PRDM14 promotes RAG-dependent Notch1 driver mutations in mouse T-ALL
| Autor: | Lauren J. Tracey, Monica J. Justice, Bernard Ayanga, Travis Brooke-Bisschop, Brandi L. Carofino |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
QH301-705.5 Science Population PRDM14 Biology General Biochemistry Genetics and Molecular Biology 03 medical and health sciences NOTCH1 hemic and lymphatic diseases medicine Recombinase Epigenetics Progenitor cell Biology (General) education RAG recombination education.field_of_study Hematopoietic stem cell Driver mutation Molecular biology Embryonic stem cell Chromatin Haematopoiesis 030104 developmental biology medicine.anatomical_structure General Agricultural and Biological Sciences T-cell acute lymphoblastic leukemia Research Article |
| Zdroj: | Biology Open Biology Open, Vol 5, Iss 5, Pp 645-653 (2016) |
| ISSN: | 2046-6390 |
| Popis: | PRDM14 is an epigenetic regulator known for maintaining embryonic stem cell identity and resetting potency in primordial germ cells. However, hematopoietic expression of Prdm14 at supraphysiological levels results in fully penetrant and rapid-onset T-cell acute lymphoblastic leukemia (T-ALL) in the mouse. Here, we show that PRDM14-induced T-ALLs are driven by NOTCH1, a frequently mutated driver of human T-ALL. Notch1 is activated in this murine model via RAG-dependent promoter deletions and subsequent production of truncated, ligand-independent protein from downstream regions of the Notch1 locus. These T-ALLs also have focal changes in H3K4me3 deposition at the Notch1 locus and global increases in both H3K4me1 and H3K4me3. Using a PRDM14-FLAG mouse model, we show that PRDM14 binds within an intron of Notch1 prior to leukemia development. Our data support the idea that PRDM14 binding promotes a chromatin state that allows access of the RAG recombinase complex to cryptic RAG signal sequences embedded at the Notch1 locus. Indeed, breeding into a RAG recombination-deficient background abrogates T-ALL development and prevents Notch1 deletions, while allowing for transient hematopoietic stem cell (HSC)-like pre-leukemia cell expansion. Together, our data suggest that PRDM14 expands a progenitor cell population while promoting a permissive epigenetic state for the creation of driver mutations (here, in Notch1), enabling cancer development through the misappropriation of endogenous cellular DNA recombination machinery. Summary: PRDM14 promotes an epigenetic state that facilitates RAG-dependent Notch1 driver mutations, coupling progenitor cell expansion with genomic instability to produce T-ALL with shorter latency than other NOTCH1-driven mouse models. |
| Databáze: | OpenAIRE |
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