Baf250a Is a Regulator of HSC Populations.
Bibliographic record
Abstract
Abstract Abstract 701 Using Meis1 as a bait to screen the cDNA library from Hoxa9+Meis1 leukemia we identified Baf250a, a component of the chromatin remodeling Swi/Snf complex, as a Meis1-interacting protein. In mammalian cells, co-immunoprecipitation experiments confirmed this interaction and showed that only a minor fraction of cellular Meis1 interacts with Baf250a, suggesting a restriction of Meis1-Baf250a( Swi/Snf ) interactions to a specific cellular context. To reveal the role of Baf250a action in normal and leukemic HSC behavior we generated mouse strains expressing Baf250a protein lacking amino acids encoded by exons 2 and 3. Baf250a+/Δ mice were born in expected proportions and exhibited no hematological abnormalities. Intercrosses of Baf250a+/Δ (C57Bl/6J) adults yielded normal proportions of wild-type(WT), Baf250a+/Δ and Baf250aΔ/Δ day E14.5dpc embryos, but no viable Baf250aΔ /Δ newborn mice. These, however, could be obtained in a mixed C57Bl/J6 x Sve129 background, suggesting existance of a mouse strain-specific modifier(s) of Baf250a activity. Examination of E14.5 dpc fetal liver (FL) cell populations obtained from Baf250aΔ /Δ and WT littermates showed that cellularity and clonogenic progenitor content of Baf250aΔ/Δ FL was comparable to the WT controls, and that erythoid, megakaryocytic and myeloid cell lineages developed normally in the presence of Baf250aΔ. Transplantation experiments in conditions of limit dilution revealed that Baf250aΔ/Δ FL comprised 8-12-fold higher HSC numbers than WT controls. After transplantation into adult WT recipients the Baf250aΔ /Δ and WT HSCs exhibited comparable proliferation potential (output of mature cells per individual transplanted HSC), suggesting that of Baf250aΔ conferred no repopulation advantage to mutant HSC, but rather enhanced the ability of fetal liver microenvironment to support expansion of HSC populations. To explore this possibility we next examined the ability of Baf250aΔ /Δ stromal cell cultures to support the in vitro self-renewal of stem/progenitor cell populations identifiable as late cobblestone area forming cells (CAFCday28), and found that Baf250aΔ/Δ stromal cell layers increased the numbers of cobblestone areas 4-6-fold compared to controls, and increased the probability of CAFCday28 self renewal divisions (n=24, p<0.05) compared to controls as determined by their ability to form secondary late cobblestone areas. These observations thus suggested that Baf250a acts as a negative regulator of fetal HSC populations. However, we also found that Baf250aΔ/Δ genetic background accelerated the onset of Hoxa9 (n=7, mean latency 140 and 90 days for WT and Baf250aΔ/Δ, respectively, p<0.05) and NUP98-Hoxa9 + Meis1 (n=8, mean latency 125 and 49 days for WT and Baf250aΔ/Δ, respectively, p<0.005) induced AML, implying that Baf250a may also act as an intrinsic regulator of primitive hemopoietic cells. Together, results of our experiments identify a novel mechanism that limits the expansion FL HSC populations regulated by the Baf250a, and suggest a tumor suppressor function for this protein in Hoxa9-induced leukemogenesis. 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) | 0.000 | 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 | 0.000 |
| 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".