (United States)
  18. Gustave Roussy Cancer Center, Villejuif (France)
  19. 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}
}

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Clonal evolution in myelodysplastic syndromes
journal, April 2017

  • da Silva-Coelho, Pedro; Kroeze, Leonie I.; Yoshida, Kenichi
  • Nature Communications, Vol. 8, Issue 1
  • DOI: 10.1038/ncomms15099

Dynamics of clonal evolution in myelodysplastic syndromes
journal, December 2016

  • Makishima, Hideki; Yoshizato, Tetsuichi; Yoshida, Kenichi
  • Nature Genetics, Vol. 49, Issue 2
  • DOI: 10.1038/ng.3742

Ongoing clonal evolution in chronic myelomonocytic leukemia on hypomethylating agents: a computational perspective
journal, March 2018


Blast-phase chronic myelomonocytic leukemia: more than just semantics
journal, August 2018


Biology and prognostic impact of clonal plasmacytoid dendritic cells in chronic myelomonocytic leukemia
journal, March 2019


EZH2 mutations in chronic myelomonocytic leukemia cluster with ASXL1 mutations and their co-occurrence is prognostically detrimental
journal, January 2018

  • Patnaik, Mrinal M.; Vallapureddy, Rangit; Lasho, Terra L.
  • Blood Cancer Journal, Vol. 8, Issue 1
  • DOI: 10.1038/s41408-017-0045-4

Infrequent occurrence of TET1, TET3, and ASXL2 mutations in myelodysplastic/myeloproliferative neoplasms
journal, March 2018

  • Lasho, Terra L.; Vallapureddy, Rangit; Finke, Christy M.
  • Blood Cancer Journal, Vol. 8, Issue 3
  • DOI: 10.1038/s41408-018-0057-8

Multicenter validation of the flow measurement of classical monocyte fraction for chronic myelomonocytic leukemia diagnosis
journal, November 2018


A miR-150/TET3 pathway regulates the generation of mouse and human non-classical monocyte subset
journal, December 2018

  • Selimoglu-Buet, Dorothée; Rivière, Julie; Ghamlouch, Hussein
  • Nature Communications, Vol. 9, Issue 1
  • DOI: 10.1038/s41467-018-07801-x

Understanding mutagenesis through delineation of mutational signatures in human cancer
journal, May 2016


The evolving role of next generation sequencing in myelodysplastic syndromes
journal, August 2019

  • Spaulding, Travis P.; Stockton, Shannon S.; Savona, Michael R.
  • British Journal of Haematology, Vol. 188, Issue 2
  • DOI: 10.1111/bjh.16212

Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors
journal, August 2018

  • Anderson, Nathaniel D.; de Borja, Richard; Young, Matthew D.
  • Science, Vol. 361, Issue 6405
  • DOI: 10.1126/science.aam8419

How I treat chronic myelomonocytic leukemia
journal, July 2017


MDS overlap disorders and diagnostic boundaries
journal, March 2019


DNA methylation identifies genetically and prognostically distinct subtypes of myelodysplastic syndromes
journal, October 2019


Comprehensive mutation profiling and mRNA expression analysis in atypical chronic myeloid leukemia in comparison with chronic myelomonocytic leukemia
journal, January 2019

  • Faisal, Muhammad; Stark, Helge; Büsche, Guntram
  • Cancer Medicine, Vol. 8, Issue 2
  • DOI: 10.1002/cam4.1946

CMML: Clinical and molecular aspects
journal, April 2017

  • Itzykson, Raphael; Duchmann, Matthieu; Lucas, Nolwenn
  • International Journal of Hematology, Vol. 105, Issue 6
  • DOI: 10.1007/s12185-017-2243-z

Turning the tide in myelodysplastic/myeloproliferative neoplasms
journal, June 2017

  • Deininger, Michael W. N.; Tyner, Jeffrey W.; Solary, Eric
  • Nature Reviews Cancer, Vol. 17, Issue 7
  • DOI: 10.1038/nrc.2017.40

A comparison of clinical and molecular characteristics of patients with systemic mastocytosis with chronic myelomonocytic leukemia to CMML alone
journal, April 2018

  • Patnaik, Mrinal M.; Vallapureddy, Rangit; Lasho, Terra L.
  • Leukemia, Vol. 32, Issue 8, p. 1850-1856
  • DOI: 10.1038/s41375-018-0121-1

Blast phase chronic myelomonocytic leukemia: Mayo-MDACC collaborative study of 171 cases
journal, April 2018


Heterogeneous expression of cytokines accounts for clinical diversity and refines prognostication in CMML
journal, July 2018


Dynamic gene regulation by nuclear colony-stimulating factor 1 receptor in human monocytes and macrophages
journal, April 2019

  • Bencheikh, Laura; Diop, M’Boyba Khadija; Rivière, Julie
  • Nature Communications, Vol. 10, Issue 1
  • DOI: 10.1038/s41467-019-09970-9

Incidence and survival outcomes of chronic myelomonocytic leukemia in the United States
journal, November 2016


Mutational landscape and response are conserved in peripheral blood of AML and MDS patients during decitabine therapy
journal, March 2017


How I treat MDS after hypomethylating agent failure
journal, February 2019


Direct modulation of the bone marrow mesenchymal stromal cell compartment by azacitidine enhances healthy hematopoiesis
journal, December 2018


A clinical-molecular update on azanucleoside-based therapy for the treatment of hematologic cancers
journal, June 2016


The repertoire of mutational signatures in human cancer
journal, February 2020


Comprehensive mutation profiling and mRNA expression analysis in atypical chronic myeloid leukemia in comparison with chronic myelomonocytic leukemia
journal, January 2019

  • Faisal, Muhammad; Stark, Helge; Büsche, Guntram
  • Cancer Medicine, Vol. 8, Issue 2
  • DOI: 10.1002/cam4.1946

Number and type of TET2 mutations in chronic myelomonocytic leukemia and their clinical relevance
journal, September 2016

  • Patnaik, M. M.; Zahid, M. F.; Lasho, T. L.
  • Blood Cancer Journal, Vol. 6, Issue 9
  • DOI: 10.1038/bcj.2016.82

Clonal evolution in myelodysplastic syndromes
journal, April 2017

  • da Silva-Coelho, Pedro; Kroeze, Leonie I.; Yoshida, Kenichi
  • Nature Communications, Vol. 8, Issue 1
  • DOI: 10.1038/ncomms15099

Blast phase chronic myelomonocytic leukemia: Mayo-MDACC collaborative study of 171 cases
journal, April 2018


EZH2 mutations in chronic myelomonocytic leukemia cluster with ASXL1 mutations and their co-occurrence is prognostically detrimental
journal, January 2018

  • Patnaik, Mrinal M.; Vallapureddy, Rangit; Lasho, Terra L.
  • Blood Cancer Journal, Vol. 8, Issue 1
  • DOI: 10.1038/s41408-017-0045-4

Infrequent occurrence of TET1, TET3, and ASXL2 mutations in myelodysplastic/myeloproliferative neoplasms
journal, March 2018

  • Lasho, Terra L.; Vallapureddy, Rangit; Finke, Christy M.
  • Blood Cancer Journal, Vol. 8, Issue 3
  • DOI: 10.1038/s41408-018-0057-8

The repertoire of mutational signatures in human cancer
journal, February 2020


Seave: a comprehensive web platform for storing and interrogating human genomic variation
journal, July 2018


Dark selection for JAK/STAT-inhibitor resistance in chronic myelomonocytic leukemia
preprint, October 2017

  • Kaznatcheev, Artem; Grimes, David Robert; Velde, Robert Vander
  • DOI: 10.1101/211151

CBL family E3 ubiquitin ligases control JAK2 ubiquitination and stability in hematopoietic stem cells and myeloid malignancies
journal, May 2017


A clinical-molecular update on azanucleoside-based therapy for the treatment of hematologic cancers
journal, June 2016


Genomic Biomarkers to Predict Resistance to Hypomethylating Agents in Patients With Myelodysplastic Syndromes Using Artificial Intelligence
journal, December 2019

  • Nazha, Aziz; Sekeres, Mikkael A.; Bejar, Rafael
  • JCO Precision Oncology, Issue 3
  • DOI: 10.1200/po.19.00119