title: inv(16) and NPM1mut AMLs engraft human cytokine knock-in mice.
abstract: Favorable-risk human acute myeloid leukemia (AML) engrafts poorly in currently used immunodeficient mice, possibly because of insufficient environmental support of these leukemic entities. To address this limitation, we here transplanted primary human AML with isolated nucleophosmin (NPM1) mutation and AML with inv(16) in mice in which human versions of genes encoding cytokines important for myelopoiesis (macrophage colony-stimulating factor [M-CSF], interleukin-3, granulocyte-macrophage colony-stimulating factor, and thrombopoietin) were knocked into their respective mouse loci. NPM1mutAML engrafted with higher efficacy in cytokine knock-in (KI) mice and showed a trend toward higher bone marrow engraftment levels in comparison with NSG mice. inv(16) AML engrafted with high efficacy and was serially transplantable in cytokine KI mice but, in contrast, exhibited virtually no engraftment in NSG mice. Selected use of cytokine KI mice revealed that human M-CSF was required for inv(16) AML engraftment. Subsequent transcriptome profiling in an independent AML patient study cohort demonstrated high expression of M-CSF receptor and enrichment of M-CSF inducible genes in inv(16) AML cases. This study thus provides a first xenotransplantation mouse model for and informs on the disease biology of inv(16) AML.
authors: Hematology, University Hospital and University of Zurich, Zurich, Switzerland.
authors: Jana M
authors: JM
authors: Ellegast
authors: Hematology, University Hospital and University of Zurich, Zurich, Switzerland; Department of Medicine, Boston University School of Medicine, Boston, MA.
authors: Philipp J
authors: PJ
authors: Rauch
authors: Hematology, University Hospital and University of Zurich, Zurich, Switzerland.
authors: Larisa V
authors: LV
authors: Kovtonyuk
authors: Hematology, University Hospital and University of Zurich, Zurich, Switzerland.
authors: Rouven
authors: R
authors: Müller
authors: Institute of Surgical Pathology, University Hospital of Zurich, Zurich, Switzerland.
authors: Ulrich
authors: U
authors: Wagner
authors: Hematology, University Hospital and University of Zurich, Zurich, Switzerland; Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan; and.
authors: Yasuyuki
authors: Y
authors: Saito
authors: Hematology, University Hospital and University of Zurich, Zurich, Switzerland.
authors: Nicole
authors: N
authors: Wildner-Verhey van Wijk
authors: Institute of Surgical Pathology, University Hospital of Zurich, Zurich, Switzerland.
authors: Christine
authors: C
authors: Fritz
authors: Hematology, University Hospital and University of Zurich, Zurich, Switzerland.
authors: Anahita
authors: A
authors: Rafiei
authors: Hematology, University Hospital and University of Zurich, Zurich, Switzerland.
authors: Veronika
authors: V
authors: Lysenko
authors: Hematology, University Hospital and University of Zurich, Zurich, Switzerland.
authors: Ewa
authors: E
authors: Dudkiewicz
authors: Hematology, University Hospital and University of Zurich, Zurich, Switzerland.
authors: Alexandre P
authors: AP
authors: Theocharides
authors: Institute of Surgical Pathology, University Hospital of Zurich, Zurich, Switzerland.
authors: Davide
authors: D
authors: Soldini
authors: Hematology, University Hospital and University of Zurich, Zurich, Switzerland.
authors: Jeroen S
authors: JS
authors: Goede
authors: Department of Immunobiology and Howard Hughes Medical Institute, Yale University, New Haven, CT.
authors: Richard A
authors: RA
authors: Flavell
authors: Hematology, University Hospital and University of Zurich, Zurich, Switzerland.
authors: Markus G
authors: MG
authors: Manz
mesh_terms: D000818:Animals; D002869:Chromosome Aberrations; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D016207:Cytokines; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D064593:Heterografts; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology; D051379:Mice; D009154:Mutation; D009368:Neoplasm Transplantation / Q000379:methods*; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D014183:Transplantation, Heterologous / Q000379:methods*
chemical_list: D016207:Cytokines; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D000090243:Nucleophosmin