Abstract 1973: Tumor suppressor p15Ink4b determines cell fate of hematopoietic progenitors: Implications for development of human blood disorders.
Bibliographic record
Abstract
Abstract Red blood cells (RBCs) are a vital component of mammalian blood. Since they are short lived, they must be continuously replenished by erythropoiesis, a stepwise commitment of blood stem and progenitor cells to mature erythrocytes. The anemia due to the loss of RBC is a life threatening condition, often accompanying blood diseases such as leukemias and myelodysplastic syndromes (MDS). A striking 60-80% of these diseases have deleted or silenced expression of p15INK4B. An increased understanding of the factors that drive erythroid lineage commitment in progenitor cells is critical for developing new treatments for blood disorders. Previous examination of p15Ink4b knock-out mouse models, revealed skewing of hematopoietic progenitor differentiation towards myeloid lineage (granulocytes, macrophages). Here, we demonstrate a novel function for p15Ink4b in driving commitment to the erythroid lineage. Mice lacking p15Ink4b have lower numbers of primitive RBC progenitors and died shortly after induction of hemolytic anemia by phenylhydrazine injection. Expression of p15Ink4b in blood progenitors induced dynamic changes at the molecular level that rendered multi-lineage cells more permissive to erythroid commitment and less permissive to myeloid commitment. Noticeably, we found that p15Ink4b regulates a switch that controls the balance between myeloid and erythroid differentiation through activation of MEK/ERK signaling. In a time-coordinated manner expression of p15Ink4b induced rapid phosphorylation of MEK/ERK that led to rapid degradation of GATA-2 and activation of the GATA-1 transcription factors. Subsequently, the active GATA-1 executed lineage commitment through activation of the Erythropoietin receptor (EpoR), the “master regulator” of erythroid differentiation. The p15Ink4b mediated increase in GATA-1 expression, also resulted in decreased expression of the myeloid specific transcription factor PU.1, suppressing myeloid differentiation. In summary, we have defined a framework that determines how multipotent progenitors coordinate the balance between myeloid and erythroid differentiation. Central to this activity is p15Ink4b, which promotes erythroid fate while suppressing myeloid cell formation, a function that is particularly important in rapid RBC replenishment following stress. Our finding has implications not only for MDS and myeloid leukemia, where loss of tumor suppressor p15INK4B is a common event, but also for other forms of human refractory anemia. Citation Format: Rita Humeniuk, Michael Rosu-Myles, Linda Wolff. Tumor suppressor p15Ink4b determines cell fate of hematopoietic progenitors: Implications for development of human blood disorders. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1973. doi:10.1158/1538-7445.AM2013-1973
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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) | 0.000 | 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) | 0.001 | 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".