PRDM14 promotes RAG-dependent Notch1 driver mutations in mouse T-ALL.
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.
Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, 77030 USA Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030 USA.
Brandi L
BL
Carofino
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030 USA.
Bernard
B
Ayanga
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A8 Canada Genetics and Genome Biology, The Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, Ontario, M5G 0A4 Canada.
Lauren J
LJ
Tracey
Genetics and Genome Biology, The Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, Ontario, M5G 0A4 Canada.
Travis
T
Brooke-Bisschop
Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, 77030 USA Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030 USA Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A8 Canada Genetics and Genome Biology, The Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, Ontario, M5G 0A4 Canada monica.justice@sickkids.ca.
Monica J
http://orcid.org/0000-0003-3562-2099
MJ
Justice
Driver mutation; NOTCH1; PRDM14; RAG recombination; T-cell acute lymphoblastic leukemia