Submitted May 21, 2008
Accepted September 21, 2008
Primitive quiescent CD34+ cells in chronic myeloid leukemia are targeted by
in vitro expanded natural killer cells, which are functionally enhanced by bortezomib
Agnes SM Yong*, Keyvan Keyvanfar, Nancy Hensel, Rhoda Eniafe, Bipin N Savani, Maria Berg, Andreas Lundqvist, Sharon Adams, Elaine M Sloand, John M Goldman, Richard Childs, and A John Barrett
Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States
Vanderbilt University and VAMC Transplant Program, Nashville, Tennessee, United States
Department of Haematology, Imperial College London, Hammersmith Hospital, London, United Kingdom
* Corresponding author; email: yonga{at}nhlbi.nih.gov.
Primitive quiescent CD34+ chronic myeloid leukemia (CML) cells are more biologically resistant to tyrosine kinase inhibitors than their cycling counterparts; however, graft-versus-leukemia (GVL) effects following allogeneic stem cell transplantation (SCT) probably eliminate even these quiescent cells in long-term surviving CML transplant recipients. We studied the progeny of CD34+ cells from CML patients prior to SCT, which were cultured 4 days in serum-free media with hematopoietic growth factors. BCR-ABL expression was similar in both cycling and quiescent non-cycling CD34+ populations. Quiescent CD34+ cells from CML patients were less susceptible than their cycling CD34+ and CD34-negative counterparts to lysis by natural killer (NK) cells from their HLA-identical sibling donors. Compared to cycling populations, quiescent CD34+ CML cells had higher surface expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors DR4 and DR5. Bortezomib upregulated TRAIL receptor expression on quiescent CD34+ CML cells, and further enhanced their susceptibility to cytotoxicity by in vitro expanded donor NK cells. These results suggest that donor-derived NK-mediated GVL effects may be improved by sensitizing residual quiescent CML cells to NK-cytotoxicity post-SCT. Such treatment, as an adjunct to donor lymphocyte infusions and pharmacological therapy, may reduce the risk of relapse in CML patients who require treatment by SCT.
