Enhanced Zebrafish Xenograft Platform Improves Hematopoietic Stem Cell Engraftment and Leukemogenesis

The hallmark of hematopoietic stem cells (HSCs) is their ability to self-renew and differentiate into multiple blood cell types. Transplantation of human HSCs into immunocompromised mice is the gold standard for evaluating functionality and has been adapted to study leukemia initiating cells (LICs). However, specific cellular subsets do not survive post-xenotransplantation, due to a dependence on factors that may be missing in a non-primate microenvironment.We have been optimizing the zebrafish as a xenograft platform. We created novel zebrafish that express human stem cell factor (SCF/KITLG), granulocyte-macrophage colony stimulating factor (GM-CSF/CSF2) and stromal cell-derived factor 1 alpha (SDF1α/CXCL12) - factors essential for survival and expansion of HSCs.CMK (Down Syndrome- acute myeloid leukemia (AML)) and Jurkat (T-cell acute lymphoblastic leukemia) cell lines injected into the yolk sac of these multi-cytokine zebrafish larvae exhibit increased proliferation and migration to hematopoietic niches, namely the caudal hematopoietic tissue (=fetal liver) at 7 days post-injection (dpi) and the kidney marrow at 11 dpi, compared to injections in control casper larvae.Patient-derived AML bone marrow samples (n=3) injected into the circulation of these multi-cytokine fish similarly displayed enhanced proliferation and migration with associated larval mortality from increased disease burden. Historically, human HSCs do not survive beyond 24 hpi in zebrafish xenografts (...
Source: Blood - Category: Hematology Authors: Tags: 506. Hematopoiesis and Stem Cells: Microenvironment, Cell Adhesion, and Stromal Stem Cells: Poster I Source Type: research