Enhanced Zebrafish Xenograft Platform Improves Hematopoietic Stem Cell Engraftment and Leukemogenesis
Bibliographic record
Abstract
Abstract 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 (Pruvot et al. 2011). Remarkably, human umbilical cord blood-derived HSCs injected into the circulation of zebrafish larvae survived past three days-post-injection in multi-cytokine fish but not in casper controls. Transgenic zebrafish expressing human cytokines provide an enhanced model for studying human leukemia and HSC biology in a system that more closely recapitulates the human microenvironment. By employing these humanized zebrafish and exploiting the inherent capacity of this small organism for rapid chemical screening, we have created a new preclinical paradigm for testing anti-leukemic therapies and HSC enhancing agents. Disclosures No relevant conflicts of interest to declare.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".