Expression of Leukemogenic Ptpn11 Causes a Fatal Myeloproliferative Disorder by Affecting Multiple Stages of Hematopoiesis
Bibliographic record
Abstract
Abstract The Src homology-2 (SH2) domain-containing phosphatase 2 (Shp2), encoded by Ptpn11, is an ubiquitously expressed non-receptor protein tyrosine phosphatase (PTP) that positively regulates Ras/Erk activation in many receptor protein tyrosine kinases (RTK) and cytokine receptors. Mutations in PTPN11 are found in ~35% of patients with juvenile myelomonocytic leukemia (JMML) and at lower incidence in other neoplasms. To model JMML pathogenesis, we generated knock-in mice that conditionally express the leukemia-associated mutant Ptpn11D61Y. Ptpn11D61Y expression in all hematopoietic cells evokes a fatal myeloproliferative disorder (MPD), featuring leukocytosis, anemia, hepatosplenomegaly with extramedullary hematopoiesis, and factor-independent colony formation by bone marrow (BM) and spleen cells. The Lin−Sca1+cKit+ (LSK) compartment is expanded and “right-shifted”, accompanied by increased stem cell factor (SCF)-evoked colony formation and Erk and Akt activation. However, stem cell activity is decreased in diseased mice, and mice engrafted with Ptpn11D16Y stem cells fail to develop MPD. Ptpn11D16Y common myeloid (CMP) and granulocyte-monocyte (GMP) progenitors produce cytokine-independent colonies in a cell-autonomous manner, and demonstrate elevated Erk and Stat5 activation in response to granulocyte-macrophage colony-stimulating factor (GM-SCF) stimulation. Ptpn11D61Y megakaryocyte-erythrocyte progenitors (MEP) yield increased numbers of erythrocyte burst-forming units (BFU-E), but MEP and erythrocyte-committed progenitors (EP) produce fewer erythrocyte colonyforming units (CFU-E), indicating defective erythroid differentiation. Our studies provide a mouse model for Ptpn11-evoked MPD and show that this disease results from cellautonomous, and distinct lineage-specific effects of mutant Ptpn11 on multiple stages of hematopoiesis.
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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) | 0.000 | 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".