Alpha-defensins secreted by dysplastic granulocytes inhibit the differentiation of monocytes in chronic myelomonocytic leukemia.
Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic disorder that occurs in elderly patients. One of the main diagnostic criteria is the accumulation of heterogeneous monocytes in the peripheral blood. We further explored this cellular heterogeneity and observed that part of the leukemic clone in the peripheral blood was made of immature dysplastic granulocytes with a CD14(-)/CD24(+) phenotype. The proteome profile of these cells is dramatically distinct from that of CD14(+)/CD24(-) monocytes from CMML patients or healthy donors. More specifically, CD14(-)/CD24(+) CMML cells synthesize and secrete large amounts of alpha-defensin 1-3 (HNP1-3). Recombinant HNPs inhibit macrophage colony-stimulating factor (M-CSF)-driven differentiation of human peripheral blood monocytes into macrophages. Using transwell, antibody-mediated depletion, suramin inhibition of purinergic receptors, and competitive experiments with uridine diphosphate (UDP)/uridine triphosphate (UTP), we demonstrate that HNP1-3 secreted by CD14(-)/CD24(+) cells inhibit M-CSF-induced differentiation of CD14(+)/CD24(-) cells at least in part through P2Y6, a receptor involved in macrophage differentiation. Altogether, these observations suggest that a population of immature dysplastic granulocytes contributes to the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the differentiation capabilities of monocytes.
Inserm UMR866, Dijon, France.
Nathalie
N
Droin
Arnaud
A
Jacquel
Jean-Baptiste
JB
Hendra
Cindy
C
Racoeur
Caroline
C
Truntzer
Delphine
D
Pecqueur
Naïma
N
Benikhlef
Marion
M
Ciudad
Leslie
L
Guery
Valérie
V
Jooste
Erick
E
Dufour
Pierre
P
Fenaux
Bruno
B
Quesnel
Olivier
O
Kosmider
Michaëla
M
Fontenay
Patrick
P
Ducoroy
Eric
E
Solary
D051927:CD24 Antigen / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D006098:Granulocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D015477:Leukemia, Myelomonocytic, Chronic / Q000378:metabolism / Q000473:pathology*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects / Q000473:pathology*; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D014530:Uridine Diphosphate / Q000494:pharmacology; D014544:Uridine Triphosphate / Q000494:pharmacology; D023084:alpha-Defensins / Q000378:metabolism* / Q000494:pharmacology
D051927:CD24 Antigen; D016207:Cytokines; D018950:Lipopolysaccharide Receptors; D018048:Receptors, Purinergic P2; D023084:alpha-Defensins; C099845:purinoceptor P2Y6; D014530:Uridine Diphosphate; D016173:Macrophage Colony-Stimulating Factor; D014544:Uridine Triphosphate