Cbl-b Deficiency Enhances Motility and Impairs Leukemogenesis by Bcr-Abl.
Bibliographic record
Abstract
Abstract One of the prominent tyrosine phosphorylated substrates of BCR-ABL identified in cells from chronic-phase Chronic Myeloid Leukemia (CML) patients is the Cbl ubiquitin ligase and adaptor protein. Bone marrow transplantation studies have revealed that Cbl is dispensable for CML development, as animals receiving Cbl-deficient bone marrow cells expressing BCR-ABL develop a myeloproliferative disease (MPD) with a similar latency and phenotype as wild type bone marrow recipients (Dinulescu et al. 22: 8852–60, 2003). Cbl belongs to a family of E3 ubiquitin ligases that also contains Cbl-b and Cbl-3. In contrast to the equivalent Cbl protein expression displayed in hematopoietic cell lines expressing BCR-ABL, addition of the oncogene leads to a decreased expression of the related family member, Cbl-b. The objective of this study was to determine whether Cbl-b is a critical signaling intermediate downstream of BCR-ABL. To investigate this objective, we performed retroviral transduction of wild type- and Cbl-b- deficient bone marrow with BCR-ABL and utilized these cells for bone marrow transplantation of lethally irradiated mice. Recipients of wild type donor cells transduced with the p210 isoform of BCR-ABL, succumb to a rapidly fatal CML-like MPD, while the lack of Cbl-b produces a significant delay in morbidity (average latency of 32 days as compared with 18 days for recipients of wild-type marrow). Expansion of differentiated neutrophils, as visualized by histopathological analysis, is evident in the peripheral blood, bone marrow and spleen of all transplanted animals. However, circulating white blood cells are augmented in number (average wbc count for Cbl-b(+/+), 150 × 106 cells / mL; Cbl-b(−/−), 83 × 106 cells / mL) and enhanced spleen size is observed in Cbl-b(+/+) mice (35 mg / g of body mass) as compared to Cbl-b(−/−) (19 mg/g) animals. Liver masses were comparable between the two transplants. In depth flow cytometric studies of splenic cells reveals the characteristic decrease in B and T cells and enhanced myeloid lineages. Notably, an increased number of granulocytes (Gr-1+/Mac-1+ cells) is observed in the Cbl-b-knockout animals, suggesting enhanced migration but decreased survival of leukemic cells in the Cbl-b−/− spleen. In support of this hypothesis, fibroblasts deficient in Cbl-b display enhanced chemotactic migration toward Fetal Calf Serum. As migration is a key determinant of cellular retention in the bone marrow, the loss of Cbl-b could ultimately be affecting cell localization. Therefore, our data supports a continued study of Cbl-b as a motility regulator in BCR-ABL-dependent CML progression.
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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 | 0.001 |
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".