Enhancment of SCA1 Positive Hematopoietic Progenitors in Polycythemic Mice Inhibits Leukemogenesis
Bibliographic record
Abstract
Abstract PV is a myeloproliferative disease, displaying a pronounced increase in the number of erythroid cells. Despite this increase, PV patients exhibit a lower incidence of acute leukemia and in particular erythroleukemia compared to its related disorder CML. In this study we induced erythroleukemia in a mouse model of familiar polycythemia, carrying a truncated form of the human erythropoietin-receptor (Epo-R). Previous studies have shown that these mice develop a disease similar to patients with familiar polycythemia, from whom this gain-of-function receptor was isolated and introduced as transgene. We show that the progression of erythroleukemia induced by Friend virus is significantly delayed in this genetic mouse model of polycythemia. These mice exhibit a massive enrichment of Sca1+/cKit− progenitors and mature immune cells compared to normal mice. Co-transplantation experiments revealed that Sca1+/cKit− progenitors inhibit the robust tumorigenic potential of Sca1−/cKit+ erythroleukemic cells. In order to determine the mechanism of erythroleukemia inhibition, we established cell lines from Sca1+/cKit− cell populations and demonstrated a similar anti-leukemic inhibition in vivo. These cells also express cell surface markers for early B-cells (B220) and macrophages (Mac1), and are able to undergo differentiation into macrophages and dendritic cells following treatment with GM-CSF and IL4. We have shown that these cells also secrete factors that inhibit proliferation of erythroleukemic cells in culture, such as Nitric Oxide (NO). Accordingly, an NO inhibitor can suppress the inhibitory effect of the Sca-1+/cKit−/B220+/Mac1+ cells. To further demonstrate the importance of these leukemic inhibitory cells, we induced a polycythemia in normal mice through administration of Epo. Epo administration delayed the development of Friend virus-induced erythroleukemia and significantly increased the number of leukemic inhibitory Sca1+ cells. Our study also demonstrates a significant increase in the number of leukemic inhibitory cells with anti-proliferative effects in response to Epo and granulocyte macrophage-colony stimulating factor (GM-CSF) stimulation. We therefore propose that administration of Epo and GM-CSF in combination with NO agonistic drugs, as well as the identification of novel drugs that can induce the inhibitory Sca-1+/cKit−/B220+/Mac1+ cells, may lead to improved therapies for the treatment of myelodysplastic syndrome. Together, our results identify Sca-1+/cKit−/B220+/Mac1+ cells as potent cellular inhibitors of leukemia and unravel a potentially novel therapeutic approach.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".