Humanized zebrafish enhance human hematopoietic stem cell survival and promote acute myeloid leukemia clonal diversity
- Rajan, V., Melong, N., Wong, W.H., King, B., Tong, R.S., Mahajan, N., Gaston, D., Lund, T., Rittenberg, D., Dellaire, G., Campbell, C.J.V., Druley, T., Berman, J.N.
- Haematologica 105(10): 2391-2399 (Journal)
- Registered Authors
- Berman, Jason, Lund, Troy
- Acute Myeloid Leukemia, Cytokines, Hematopoiesis, Hematopoietic Stem Cell, Zebrafish
- MeSH Terms
- Cell Differentiation
- Hematopoietic Stem Cells
- Leukemia, Myeloid, Acute*/genetics
- Leukemia, Myeloid, Acute*/therapy
- Tumor Microenvironment
- 33054079 Full text @ Haematologica
Rajan, V., Melong, N., Wong, W.H., King, B., Tong, R.S., Mahajan, N., Gaston, D., Lund, T., Rittenberg, D., Dellaire, G., Campbell, C.J.V., Druley, T., Berman, J.N. (2019) Humanized zebrafish enhance human hematopoietic stem cell survival and promote acute myeloid leukemia clonal diversity. Haematologica. 105(10):2391-2399.
Xenograft models are invaluable tools in establishing the current paradigms of hematopoiesis and leukemogenesis. The zebrafish has emerged as a robust alternative xenograft model but, like mice, lack specific cytokines that mimic the microenvironment found in human patients. To address this critical gap, we generated the first humanized zebrafish that express human hematopoietic-specific cytokines (GM-CSF, SCF, and SDF1α). Termed GSS fish, these zebrafish promote survival, self-renewal and multilineage differentiation of human hematopoietic stem and progenitor cells and result in enhanced proliferation and hematopoietic niche-specific homing of primary human leukemia cells. Using error-corrected RNA sequencing, we determined that patient-derived leukemias transplanted into GSS zebrafish exhibit broader clonal representation compared to transplants into control hosts. GSS zebrafish incorporating error-corrected RNA sequencing establish a new standard for zebrafish xenotransplantation that more accurately recapitulates the human context, providing a more representative cost-effective preclinical model system for evaluating personalized response-based treatment in leukemia and therapies to expand human hematopoietic stem and progenitor cells in the transplant setting.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes