In vitro models of acute myeloid leukemia in primary primitive human hematopoietic cells
Bibliographic record
Abstract
Acute myeloid leukemia (AML) is a cancer of the blood system characterized by an accumulation of myeloid blasts that fail to differentiate to form functional mature cells. Despite improvements in our understanding of AML at both a cellular and genetic level, treatment options remain limited, and mortality rates are high. For this reason, the development of new, more targeted treatment strategies is of great importance. In particular, therapies are being designed that specifically target the underlying biological pathways of AML. However, despite the fact that genetic abnormalities associated with the transition from normal to malignant hematopoiesis are readily identified, our understanding of how these alterations contribute to leukemogenesis requires relevant in vitro and in vivo models. Traditionally, most of our understanding of the leukemogenic process and the genes involved was extrapolated from analysis of human leukemic cell lines and from mouse models. However, these approaches are limited in that they may not accurately recapitulate what occurs in normal primitive human hematopoietic cells. Over the past decade we and others have begun using retroviral gene transfer to introduce putative oncogenes into primary human hematopoietic precursors. In the studies presented here, we introduced the leukemic fusion protein TLS-ERG, which has been identified in a wide range of leukemic subtypes. We report the step-wise transformation and immortalization of primary lineage-depleted cord blood cells following the introduction of TLS-ERG. TLS-ERG disrupts the normal differenation, proliferation and self-renewal of hematopoietic precursors, and establishes a pre-leukemic state in which additional genetic events relevant to leukemogenesis can accumulate. Here we show that this disruption is the result of at least two independent transforming pathways initiating from the TLS-ERG oncogene. Furthermore, we have used this model of TLS-ERG mediated pre-leukemia to investigate the role of telomerase in both normal and malignant hematopoiesis. We show that upregulation of telomerase activity as measured in vitro is insufficient to maintain telomere lengths, in contrast to what has been observed in other somatic cell types. Our results point to cell context specific differences in the regulation of telomerase, and highlight the need to study leukemogenic events in the correct cellular context.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.002 | 0.001 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.004 | 0.004 |
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".