JAK2V617F homozygosity drives a phenotypic switch in myeloproliferative neoplasms, but is insufficient to sustain disease
Bibliographic record
Abstract
Genomic regions of acquired uniparental disomy (UPD) are common in malignancy and frequently harbor mutated oncogenes. Homozygosity for such gain-of-function mutations is thought to modulate tumor phenotype, but direct evidence has been elusive. Polycythemia vera (PV) and essential thrombocythemia (ET), 2 subtypes of myeloproliferative neoplasms, are associated with an identical acquired JAK2V617F mutation but the mechanisms responsible for distinct clinical phenotypes remain unclear. We provide direct genetic evidence and demonstrate that homozygosity for human JAK2V617F in knock-in mice results in a striking phenotypic switch from an ET-like to PV-like phenotype. The resultant erythrocytosis is driven by increased numbers of early erythroid progenitors and enhanced erythroblast proliferation, whereas reduced platelet numbers are associated with impaired platelet survival. JAK2V617F-homozygous mice developed a severe hematopoietic stem cell defect, suggesting that additional lesions are needed to sustain clonal expansion. Together, our results indicate that UPD for 9p plays a causal role in the PV phenotype in patients as a consequence of JAK2V617F homozygosity. The generation of a JAK2V617F allelic series of mice with a dose-dependent effect on hematopoiesis provides a powerful model for studying the consequences of mutant JAK2 homozygosity.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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".