Abstract B08: Loss of functional Miz-1 impairs c-Myc-dependent B cell lymphomagenesis
Bibliographic record
Abstract
Abstract Objective: The Myc-interacting zinc finger protein 1 (Miz-1) is a ubiquitous BTB/POZ domain and zinc finger protein that acts as both a transcriptional repressor and activator. The POZ domain of Miz-1 enables protein-protein interactions and facilitates a stable association with chromatin. Miz-1 binds to the proto-oncogen c-Myc and modulates c-Myc target gene expression. Overexpression of c-Myc is an important feature of Burkitt-type B cell lymphomas (BL) caused by c-Myc gene rearrangements. The aim of this project is to determine if Miz-1 is a crucial collaborator of c-Myc in transcriptional regulation of B cells and in the development of c-Myc-dependent B-cell lymphomas. Methods: We are using the Eµ-Myc mouse model to generate Burkitt type c-Myc dependent lymphomas to study the implication of Miz-1 in a c-Myc driven process of malignant transformation. Mice carrying the Eµ-Myc transgene (c-Myc gene placed under the control of Eµ enhancer of the IgH locus) overexpress c-Myc in lymphoid cells and develop a disease similar to Burkitt's lymphoma. Mice that express a conditional non-functional Miz-1 allele lacking the part coding for the POZ domain in B cells (Mb1-Cre-Miz-1fl/fl mice, hereafter called ΔPOZ mice) were crossed with Eµ-Myc transgenic mice. We monitored Eµ-Myc animals expressing wild type or ΔPOZ Miz-1 protein over a period of 500 days. Incidence and latency periods of the development of tumors in both cohorts was compared. Pre-cancerous mice of all genotypes were also investigated to evaluate the influence of Miz-1 during the development of the c-Myc dependant lymphomas. To identify underlying molecular mechanisms, global mRNA expression profiles of pre-neoplastic and tumor cells derived from Eµ-Myc and ΔPOZ/Eµ-Myc mice were performed using high throughput sequencing (RNA-seq). To address the role of Miz-1 in the deregulation of chromatin associated with c-Myc overexpression, chromatin immunoprecipitation coupled to high throughput sequencing (ChIP-seq) was performed on B-lymphoma and pre-tumoral B-cells and compared to normal B-cells. Binding to chromatin of Miz-1 and c-Myc was assessed. Results: ΔPOZ/Eµ-Myc mice develop lymphomas with a significant longer latency and lower incidence than Eµ-Myc mice expressing functional Miz-1 proteins. Additionally, blood analysis of sick animals reveal a lower amount of Large Unstained Cells (LUC) when Miz-1 is mutated. Accordingly, in 40 day old pre-tumoral ΔPOZ/Eµ-Myc animals compared to Eµ-Myc mice, less pre-B and/or pro-B cells were observed in lymphoid organs and little or no LUC were present in the blood. This suggests that Myc driven lymphoma and leukemia is impaired when a ΔPOZ Miz-1 protein is expressed. Our RNA-seq analyses of pre-neoplastic and tumor cells revealed that the expression of ΔPOZ Miz-1 induces deregulation of several genes belonging to different GO (Gene Ontology) functions like “small GTPase-mediated signal transduction”. Interestingly, comparision of RNA-seq and Miz-1 ChIP-seq analyses indicates that some Miz-1 bound genes are deregulated in cells from ΔPOZ/Eµ-Myc mice (e.g: Aurora kinase A (Aurka)). Conclusion: Our data indicate that Miz-1 is required for the efficient development of aggressive c-Myc-driven lymphomas. Miz-1 is probably cooperating with c-Myc in the abnormal transcriptional program that is occuring in lymphoma cells. Therefore, targeting Miz-1 in B-lymphomas could lead to the development of new therapeutic approaches. Citation Format: Julie Ross, René Winkler, Charles Vadnais, Marissa Rashkovan, Christian Kosan, Tarik Möröy. Loss of functional Miz-1 impairs c-Myc-dependent B cell lymphomagenesis. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B08.
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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 | 0.000 |
| 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".