Independent and Converging Pathways in Leukemia Stem Cells.
Bibliographic record
Abstract
Abstract Leukemias are considered hierarchically organized where a leukemia stem cell (LSC) maintains the disease, can reinitiate disease upon transplantation, and gives rise to more mature cells which can not establish the disease after secondary transplantation. While LSCs become the primary focus for targeted therapies, little is known about the pathways regulating LSC activity. Overexpression of HOX genes characterize the large group of acute myeloid leukemia (AML) patients with NPM1 mutations whereas overexpression of MN1 is highly correlated with wildtype-NPM1 AML (Verhaak et al. 2005). We hypothesized that the LSCs in these two AML populations are differentially regulated as patients with NPM1 mutations tend to have better outcomes. To test this hypothesis we applied a transplantation model using murine bone marrow (BM) cells retrovirally transduced with MN1 or MN1+NUP98HOXD13 (ND13). Overexpression of ND13 in mouse BM leads to a “preleukemic” or MDS-like phenotype. In contrast, previously we found that overexpression of MN1 is alone sufficient to induce AML. MN1-induced leukemias were compared to MN1+ND13-induced leukemias. Mice transplanted with 1x10E6 BM cells overexpressing either MN1 or MN1+ND13 died after a median latency of 35 and 40 days, respectively (P=0.26). However, in limiting-dilution analysis of MN1 expressing cells the frequency of leukemia-stem cells (LSC) was 1 in 5465 and 1 in 3411 (two independent experiments, 0.024 percent of total cells), whereas it was 34-fold increased in MN1+ND13 coexpressing cells (0.82 percent of total cells, mean of two independent experiments; the 95 percent CIs do not overlap suggesting a significant difference). In addition, the disease latencies at limiting dilution differed significantly (MN1: 82 vs. MN1+ND13: 44 days, P=0.009), demonstrating that the addition of ND13 to MN1 enhanced the potency of the individual LSC besides its frequency. Addition of ND13 to MN1 changed the leukemic phenotype towards characteristics associated with ND13. To better understand non-redundant and redundant downstream pathways expression of several genes reportedly involved in stem-cell regulation and of HOXA and HOXB genes was quantified by qRT-PCR in MN1, ND13, or MN1+ND13 expressing cells and compared to their expression in normal BM cells. Increased expression of Bmi-1, mel18, HoxA11, and HoxB6 was observed in MN1 cells compared to normal BM. Increased expression in ND13 cells compared to normal BM were found for HoxA3, HoxA7, HoxB5, HoxB7, and HoxB8, whereas HoxA9, HoxA10, and Gata-2 showed increased expression compared to normal BM for both genes. Other important stem cell regulators like Notch1 (MN1, ND13) and HoxB4 (MN1) were expressed at lower levels than in normal BM. In summary, functional and gene expression data suggest activation of non-redundant (and redundant) pathways in MN1 compared to HOX-mediated leukemias. By modulating the LSC activity we show that addition of ND13 to MN1 has a pronounced effect on the frequency and activity of LSCs and that more aggressive LSCs are obtained by dysregulation of an additional/independent pathway. This suggests that elimination of LSCs in aggressive leukemias may require inhibition of multiple pathways.
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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) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.000 | 0.002 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.011 | 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".