title: Chemotherapeutic treatment of bone marrow stromal cells strongly affects their protective effect on acute myeloid leukemia cell survival.
abstract: Bone marrow stromal cells (BMSCs) have been found to support leukemic cell survival; however, the mechanisms responsible are far from elucidated yet. Therefore, the effect of BMSCs on both proliferation and apoptosis characteristics of acute myeloid leukaemia (AML) cells was investigated as well as the effect of BMSCs exposure to chemotherapy on the stromal supportive capacity. Leukemic HL-60 and primary AML cells were either untreated or treated with cytarabine and subsequently cultured for 3-4 days, in the presence or absence of untreated or cytarabine-treated BMSCs. The effect on proliferation and apoptosis was investigated with flow cytometry using CFSE labeling and Syto16 and 7AAD staining. BMSCs were found to maintain cytarabine-exposed primary AML cells by protection against spontaneous apoptosis. Accordingly, an increase in phosphorylated-AKT and Bcl-2 expression was found. Concomitant exposure of BMSCs to cytarabine resulted in a dose-dependent decrease of protective capacity of BMSCs. Thus, inhibition of spontaneous apoptosis of leukemic cells mediated by phosphorylation of AKT/Bcl-2 pathway results in protection of leukemic cells by BMSCs, which decreases after BMSCs exposure to chemotherapy. Targeting both the tumor cells and intervening in their interaction with the bone marrow microenvironment may thus affect clinical outcome in AML.
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Bijan
authors.initials: B
authors.lastname: Moshaver
authors.forename: Marjolein A
authors.initials: MA
authors.lastname: van der Pol
authors.forename: August H
authors.initials: AH
authors.lastname: Westra
authors.forename: Gert J
authors.initials: GJ
authors.lastname: Ossenkoppele
authors.forename: Sonja
authors.initials: S
authors.lastname: Zweegman
authors.forename: Gerrit Jan
authors.initials: GJ
authors.lastname: Schuurhuis
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001853:Bone Marrow; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects*; D003561:Cytarabine / Q000494:pharmacology; D015195:Drug Design; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects* / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D003561:Cytarabine; D051057:Proto-Oncogene Proteins c-akt