Exon array data from mouse APL tumors

Acute Promyelocytic Leukemia (APL) is characterized by the t(15;17)(q22;q11.2) translocation, which creates a PML-RARA fusion gene that can initiate APL in mice. To discover cooperating mutations in this model, we sequenced a mouse APL genome to 15.6x haploid coverage, and discovered three somatic, non-synonymous mutations, of which one (Jak1 V657F) was recurrent. This mutation is identical to the JAK1 V658F mutation previously found in human APL and ALL samples. JAK1 V658F cooperates in vivo with PML-RARA, causing a rapidly fatal leukemia. We also discovered a somatic 150kb deletion involving the Kdm6a/Utx gene in the mouse APL genome; 3/14 additional mouse APL samples had similar deletions involving Kdm6a/Utx. Kdm6A/Utx, a histone H3K27 demethylase, was also deleted in 1/150 human AML samples tested. Whole genome sequencing of mouse cancer genomes provides an unbiased approach for discovering functionally relevant mutations that are also present in human leukemias. Spleens from Bl/6 Taconic mice were harvested and total RNA was extracted. A total of 15 specimens were analyzed using the Affymetrix Mouse Exon 1.0 ST platform.