MN1 Overexpression Promotes Proliferation and Self-Renewal of Primitive Normal Human Hematopoietic Cells
Bibliographic record
Abstract
Abstract Overexpression of MN1 is a negative prognostic factor in patients with acute myeloid leukemia (AML) with normal cytogenetics. We have previously demonstrated that overexpression of MN1 is sufficient as a single genetic event to induce AML in mice with very short latency (Blood110:1639, 2007). To investigate the effects of MN1 on the functional activity of primitive human hematopoietic cells, we transduced CD34+ human cord blood cells with an oncoretrovirus (3 experiments) or lentivirus (3 experiments) encoding GFP ± MN1. Immediately post-transduction primary colony-forming cell (CFC) assays showed no significant differences in the number or type of colonies generated from the MN1 and control-transduced cells. However, the number of CFCs detectable in secondary assays of the MN1-transduced cells was 17-fold higher than from the GFP-transduced cells and this difference was found to increase a further 234-fold as detected by tertiary CFC assays. To assess the effect of MN1 on cells that can be propagated for more prolonged periods on mouse fibroblast feeders engineered to produce human Steel factor, IL-3 and G-CSF, 104 unsorted cord blood cells were plated into such cultures and the number and types of cells present was then determined 8 weeks later. The remarkable potency of MN1 in stimulating the output of primitive cells under these long-term culture (LTC) conditions was evident from the 1700 greater increase in total cell output and 277-fold higher output of CFCs as compared to control cultures and an accompanying large expansion of CD34+ cells (representing up to 18 % of the final population) whereas CD34+ cells were no longer detectable in the control cultures. Further analysis by limit dilution assay (2 experiments) showed that the frequency of cells able to produce CFCs for at least 6 weeks in these stromal based cultures was increased 10-fold (1/7656 control cells vs 1/718 MN1-transduced cells). In addition the CFC output of each of these was enhanced, on average, 6-fold. Remarkably, these effects of MN1 were sustained for a further 16 weeks as shown by the analysis of the cells they produced in secondary and tertiary LTCs. Overall this resulted in a cumulative 6250-fold increase in total cells over 24 weeks, whereas control cells declined to undetectable levels within 16 weeks. Cells harvested from the secondary and tertiary LTCs initiated with MN1-transduced cells also showed a continuing output of 878,967 ± 332,300 and 264,458 ± 120,600 CFCs after 16 and 24 weeks, respectively. This study sets the stage for further investigation of the effect of MN1 on human NOD/SCID/γcnull mouse repopulating cells and the molecular mechanisms by which MN1 blocks the differentiation fate of primitive human hematopoietic cells and how this may be related to its contribution to the genesis of poor prognosis AML.
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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) | 0.000 | 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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".