Biology and prognostic impact of clonal plasmacytoid dendritic cells in chronic myelomonocytic leukemia.
Lucas N, Duchmann M, Rameau P, Noël F, Michea P, Saada V, Kosmider O, Pierron G, Fernandez-Zapico ME, Howard MT, King RL, Niyongere S, Diop MK, Fenaux P, Itzykson R, Willekens C, Ribrag V, Fontenay M, Padron E, Soumelis V, Droin N, Patnaik MM, Solary E
Islands of CD123 cells have been commonly described in the bone marrow of patients with chronic myelomonocytic leukemia (CMML). Using a multiparameter flow cytometry assay, we detected an excess of CD123 mononucleated cells that are lineage-negative, CD45, CD11c, CD33, HLA-DR, BDCA-2, BDCA-4 in the bone marrow of 32/159 (20%) patients. Conventional and electron microscopy, flow cytometry detection of cell surface markers, gene expression analyses, and the ability to synthesize interferon alpha in response to Toll-like receptor agonists identified these cells as bona fide plasmacytoid dendritic cells (pDCs). Whole-exome sequencing of sorted monocytes and pDCs identified somatic mutations in genes of the oncogenic RAS pathway in the two cell types of every patient. CD34 cells could generate high amount of pDCs in the absence of FMS-like tyrosine kinase 3-ligand (FLT3L). Finally, an excess of pDCs correlates with regulatory T cell accumulation and an increased risk of acute leukemia transformation. These results demonstrate the FLT3L-independent accumulation of clonal pDCs in the bone marrow of CMML patients with mutations affecting the RAS pathway, which is associated with a higher risk of disease progression.Lire l‘article