Etv6-NTRK3/⁺;CD19-Cre mice develop rapid pre–B acute lymphoblastic leukemia. (A) Kaplan-Meier curve of Etv6-NTRK3/⁺;CD19-Cre mice (n = 27) compared with Etv6-NTRK3/⁺ controls (n = 28). (B) Body weight and (C) splenic weight for Etv6-NTRK3/⁺;CD19-Cre, and Etv6-NTRK3/⁺ mice. Error bars represent mean ± standard deviation. *P < .05, ****P < .0001 by Student t test. (D) Breakdown of disease signs in Etv6-NTRK3/⁺;CD19-Cre mice. (E) Tissues of Etv6-NTRK3/⁺;CD19-Cre mice showing infiltration of leukemic blasts into spleen and bone marrow with disruption of normal architecture by diffuse infiltration of leukemic cells (original magnification ×10; hematoxylin and eosin stain). Sagittal section of the brain showing masslike infiltration of blasts into the meninges, displacing the cortex (arrows). Transverse section of the spinal cord showing infiltration of leukemic blasts ventral to the vertebra, resulting in spinal cord compression (arrows). (F) Representative analysis of bone marrow of diseased animals gated on YFP⁺ cells by flow cytometry. (G) Microarray-based comparative genomic hybridization (aCGH) on 12 bone marrow or spleen samples from Etv6-NTRK3/⁺;CD19-Cre mice. A focal deletion at the 3′ end of Etv6 was identified in all samples, resulting from recombination at this locus. One case harbored a focal deletion of Ikzf1. (H) Transcriptome sequencing displaying up- and downregulated genes compared with normal pre–B cells.