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Article Dans Une Revue Blood Année : 2013

Clonal architecture of chronic myelomonocytic leukemias.

Olivier Kosmider
Lionel Adès
Pierre Fenaux
  • Fonction : Auteur
Michaela Fontenay

Résumé

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.

Dates et versions

hal-00923316 , version 1 (02-01-2014)

Identifiants

Citer

Raphaël Itzykson, Olivier Kosmider, Aline Renneville, Margot Morabito, Claude Preudhomme, et al.. Clonal architecture of chronic myelomonocytic leukemias.. Blood, 2013, 121 (12), pp.2186-98. ⟨10.1182/blood-2012-06-440347⟩. ⟨hal-00923316⟩
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