title: High susceptibility of c-KIT+CD34+ precursors to prolonged doxorubicin exposure interferes with Langerhans cell differentiation in a human cell line model.
abstract: As neoadjuvant and adjuvant chemotherapy schedules often consist of multiple treatment cycles over relatively long periods of time, it is important to know what effects protracted drug administration can have on the immune system. Here, we studied the long-term effects of doxorubicin on the capacity of dendritic cell (DC) precursors to differentiate into a particular DC subset, the Langerhans cells (LC). In order to achieve high telomerase activity as detected in hematological stem cells, precursor cells from the acute-myeloid leukemia (AML)-derived cell line MUTZ3 were stably transduced with human telomerase reverse transcriptase (hTERT) to facilitate their growth potential, while preventing growth, and drug-induced senescence, and preserving their unique capacity for cytokine-dependent DC and LC differentiation. The hTERT-MUTZ3 cells were selected with increasing concentrations of the anthracyclin doxorubicin. After 1-2 months of selection with 30-90 nM doxorubicin, the cells completely lost their capacity to differentiate into LC. This inhibition turned out to be reversible, as the cells slowly regained their capacity to differentiate after a 3- to 4-month drug-free period and with this became capable again of priming allogeneic T cells. Of note, the loss and gain of this capacity to differentiate coincided with the loss and gain of a subpopulation within the CD34(+) proliferative compartment with surface expression of the stem cell factor receptor (SCF-R/CD117/c-Kit). These data are in favor of cytostatic drug-free intervals before applying autologous DC-based vaccination protocols, as specific DC precursors may need time to recover from protracted chemotherapy treatment and re-emerge among the circulating CD34(+) hematopoietic stem and precursor cells.
authors: Division of Immunotherapy, Department of Medical Oncology, VU University Medical Center, De Boelelaan, Amsterdam, The Netherlands.
authors: Rieneke
authors: R
authors: van de Ven
authors: Sue Ellen
authors: SE
authors: Verbrugge
authors: Anneke W
authors: AW
authors: Reurs
authors: Hetty J
authors: HJ
authors: Bontkes
authors: Erik
authors: E
authors: Hooijberg
authors: Gerrit
authors: G
authors: Jansen
authors: Rik J
authors: RJ
authors: Scheper
authors: George L
authors: GL
authors: Scheffer
authors: Tanja D
authors: TD
authors: de Gruijl
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D018952:Antigens, CD34 / Q000378:metabolism*; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D007801:Langerhans Cells / Q000166:cytology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008954:Models, Biological; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000235:genetics / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D018952:Antigens, CD34; D012333:RNA, Messenger; D004317:Doxorubicin; D019009:Proto-Oncogene Proteins c-kit; C509186:TERT protein, human; D019098:Telomerase