Modeling BCR-ABL and MLL-AF9 leukemia in a human bone marrow-like scaffold-based xenograft model

• Published in: Leukemia 2016-10, Vol.30 (10), p.2064-2073
• Main Authors: Sontakke, P, Carretta, M, Jaques, J, Brouwers-Vos, A Z, Lubbers-Aalders, L, Yuan, H, de Bruijn, J D, Martens, A C M, Vellenga, E, Groen, R W J, Schuringa, J J
• Format: Article
• Language: English
• Subjects: 13/100; 13/31; 13/95; 38/39; 42/100; 45/100; 631/45/612/1243; 631/67/1990/283; 631/67/70; 64/60; 692/699/1541/1990/283/1897; 692/699/1541/1990/283/2125; 692/700/565/545/576; Acute myeloid leukemia; Animals; BCR-ABL protein; Bone marrow; Bone Marrow - pathology; Cancer Research; Care and treatment; Chronic myeloid leukemia; Critical Care Medicine; Cytokines; Diagnosis; Disease Models, Animal; Fusion protein; Fusion Proteins, bcr-abl; Gene expression; Hematology; Humans; Hypoxia; In vivo methods and tests; Intensive; Internal Medicine; Leukemia; Leukemia, Myeloid, Acute - pathology; Lymphatic leukemia; Medical research; Medicine; Medicine & Public Health; Mesenchyme; Metabolism; Mice; Mitochondria; Myeloid-Lymphoid Leukemia Protein; Oncogene Proteins, Fusion; Oncology; original-article; Phenotypes; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Scaffolds; Stem cells; Stromal cells; Transcriptomes; Transplantation; Transplantation, Heterologous; Xenografts; Xenotransplantation
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2016.108

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.