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Modeling BCR-ABL and MLL-AF9 leukemia in a human bone marrow-like scaffold-based xenograft model
P Sontakke1, M Carretta1, J Jaques1
1Department of Experimental Hematology, Cancer Research Center Groningen (CRCG), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Leukemia
|April 30, 2016
Summary
Researchers developed a human bone marrow (huBM-sc) niche in mice to better study human leukemia. This model accurately recapitulates leukemia stemness and allows detailed investigation of BCR-ABL+ and MLL-AF9+ leukemias.
Area of Science:
- Hematology
- Oncology
- Biomedical Engineering
Background:
- Current NOD-SCID IL2Rγ-/- (NSG) xenograft models lack a human niche, limiting accurate human leukemia recapitulation.
- A functional human bone marrow (huBM-sc) niche is crucial for studying leukemia development and progression in vivo.
Purpose of the Study:
- To establish a humanized bone marrow niche model in NSG mice using ceramic scaffolds seeded with human mesenchymal stromal cells.
- To investigate the capacity of this huBM-sc niche to support the development and maintenance of human leukemia.
Main Methods:
- Implantation of ceramic scaffolds seeded with human mesenchymal stromal cells into NSG mice to create a huBM-sc niche.
- Induction of leukemia using BCR-ABL or MLL-AF9 expression within the humanized niche.
- Serial transplantation assays to assess leukemia stemness.
- Comparison of transcriptomes between leukemias grown in humanized versus murine niches.
- In vivo evaluation of I-BET151 inhibitor efficacy in a huBM-sc MLL-AF9 B-ALL model.
Main Results:
- The huBM-sc niche supported the induction of both acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) upon BCR-ABL or MLL-AF9 expression.
- Leukemia stemness was preserved in the huBM-sc niche, as confirmed by serial transplantation.
- Patient-derived AML MLL-AF9 and blast-crisis chronic myeloid leukemia cells showed efficient engraftment and maintained their immature phenotype in the huBM-sc niche.
- Transcriptomic analysis revealed significant differences in genes related to hypoxia, mitochondria, and metabolism between leukemias from humanized and murine niches.
- The huBM-sc MLL-AF9 B-ALL model demonstrated efficacy of the I-BET151 inhibitor in vivo.
Conclusions:
- Established humanized bone marrow niche models enable detailed study of myeloid and lymphoid features in BCR-ABL+ and MLL-AF9+ leukemias.
- This model overcomes limitations of previous xenograft models by providing a relevant human microenvironment.
- The huBM-sc niche model is suitable for investigating leukemia pathogenesis and evaluating therapeutic interventions.
