Abstract
The mechanism by which leukemic cells interfere with normal hematopoiesis remains unclear. We show that, whereas the leukemic KG1a cells are naturally devoid from cellular cytotoxicity, once activated by TNFα, they display cytolytic activity towards various cellular targets including CFU-GM. This mechanism is dependent on stimulation of Granzyme B/Perforin system. In addition, KG1a cells expressed the NKG2D receptor and its signal-transducing adaptator DAP10, which were functional as confirmed by redirected lysis experiments. Interestingly, flow cytometry analysis of 20 samples of patient with acute myeloid leukemia (AML) (FAB M0 to M5) revealed the expression of NKG2D (40%) and other natural cytotoxicity receptors (40% for NKp30, 74% for NKp44, 39% for NKp46) by pool >15% of leukemic cells. Futhermore, CD34+ hematopoietic progenitors undergoing granulo-monocytic differentiation expressed NKG2D ligands. Altogether, we propose a model in which upon stimulation by TNFα leukemic cells may exert cytotoxicity against myeloid progenitors. This finding may have important clinical implications in the context of diseases characterized by TNFα accumulation, such as AML or myelodisplasic syndromes.
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