title: Modeling BCR-ABL and MLL-AF9 leukemia in a human bone marrow-like scaffold-based xenograft model.
abstract: Although NOD-SCID IL2Rγ-/-(NSG) xenograft mice are currently the most frequently used model to study human leukemia in vivo, the absence of a human niche severely hampers faithful recapitulation of the disease. We used NSG mice in which ceramic scaffolds seeded with human mesenchymal stromal cells were implanted to generate a human bone marrow (huBM-sc)-like niche. We observed that, in contrast to the murine bone marrow (mBM) niche, the expression of BCR-ABL or MLL-AF9 was sufficient to induce both primary acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL). Stemness was preserved within the human niches as demonstrated by serial transplantation assays. Efficient engraftment of AML MLL-AF9 and blast-crisis chronic myeloid leukemia patient cells was also observed, whereby the immature blast-like phenotype was maintained in the huBM-sc niche but to a much lesser extent in mBM niches. We compared transcriptomes of leukemias derived from mBM niches versus leukemias from huBM-like scaffold-based niches, which revealed striking differences in the expression of genes associated with hypoxia, mitochondria and metabolism. Finally, we utilized the huBM-sc MLL-AF9 B-ALL model to evaluate the efficacy of the I-BET151 inhibitor in vivo. In conclusion, we have established human niche models in which the myeloid and lymphoid features of BCR-ABL+and MLL-AF9+leukemias can be studied in detail.
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen (CRCG), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Sontakke
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen (CRCG), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Carretta
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen (CRCG), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Jaques
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen (CRCG), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: A Z
authors.initials: AZ
authors.lastname: Brouwers-Vos
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Lubbers-Aalders
authors.affiliation: Xpand Biotechnology BV, Bilthoven, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Queen Mary University of London, School of Engineering and Materials Science (SEMS), London, UK.
authors.forename: J D
authors.initials: JD
authors.lastname: de Bruijn
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: A C M
authors.initials: AC
authors.lastname: Martens
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen (CRCG), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Vellenga
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: R W J
authors.initials: RW
authors.lastname: Groen
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen (CRCG), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: J J
authors.initials: JJ
authors.lastname: Schuringa
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology*; D004195:Disease Models, Animal; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein; D015514:Oncogene Proteins, Fusion; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D014183:Transplantation, Heterologous
chemical_list: C474558:MLL-AF9 fusion protein, human; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein; D016044:Fusion Proteins, bcr-abl