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Title: Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents

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] ;  [5] ;  [6] ;  [7] ;  [8] ;  [7] ;  [1] ;  [9] ;  [10] ;  [11] ;  [1] ;  [1] ;  [12] ;  [1] ;  [13] more »;  [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:
OSTI Identifier:
1246362
Report Number(s):
LA-UR--15-24070
Journal ID: ISSN 2041-1723; ncomms10767
Grant/Contract Number:
AC52-06NA25396
Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 7; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Research Org:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES biological sciences; cancer; genetics