A Sensitized Screen Uncovers a Novel Platelet Phenotype in a Loss-of-Function Jak2 Allele.
Bibliographic record
Abstract
Abstract Abstract 2516 Poster Board II-493 Our group has undertaken a concerted effort to develop novel heritable mouse strains via ethylnitrosourea (ENU)-based random mutagenesis. We have complemented this strategy to perform a dominant sensitized screen to identify mouse mutants with altered recovery following treatment with 5-fluoruracil (5-FU). We isolated a heritable line with elevated platelets as well as an overshoot in platelet numbers when exposed to 5-FU. Affected mice also displayed megakaryocytosis and centrilobular hepatic lipidosis. The mutation was mapped to a 8.7Mb region on mouse Chromosome 19, which contained the candidate gene Jak2. The entire coding region of Jak2 was sequenced and a mutation in exon 19 was found. The causative mutation was located at nucleotide 2740 and leads to an A to T transversion in exon 19 of JAK2 and causes a substitution of a Lys to a premature stop codon at amino acid 914. The resulting protein product terminates within the JH1 kinase domain of JAK2. JAK2 914 is distinct from the JAK2 null allele characterized by the Ihle and Pfeffer labs. For example, JAK2−/− embryos die at E12.5, whereas JAK2914/914 embryos survive until E13.5, suggesting that the truncated protein product may serve as a scaffold. Differences were also observed in clonogenic potential of both strains. For example, JAK2+/− mice had increased CFU-C whereas JAK2914/+ were normal. Splenic BFU-E and CFU-C were increased in JAK2+/− mice while both cell types were decreased in JAK2914/+. In contrast, bone marrow CFU-E were increased in both strains of mice and splenic CFU-E were normal in JAK2+/− and JAK2914/+. In addition, both mouse strains display elevated platelets when animals are housed under resting conditions. The hepatic phenotype is phenocopied by Leptin Receptor null mice that are hyperphagic, poorly cold-adapted, sterile and have enhanced fat conversion resulting in lipidosis. In conclusion, a sensitized screen has shown that JAK2 regulates the response to the chemotherapeutic drug, 5-fluorouracil. These findings have significance to potential myelosuppressive effects of the clinical use of 5-FU in colorectal and pancreatic cancer. 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) | 0.001 | 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 | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".