title: Targeted positron emission tomography imaging of CXCR4 expression in patients with acute myeloid leukemia.
abstract: Acute myeloid leukemia originates from leukemia-initiating cells that reside in the protective bone marrow niche. CXCR4/CXCL12 interaction is crucially involved in recruitment and retention of leukemia-initiating cells within this niche. Various drugs targeting this pathway have entered clinical trials. To evaluate CXCR4 imaging in acute myeloid leukemia, we first tested CXCR4 expression in patient-derived primary blasts. Flow cytometry revealed that high blast counts in patients with acute myeloid leukemia correlate with high CXCR4 expression. The wide range of CXCR4 surface expression in patients was reflected in cell lines of acute myeloid leukemia. Next, we evaluated the CXCR4-specific peptide Pentixafor by positron emission tomography imaging in mice harboring CXCR4 positive and CXCR4 negative leukemia xenografts, and in 10 patients with active disease. [(68)Ga]Pentixafor-positron emission tomography showed specific measurable disease in murine CXCR4 positive xenografts, but not when CXCR4 was knocked out with CRISPR/Cas9 gene editing. Five of 10 patients showed tracer uptake correlating well with leukemia infiltration assessed by magnetic resonance imaging. The mean maximal standard uptake value was significantly higher in visually CXCR4 positive patients compared to CXCR4 negative patients. In summary, in vivo molecular CXCR4 imaging by means of positron emission tomography is feasible in acute myeloid leukemia. These data provide a framework for future diagnostic and theranostic approaches targeting the CXCR4/CXCL12-defined leukemia-initiating cell niche.
authors.affiliation: III Medical Department, Technische Universität München, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Herhaus
authors.affiliation: III Medical Department, Technische Universität München, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Habringer
authors.affiliation: III Medical Department, Technische Universität München, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Philipp-Abbrederis
authors.affiliation: Nuclear Medicine Department, Technische Universität München, Germany.
authors.forename: Tibor
authors.initials: T
authors.lastname: Vag
authors.affiliation: Nuclear Medicine Department, Technische Universität München, Germany.
authors.forename: Carlos
authors.initials: C
authors.lastname: Gerngross
authors.affiliation: Pharmaceutical Radiochemistry, Technische Universität München, Germany.
authors.forename: Margret
authors.initials: M
authors.lastname: Schottelius
authors.affiliation: Department of Pathology, Technische Universität München, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Slotta-Huspenina
authors.affiliation: Department of Pathology, Technische Universität München, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Steiger
authors.affiliation: III Medical Department, Ludwig-Maximilians-Universität, Munich, Germany, Germany.
authors.forename: Torben
authors.initials: T
authors.lastname: Altmann
authors.affiliation: III Medical Department, Technische Universität München, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Weißer
authors.affiliation: III Medical Department, Technische Universität München, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Steidle
authors.affiliation: III Medical Department, Technische Universität München, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schick
authors.affiliation: Nuclear Medicine Department, Technische Universität München, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Jacobs
authors.affiliation: Nuclear Medicine Department, Technische Universität München, Germany.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Slawska
authors.affiliation: III Medical Department, Technische Universität München, Germany.
authors.forename: Catharina
authors.initials: C
authors.lastname: Müller-Thomas
authors.affiliation: III Medical Department, Technische Universität München, Germany.
authors.forename: Mareike
authors.initials: M
authors.lastname: Verbeek
authors.affiliation: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany III Medical Department, Ludwig-Maximilians-Universität, Munich, Germany, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Subklewe
authors.affiliation: III Medical Department, Technische Universität München, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Peschel
authors.affiliation: Department of Pathology, Technische Universität München, Germany.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Wester
authors.affiliation: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Nuclear Medicine Department, Technische Universität München, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaiger
authors.affiliation: III Medical Department, Technische Universität München, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Götze
authors.affiliation: III Medical Department, Technische Universität München, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany ulrich.keller@tum.de.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Keller
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D056831:Coordination Complexes; D004195:Disease Models, Animal; D015870:Gene Expression; D055786:Gene Knockout Techniques; D018390:Gene Targeting; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000000981:diagnostic imaging* / Q000235:genetics* / Q000473:pathology; D008279:Magnetic Resonance Imaging / Q000379:methods; D057054:Molecular Imaging / Q000379:methods; D010456:Peptides, Cyclic; D049268:Positron-Emission Tomography / Q000379:methods; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C000597686:68Ga-pentixafor; D056831:Coordination Complexes; D010456:Peptides, Cyclic; D019718:Receptors, CXCR4