Impaired NK cell differentiation of blood-derived CD34+ progenitors from patients with myeloid metaplasia with myelofibrosis.
Cultured blood CD34(+) progenitors from patients with myeloid metaplasia with myelofibrosis (MMM) failed to differentiate into natural killer (NK) cells with recombinant interleukin (IL)-15. No NK cells either could be induced in coculture with IL-15-expressing fibroblasts from MMM patients' spleens. The impaired NK differentiation could be circumvented by using normal blood CD34(+) cells in the coculture. In this case, cell-to-cell contact and IL-15 interaction were crucial for NK cell differentiation. Pretreatment of normal CD34(+) progenitors with anti-IL-15 monoclonal antibody markedly reduced NK cell production while MMM fibroblast pretreatment did not. Both normal and MMM progenitors constitutively expressed IL-15. Analysis of endogenous IL-15 signaling pathway revealed a constitutive gammac/Jak3 association and STAT3 activation in the two types of progenitors. Anti-IL-15 monoclonal antibody treatment caused a downregulation of IL-15 signaling in normal but not MMM blood cells. The impaired NK differentiation in MMM may thus arise from a deregulated control of an endogenous IL-15 involved in hematopoietic progenitors' lymphoid differentiation.
Briard
Diane
D
Inserm U268, Hôpital Paul Brousse, Villejuif cedex 94807, France.
Brouty-Boyé
Danièle
D
Giron-Michel
Julien
J
Azzarone
Bruno
B
Jasmin
Claude
C
Le Bousse-Kerdilès
Caroline
C
D000368:Aged; D018952:Antigens, CD34 / Q000032:analysis*; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D016130:Immunophenotyping; D019409:Interleukin-15 / Q000032:analysis / Q000502:physiology; D007694:Killer Cells, Natural / Q000502:physiology*; D008875:Middle Aged; D055728:Primary Myelofibrosis / Q000276:immunology*; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism
D018952:Antigens, CD34; D004268:DNA-Binding Proteins; D019409:Interleukin-15; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators