Expression of Ezh2^Y641F in hematopoietic stem cells shortens overall survival. (A) Genetic alterations in EZH2 across mature B-cell neos, BLL, and acute myeloid leukemia (AML), analyzed using The Cancer Genome Atlas data from the Genomics Evidence Neoplasia Information Exchange (GENIE) cohort (version 16.1) on cBioPortal (B-cell neos, n = 6444; BLL, n = 911; AML, n = 3859). (B) Frequency of EZH2^Y641F mutations across various cancer types, based on GENIE cohort (v16.1) data analyzed via cBioPortal. (C) Schematic of Cre-lox strategy to induce Ezh2^Y641F expression from the mouse endogenous locus. (D) PCR confirmation of Ezh2 recombination in specific tissues by each Cre allele. (E) Western blot for Ezh2 protein expression in the indicated genotypes. (F) Disease-free survival curves for Mx1-Cre Ezh2^Y641F compared to Cre-only ctrls (log-rank test P < .0001); median survival for Mx1-Cre Ezh2^Y641F mice is 329 days. BLL, B Lymphoblastic Leukemia; BM, bone marrow; ctrl, control; GAPDH, Glyceraldehyde-3-phosphate Dehydrogenase; Lymph, lymphoma; neo, neoplasm; NOS, not otherwise specified; OE, overexpression; recomb., recombination; WT, wild-type.