title: Microenvironmental hypoxia regulates FLT3 expression and biology in AML.
abstract: Fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase constitutively expressed by acute myeloid leukaemia (AML) blasts. In addition, 25% of AML patients harbour a FLT3-ITD mutation, associated with inferior outcome due to increased relapse rate. Relapse might be propagated by interactions between AML blasts and the bone marrow microenvironment. Besides cellular elements of the microenvironment (e.g. mesenchymal stromal cells), bone marrow hypoxia has emerged as an additional crucial component. Hence, effects of hypoxia on FLT3 expression and biology could provide novel insight into AML biology. Here we show that 25% of AML patients down-regulate FLT3 expression on blasts in response to in vitro hypoxia (1% O2), which was independent of its mutational state. While virtually no AML cell lines regulate FLT3 in response to hypoxia, the down-regulation could be observed in Ba/F3 cells stably transfected with different FLT3 mutants. Hypoxia-mediated down-regulation was specific for FLT3, reversible and proteasome-dependent; with FLT3 half-life being significantly shorter at hypoxia. Also, PI-3K inhibition could partially abrogate down-regulation of FLT3. Hypoxia-mediated down-regulation of FLT3 conferred resistance against cytarabine in vitro. In conclusion, FLT3 expression in AML is dependent on the oxygen partial pressure, but response to hypoxia differs.
authors.affiliation: Department of Internal Medicine III, Klinikum der Universität München, Munich, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Sironi
authors.affiliation: Department of Internal Medicine III, Klinikum der Universität München, Munich, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Wagner
authors.affiliation: Department of Internal Medicine III, Klinikum der Universität München, Munich, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kuett
authors.affiliation: Department of Internal Medicine III, Klinikum der Universität München, Munich, Germany.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Drolle
authors.affiliation: Department of Internal Medicine III, Klinikum der Universität München, Munich, Germany.|Clinical Cooperation Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Polzer
authors.affiliation: Department of Internal Medicine III, Klinikum der Universität München, Munich, Germany.|Clinical Cooperation Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Spiekermann
authors.affiliation: Department of Internal Medicine III, Klinikum der Universität München, Munich, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Rieger
authors.affiliation: Department of Internal Medicine III, Klinikum der Universität München, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Fiegl
mesh_terms: D001784:Blood Gas Analysis; D045744:Cell Line, Tumor; D015536:Down-Regulation; D015870:Gene Expression; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D009154:Mutation; D010101:Oxygen Consumption; D011379:Prognosis; D014162:Transfection; D059016:Tumor Microenvironment / Q000235:genetics*; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: D051941:fms-Like Tyrosine Kinase 3