Primitive quiescent CD34 + chronic my- eloid leukemia (CML) cells are more bio- logically resistant to tyrosine kinase in- hibitors than their cycling counterparts; however, graft-versus-leukemia (GVL) ef-fects after allogeneic stem cell transplan- tation (SCT) probably eliminate even these quiescent cells in long-term surviving CML transplant recipients. We studied the progeny of CD34 + cells from CML patients before SCT, which were cultured 4 days in serum-free media with hemato-poietic growth factors. BCR-ABL expres- sion was similar in both cycling and quies- cent noncycling CD34 + populations. Quiescent CD34 + cells from CML patients were less susceptible than their cycling CD34 + and CD34 - counterparts to lysis by natural killer (NK) cells from their HLA-identical sibling donors. Compared with cycling populations, quiescent CD34 + CML cells had higher surface ex- pression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) recep- tors DR4 and DR5. Bortezomib up- regulated TRAIL receptor expression on quiescent CD34 + CML cells, and further enhanced their susceptibility to cytotoxic- ity by in vitro expanded donor NK cells. These results suggest that donor-derived NK cell-mediated GVL effects may be im- proved by sensitizing residual quiescent CML cells to NK-cell cytotoxicity after SCT. Such treatment, as an adjunct to donor lymphocyte infusions and pharma- cologic therapy, may reduce the risk of relapse in CML patients who require treat- ment by SCT.
ASJC Scopus subject areas
- Cell Biology