Blood Journal
Leading the way in experimental and clinical research in hematology

Clonal architecture of chronic myelomonocytic leukemias

  1. Raphaël Itzykson1,
  2. Olivier Kosmider2,
  3. Aline Renneville3,
  4. Margot Morabito4,
  5. Claude Preudhomme5,
  6. Céline Berthon6,
  7. Lionel Adès7,
  8. Pierre Fenaux7,
  9. Uwe Platzbecker8,
  10. Olivier Gagey9,
  11. Philippe Rameau10,
  12. Guillaume Meurice10,
  13. Cédric Oréar10,
  14. François Delhommeau11,
  15. Olivier A. Bernard12,
  16. Michaela Fontenay13,
  17. William Vainchenker1,
  18. Nathalie Droin1, and
  19. Eric Solary1,*
  1. 1 Inserm UMR1009, Institut Gustave Roussy, Villejuif, France;
  2. 2 Assistance Publique-Hopitaux de Paris (AP-HP), Hematologie Biologique, Hopital Cochin, Paris, France;
  3. 3 Laboratory of Hematology, Biology and Pathology Center, CHRU of Lille, Lille, France;
  4. 4 Faculty of Medicine, University Paris-Sud, Le Kremlin-Bicetre, France;
  5. 5 University of Lille Nord de France, Lille, France;
  6. 6 CHRU de Lille, Clinical hematology Unit, CHU Lille, France;
  7. 7 Hopital Avicenne, Assistance Publique-Hopitaux de Paris, Service d'Hematologie Clinique, University Paris XIII, Bobigny, France;
  8. 8 Medizinische Klinik und Poliklinik I, Universitaetsklinikum 'Carl Gustav Carus' Dresden, Dresden, Germany;
  9. 9 Assistance Publique-Hopitaux de Paris (AP-HP), Service de Chirurgie Orthopedique, Le Kremlin-Bicetre, France;
  10. 10 IFR54, Institut Gustave Roussy, Villejuif, France;
  11. 11 UPMC Univ Paris 06, GRC no 07, Groupe de Recherche Clinique sur les Myeloproliferations Aigues et Chroniques MyPAC, Paris, France;
  12. 12 Inserm UMR985, Institut Gustave Roussy, Villejuif, France;
  13. 13 Faculte de Medecine, Universite Paris Descartes, Paris, France
  1. * Corresponding author; email: eric.solary{at}igr.fr

Key points

  • Early clonal dominance may distinguish chronic myelomonocytic leukemia from other chronic myeloid neoplasms with similar gene mutations

  • Early dominance of TET2 mutated cells in the hematopoietic tissue promotes myeloid differentiation skewing towards the granulomonocytic line

Abstract

Genomic studies in chronic myeloid malignancies, including myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), and MPN/MDS, have identified common mutations in genes encoding signaling, epigenetic, transcription and splicing factors. In the present study, we interrogated the clonal architecture by mutation-specific discrimination analysis of single-cell-derived colonies in 28 patients with chronic myelomonocytic leukemias (CMML), the most frequent MPN/MDS. This analysis reveals a linear acquisition of the studied mutations with limited branching through loss of heterozygosity. Serial analysis of untreated and treated samples demonstrates a dynamic architecture on which most current therapeutic approaches have limited effects. The main disease characteristics are early clonal dominance, arising at the CD34+/CD38- stage of hematopoiesis, and granulomonocytic differentiation skewing of multipotent and common myeloid progenitors. Comparison of clonal expansions of TET2 mutations in MDS, MPN and CMML, together with functional invalidation of TET2 in sorted progenitors, suggests a causative link between early clonal dominance and skewed granulomonocytic differentiation. Altogether, early clonal dominance may distinguish CMML from other chronic myeloid neoplasms with similar gene mutations.

  • Submitted June 28, 2012.
  • Accepted November 28, 2012.