Mutated EZH2 Collaborates with Myc in Inducing Lymphoma in a Mouse Model
Bibliographic record
Abstract
Abstract Abstract 227 The histone methyl-transferase EZH2 is frequently mutated in germinal-center derived diffuse-large B cell lymphoma (DLBCL) and follicular lymphoma. We and others have demonstrated that these mutations in tyrosine 641 of EZH2 represent a dominant gain-of-function, enhancing the capability to trimethylate H3K27 in combination with wildtype activity (Yap et al, Blood 2011; Sneeringer et al, PNAS 2010). To further test if these EZH2 mutations can be driver mutations in lymphomagenesis we have now generated and characterized a mouse line transgenic for EZH2 Y641F (the most commonly observed mutant form). Transgenic mice were created on the C57/Bl6 background by pronuclear microinjection of a construct where EZH2 Y641F is expressed from a lymphoid specific Emu-lck promoter. Spleen cells isolated from the transgenic mice displayed a global increase in H3K27me3 when analyzed by Western Blot. However none of the mice showed signs of lymphoma even when observed for prolonged periods of time. As EZH2 mutations often coincide with other mutations in lymphoma, we also combined the expression of EZH2 Y641F with the over-expression of Myc by crossing one of the transgenic lines with Emu-myc transgenic mice. In this combination model, we observed a dramatic acceleration of lymphoma development with the combination of Myc and EZH2 Y641F as compared to Myc alone (Myc alone (n=26) 137.5 days, Myc+EZH2 Y641F (n=20) 51 days, p < 0.0001 Log-Rank (Mantel-Cox) Test). The resulting lymphomas are characterized by a generalized massive lymphadenopathy, splenomegaly (spleen weight 0.416 +/− 0.133 g), bone marrow infiltration (72 +/− 8 %) and lymphocytosis (WBC 138.5 +/− 77.1 ×1000/μl). They show histological features of high-grade disease, and initiate disease in secondary recipients. In contrast to lymphomas observed with Emu-myc alone, all of the lymphomas observed in mice transgenic for both, Myc and EZH2 Y641F, presented with a mature B cell phenotype (B220+IgM+). This shift in differentiation can also be observed in the bone marrow even before development of overt lymphomas. While Myc transgenics mainly show an increase in the B220+IgM−compartment, this is shifted towards B220+IgM+ in double transgenics. Cell cycle analysis by in vivo Brdu incorporation before disease onset shows a drastic increase in the fraction of cells in cycle in the splenic B cells of double transgenic mice (43.3 and 44.9 % cells in S phase) as compared to mice transgenic for Myc alone (10.6 % and 14.2 % cells in S phase). Southern Blot analysis using a probe specific for JH4 showed more than one clonal rearrangement in a majority of the lymphomas in the double-transgenic mice. In summary, EZH2 Y641F can collaborate with Emu-myc in high efficiency lymphoma induction. This new murine lymphoma model now provides a powerful tool to study global changes in the epigenome caused by this frequent mutation and may be a useful system for testing novel treatments. Disclosures: No relevant conflicts of interest to declare.
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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) | 0.000 | 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".