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

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., Oct-2016, In : Leukemia. 30, 10, p. 2064-2073 10 p.

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  • Modeling BCR-ABL and MLL-AF9 leukemia in a human bone

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DOI

Although NOD-SCID IL2R gamma(-/-) (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.

Original languageEnglish
Pages (from-to)2064-2073
Number of pages10
JournalLeukemia
Volume30
Issue number10
Publication statusPublished - Oct-2016

    Keywords

  • HUMAN HEMATOPOIETIC-CELLS, HYPOXIA-INDUCIBLE FACTORS, ACUTE MYELOID-LEUKEMIA, CANCER STEM-CELLS, IMMUNODEFICIENT MICE, INITIATING CELLS, NOD/SCID MICE, SYSTEM MICE, GM-CSF, BMI1

ID: 37853744