TNFalpha stimulates NKG2D-mediated lytic activity of acute myeloid leukemic cells.
The mechanism by which leukemic cells interfere with normal hematopoiesis remains unclear. We show here that, whereas the leukemic KG1a cells are naturally devoid from cellular cytotoxicity, once activated by TNFalpha, they display cytolytic activity toward various cellular targets including CFU-GM. This mechanism is dependent on stimulation of the granzyme B/perforin system. In addition, KG1a cells expressed the NKG2D receptor and its signal-transducing adaptator DAP 10, which were functional as confirmed by redirected lysis experiments. Interestingly, flow cytometry analysis of 20 samples of patients with acute myeloid leukemia (AML) (FAB M0-M5) revealed the expression of NKG2D (40%) and other natural cytotoxicity receptors (40% for NKp30, 74% for NKp44, 39% for NKp46) by a pool >15% of leukemic cells. Furthermore, CD34+ hematopoietic progenitors undergoing granulomonocytic differentiation expressed NKG2D ligands. Altogether, we propose a model in which, upon stimulation by TNFalpha, leukemic cells may exert cytotoxicity against myeloid progenitors. This finding may have important clinical implications in the context of diseases characterized by TNFalpha accumulation, such as AML or myelodisplasic syndromes.
Guilloton
F
F
INSERMU563/CPTP, Pavillon Lefebvre Bât B, Dpt G DELSOL, Equipe G LAURENT, CHU Purpan, Toulouse, France.
de Thonel
A
A
Jean
C
C
Demur
C
C
Mansat-De Mas
V
V
Laurent
G
G
Quillet-Mary
A
A
D000208:Acute Disease; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D053804:Granzymes; D006410:Hematopoiesis; D006801:Humans; D007951:Leukemia, Myeloid / Q000276:immunology / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000235:genetics; D023461:Myeloid Progenitor Cells / Q000166:cytology*; D055655:NK Cell Lectin-Like Receptor Subfamily K; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011971:Receptors, Immunologic / Q000032:analysis / Q000502:physiology*; D055607:Receptors, Natural Killer Cell; D012697:Serine Endopeptidases / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation
C527085:KLRK1 protein, human; D008562:Membrane Glycoproteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D052899:Pore Forming Cytotoxic Proteins; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases