A Potent Stimulator of Self-Renewal in Combination with MEIS1 Overexpression Allows the Transformation of Late Committed Myeloid Progenitors.
Bibliographic record
Abstract
Abstract Abstract 1434 Poster Board I-457 Which cells are susceptible to leukemic transformation and which cellular properties need to be altered to cause transformation are critical issues in the understanding of leukemogenesis. We have identified that the engineered fusion gene between NUP98 and the homeodomain of HOXA10 (NA10hd) exhibits an extraordinary capacity to induce stem cell self-renewal in vitro without blocking differentiation in vivo and without having any detectable leukemogenic activity on its own. However, NA10hd induces rapid-onset leukemia in mice when it is co-expressed with Meis1. We have exploited this unique combination of defined factors to investigate the role of reactivation/intensification of the self-renewal program in leukemic transformation by assessing whether committed myeloid progenitors with essentially no intrinsic self-renewal activity can be transformed into cells with “stem-cell” like characteristics that drive leukemia. Populations enriched for hematopoietic stem cells (lin-Sca1+ckit+), common myeloid progenitors (lin-Sca1-ckit+CD34+CD16/32lo, CMP) and granulocyte-monocyte progenitors (lin-Sca1-ckit+CD34+CD16/32hi, GMP) were sorted from mouse bone marrow. Expression of NA10hd and Meis1 was achieved by retroviral transduction with MSCV based vectors carrying cassettes for NA10hd-IRES-GFP or Meis1-IRES-YFP. Transduced cells were assessed for colony formation (CFC assay) and transplanted into irradiated recipients to assess their potential to give rise to leukemia. We first temporally dissociated the potential stimulation of self-renewal by NA10hd as a “first hit” from Meis1 overexpression as a “second hit” by using bulk bone marrow cells or highly purified CMP and GMP from mice previously reconstituted with NA10hd-transduced stem cells. At the time of harvest, mice were healthy and progenitor populations from these mice showed a regular distribution and a limited replating potential. However, upon infection with Meis1 a sustained replating potential over multiple CFC rounds was induced. NA10hd-expressing CMP and GMP transduced with Meis1 also gave rise to rapid onset and aggressive AML (median latency of 46.5 days for bulk, 54 days for CMP and 92 days for GMP respectively) when transplanted into irradiated recipients. To further assess whether NA10hd plus Meis1 were sufficient for transformation of later progenitors, CMP and GMP were isolated from wildtype, normal mice and cotransduced with NA10hd and Meis. To minimize the chance of contamination of fractions, infections were also carried out with purified cells at limiting number (50 cells per culture). Neither CMP nor GMP transduced with NA10hd alone gave rise to significant engraftment and both were non-leukemogenic. In contrast, both CMP and GMP co-transduced with NA10hd and Meis1 gave rapid onset leukemia. Leukemias derived from CMP and GMP showed no obvious differences with respect to morphology, immunophenotype or capability to give rise to secondary transplants. However, there was an apparent small diminution in the potency of GMP to give rise to leukemias as indicated by slightly longer latency and incomplete penetrance (3/7 mice surviving with transduced bulk GMP). We conclude that late committed myeloid progenitor cells can give rise to leukemia in our model system and that reactivation of self-renewal potential appears to be a critical step in this transformation process. This novel model of leukemia induction now opens up possibilities to dissect the molecular mechanism by which transformation of differentiated progenitors can occur. Disclosures No relevant conflicts of interest to declare.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 teacher head, 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".