The Pluripotency Regulator PRDM14 Requires Hematopoietic Regulator CBFA2T3 to Initiate Leukemia in Mice
Bibliographic record
Abstract
Abstract PR domain–containing 14 (Prdm14) is a pluripotency regulator central to embryonic stem cell identity and primordial germ cell specification. Genomic regions containing PRDM14 are often amplified leading to misexpression in human cancer. Prdm14 expression in mouse hematopoietic stem cells (HSC) leads to progenitor cell expansion prior to the development of T-cell acute lymphoblastic leukemia (T-ALL), consistent with PRDM14's role in cancer initiation. Here, we demonstrate mechanistic insight into PRDM14-driven leukemias in vivo. Mass spectrometry revealed novel PRDM14–protein interactions including histone H1, RNA-binding proteins, and the master hematopoietic regulator CBFA2T3. In mouse leukemic cells, CBFA2T3 and PRDM14 associate independently of the related ETO family member CBFA2T2, PRDM14's primary protein partner in pluripotent cells. CBFA2T3 plays crucial roles in HSC self-renewal and lineage commitment, and participates in oncogenic translocations in acute myeloid leukemia. These results suggest a model whereby PRDM14 recruits CBFA2T3 to DNA, leading to gene misregulation causing progenitor cell expansion and lineage perturbations preceding T-ALL development. Strikingly, Prdm14-induced T-ALL does not occur in mice deficient for Cbfa2t3, demonstrating that Cbfa2t3 is required for leukemogenesis. Moreover, T-ALL develops in Cbfa2t3 heterozygotes with a significantly longer latency, suggesting that PRDM14-associated T-ALL is sensitive to Cbfa2t3 levels. Our study highlights how an oncogenic protein uses a native protein in progenitor cells to initiate leukemia, providing insight into PRDM14-driven oncogenesis in other cell types. Implications: The pluripotency regulator PRDM14 requires the master hematopoietic regulator CBFA2T3 to initiate leukemia in progenitor cells, demonstrating an oncogenic role for CBFA2T3 and providing an avenue for targeting cancer-initiating cells.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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".