MiR-300 Acts As a Tumor Supressor in Ph+ Progenitors By Modulating the JAK2-SET/PP2A/β-Catenin Interplay
Bibliographic record
Abstract
Abstract The persistence of tyrosine kinase inhibitor (TKI)-resistant malignant Philadelphia-positive (Ph+) hematopoietic stem cells (HSC) in chronic myelogenous leukemia (CML) TKI-treated patients in complete molecular remission, and the dismal prognosis of blast crisis CML indicate that the molecular mechanisms underlying its emergence, maintenance and progression are not totally dependent on the unrestrained kinase activity of BCR-ABL1 and might rely on other cell autonomous and/or microenvironmental signal capable of sustaining survival and self-renewal of the chronic phase and blast crisis Ph+ HSC compartment(s). We recently demonstrated that the Jak2/SET-PP2A/β-catenin pathway is essential for survival and self-renewal of quiescent TKI-resistant CD34+CD38- Ph+ HSC and that activation of such oncogenic signals requires the expression but not the activity of BCR-ABL1. Because microRNAs (miRNAs) are likely to control in a canonical and/or decoy manner the expression of different components of the Jak2 signalosome, this makes them an attractive target for further understanding the mechanisms of leukemogenesis and, perhaps, for developing new alternative therapies that selectively eradicate quiescent leukemic HSCs. In silico analysis revealed that a specific miR subset shares multiple targets of the BCR-ABL1/Jak2/SET-PP2A signalosome. Nanostring Array analysis performed on primary bone marrow cells from normal individuals and chronic phase or blast crisis CML patients revealed that expression of some of these miRNA is altered in CML. For example, expression of miR-300 and miR-101, which are predicted to simultaneously modulate directly Jak2, hnRNP-A1 and β-catenin and, indirectly, other molecules of the BCR-ABL1/Jak2/SET-PP2A/β-catenin pathway, is significantly inhibited in chronic phase CML and further decreases in advanced CML samples. Additionally, miR-300 expression is several folds lower in dividing (div. 1) compared to quiescent (CFSEMAX) CD34+ CML cells. Lentiviral-transduction of miR-300 in human BCR-ABL+ cell lines resulted in marked downmodulation of JAK2, β-Catenin hnRNPA1 and SET and, as expected, in increased PP2A activity. Moreover, ectopic miR-300 expression decreased reduced clonogenic potential and proliferation, and increased susceptibility to TKI (e.g. Imatinib) induced apoptosis. Interestingly, it appears that forced BCR-ABL1 expression in TF-1 leukemic cells decreases miR-300, consistent with the reported activation in these cells of the Jak2-SET-PP2A-β-catenin pathway. Altogether our results suggest that miR-300 expression and, potentially, that of other deregulated non-coding RNAs might be dispensable or deleterious for the phenotype of Ph+ progenitors and/or indispensable for that of Ph+ HSCs. Thus, experiments in BCR-ABL1 cell lines as well as primary stem and progenitor cell fractions are currently ongoing to assess the role of this and other miRNAs in survival, self-renewal/proliferation of CML stem and progenitor cells. Disclosures No relevant conflicts of interest to declare.
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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".