The Hox a Locus Is Strongly Targeted by MMLV in an E2a-PBX1 Induced B-Cell Leukemia Model.
Bibliographic record
Abstract
Abstract We previously developed a B-ALL model from E2a-PBX1 transgenic mice (Bijl et al. Abstract 469 ASH 2003 and paper in preparation). We now exploit this model to identify oncogenic collaborators to E2a-PBX1. To achieve this, 18 newborn E2a-PBX1 transgenic mice and 23 control littermates were intraperitonally injected with MMLV. The occurrence of B-ALL in E2a-PBX1 transgenic animals was significantly accelerated when compared to control littermates (mean survival 162 ± 31 versus 191 ± 50 days, respectively, P=0.03), suggesting the presence of E2a-PBX1 specific collaborators. Inverse PCR was performed on genomic DNA isolated from seven E2a-PBX1 and six control tumors. Seventy-two different retroviral insertion sites were recovered from the tumors. Six common integration sites (CIS) for MMLV were identified; including two novel CIS, i.e. Pde4d, a phosphodiesterase, and a hypothetical phospholipase A930027K05Rik. Strikingly, the Hox a locus was targeted in six of seven E2a-PBX1 tumors, and only one of six control tumors. MMLV integrants in the Hox a locus were detected in a 19kb region located between Hoxa6/Hoxa7 and Hoxa10. Two tumors were targeted twice in this locus. Q-PCR analysis for expression of all Hox a cluster genes identified a significant increase for the Hoxa3 to Hoxa10 genes in the transgenic tumors when compared to the expression in a control MMLV induced B-cell tumor (see table, below). Hoxa7 and Hoxa6 were the most frequently and strongly activated (6/6 and 5/6 transgenic tumors, respectively), showing values of 5700 and 6600 fold over expression in one particular tumor. Interestingly, a Hox a locus insertion in a control tumor (table: last row) did not have any effect on gene activation. In this study we demonstrate a preference for MMLV to target the Hox a locus in an E2a-PBX1context. The resultant gene activation suggests that several members of the Hox a locus are functional collaborators to E2a-PBX1 in the induction of B-cell leukemia. Fold difference in expression for Hox a cluster genes in Hox a targeted tumors compared to a control tumor. Insertions a3 a4 a5 a6 a7 a9 a10 a9/a10 −1 1 4 3 138 2 4 a3 17 55 1067 5700 6608 171 62 a10 3 1 11 98 38 3 −4 a9/a10 1 −1 2 21 9 2 −2 a9/a10 2x 13 6 19 221 191 85 2 a7/a9 + a10 8 4 11 66 44 9 149 a10 −2 −6 2 2 −2 −8 −5
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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 | 0.001 | 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 | 0.001 |
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".