ReSETting PP2A Tumor Suppressor Activity Overcomes BCR/ABL Leukemogenic Potential in Blast Crisis CML.
Bibliographic record
Abstract
Abstract A tight control of kinase and phosphatase activity is fundamental for normal cell growth, survival and differentiation. The deregulated kinase activity of the BCR/ABL oncoprotein is responsible for the emergence and maintenance of chronic myelogenous leukemia (CML). By contrast, PP2A, a serine-threonine phosphatase involved in the regulation of many cellular functions, was found genetically inactivated in many types of cancer. We show here that, in BCR/ABL-transformed cells and CD34+ CML blast crisis progenitors, the phosphatase activity of the tumor suppressor PP2A is inhibited by the physiological PP2A-inhibitor SET whose expression is enhanced by BCR/ABL and increased in blast crisis CML. In imatinib-sensitive and -resistant (T315I included) BCR/ABL+ cell lines and in CD34+ CML blast crisis cells, molecular and/or pharmacological activation of PP2A leads to dephosphorylation of important regulators of proliferation and survival of CML progenitors, suppresses BCR/ABL kinase activity and promotes BCR/ABL proteasome degradation via a mechanism that requires the SHP-1 tyrosine phosphatase activity. Furthermore, PP2A activation achieved by shRNA-mediated SET knock-down or PP2Ac overexpression or treatment with the PP2A activator forskolin results in growth suppression, enhanced apoptosis, restored differentiation, impaired clonogenic potential and decreased in vivo leukemogenesis of wild type and T315I BCR/ABL-transformed myeloid cells. Thus, functional inactivation of PP2A phosphatase activity is essential for BCR/ABL leukemogenesis and, perhaps, required for transition of CML into blast crisis.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".