title: IL-8 as mediator in the microenvironment-leukaemia network in acute myeloid leukaemia.
abstract: The bone marrow microenvironment is physiologically hypoxic with areas being as low as 1% O2, e.g. the stem cell niche. Acute myeloid leukaemia (AML) blasts misuse these bone marrow niches for protection by the local microenvironment, but also might create their own microenvironment. Here we identify IL-8 as a hypoxia-regulated cytokine in both AML cell lines and primary AML samples that is induced within 48 hours of severe hypoxia (1% O2). IL-8 lacked effects on AML cells but induced migration in mesenchymal stromal cells (MSC), an integral part of the bone marrow. Accordingly, MSC were significantly increased in AML bone marrow as compared to healthy bone marrow. Interestingly, mononuclear cells obtained from healthy bone marrow displayed both significantly lower endogenous and hypoxia-induced production of IL-8. IL-8 mRNA expression in AML blasts from 533 patients differed between genetic subgroups with significantly lower expression of IL-8 in acute promyelocytic leukaemia (APL), while in non APL-AML patients with FLT ITD had the highest IL-8 expression. In this subgroup, high IL-8 expression was also prognostically unfavourable. In conclusion, hypoxia as encountered in the bone marrow specifically increases IL-8 expression of AML, which in turn impacts niche formation. High IL-8 expression might be correlated with poor prognosis in certain AML subsets.
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: Christina
authors.initials: C
authors.lastname: Rieger
authors.affiliation: Department of Internal Medicine III, Klinikum der Universität München, Munich, Germany.
authors.forename: Deborah
authors.initials: D
authors.lastname: Perathoner
authors.affiliation: Department of Internal Medicine III, Klinikum der Universität München, Munich, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Herold
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: Silvia
authors.initials: S
authors.lastname: Sironi
authors.affiliation: Institute of Pathology, Klinikum der Universität München, Munich, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Sotlar
authors.affiliation: Institute of Pathology, Klinikum der Universität München, Munich, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Horny
authors.affiliation: Department of Internal Medicine III, Klinikum der Universität München, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Deniffel
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.
authors.forename: Michael
authors.initials: M
authors.lastname: Fiegl
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D000860:Hypoxia; D007150:Immunohistochemistry; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D008875:Middle Aged; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055153:Stem Cell Niche / Q000235:genetics*; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D016209:Interleukin-8