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, lacks specific cytokines that mimic the microenvironment found in human patients. To address this critical gap, we generated the first “humanized” zebrafish that expresses human hematopoietic-specific cytokines (granulocyte-monocyte colony-stimulating factor, stem cell factor, and stromal cell-derived factor 1α). 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 which 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.
Bibliographical noteFunding Information:
The authors would like to thank David Malloy, Connor Booker, David Maley and Gretchen Wagner for zebrafish care and maintenance and Jennifer Curran for administrative support. This work was supported by a Canadian Cancer Society Research Innovation grant to JB, Kellsie’s Hope Foundation and the Eli Seth Matthews Leukemia Foundation through a grant to TD, and a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada (NSERC) to GD. GD and JB are Senior Scientists of the Beatrice Hunter Cancer Research Institute (BHCRI), and VR was funded by the Cancer Research Training Program of the BHCRI, with funds provided by the Terry Fox Research Institute through the Dr. Linnea Veinotte Memorial Graduate Student Award. VR was also funded by a Nova Scotia Health Research Foundation (NSHRF) Scotia Scholar award.
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