Journal Article

Sequencing a mouse acute promyelocytic leukemia genome reveals genetic events relevant for disease progression

Mardis, Elaine R., Ries, Rhonda E., Lamprecht, Tamara L., Welch, John S., Kalicki, Joelle, Fan, Xian, Vickery, Tammi, McLellan, Michael D., Hoock, Mieke, Payton, Jacqueline E., Larson, David E., Koboldt, Daniel C., Ding, Li, Abbott, Rachel M., Varghese, Nobish, Graubert, Timothy A., Wilson, Richard K., Xiang, Zhifu, Uy, Geoffrey L., Wartman, Lukas D., Lin, Ling, McGrath, Sean D., Tomasson, Michael H., Li, Cheng, Dukes, Adam F., Klco, Jeffery M., Ley, Timothy J., Cook, Lisa, Chen, Ken, Cahan, Patrick, Fulton, Robert S., Schmidt, Heather

2011

Overview

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML). It is characterized by the t(15;17)(q22;q11.2) chromosomal translocation that creates the promyelocytic leukemia-retinoic acid receptor α (PML-RARA) fusion oncogene. Although this fusion oncogene is known to initiate APL in mice, other cooperating mutations, as yet ill defined, are important for disease pathogenesis. To identify these, we used a mouse model of APL, whereby PML-RARA expressed in myeloid cells leads to a myeloproliferative disease that ultimately evolves into APL. Sequencing of a mouse APL genome revealed 3 somatic, nonsynonymous mutations relevant to APL pathogenesis, of which 1 (Jak1 V657F) was found to be recurrent in other affected mice. This mutation was identical to the JAK1 V658F mutation previously found in human APL and acute lymphoblastic leukemia samples. Further analysis showed that JAK1 V658F cooperated in vivo with PML-RARA, causing a rapidly fatal leukemia in mice. We also discovered a somatic 150-kb deletion involving the lysine (K)-specific demethylase 6A (Kdm6a, also known as Utx) gene, in the mouse APL genome. Similar deletions were observed in 3 out of 14 additional mouse APL samples and 1 out of 150 human AML samples. In conclusion, whole genome sequencing of mouse cancer genomes can provide an unbiased and comprehensive approach for discovering functionally relevant mutations that are also present in human leukemias.

• Publisher: American Society for Clinical Investigation
• Subject: Amino Acid Sequence / Amino Acid Substitution / Animals / Base Sequence / Biomedical research / Cancer / Cooperation / Disease Progression / DNA sequencing / DNA, Neoplasm - genetics / Genetic aspects / Genomes / Humans / Janus Kinase 1 - genetics / Jumonji Domain-Containing Histone Demethylases - genetics / Leukemia / Leukemia, Experimental - genetics / Leukemia, Promyelocytic, Acute - genetics / Mice / Mice, 129 Strain / Molecular Sequence Data / Mutation / Nucleotide sequencing / Oncogene Proteins, Fusion - genetics / Pathogenesis / Polymorphism, Single Nucleotide / Sequence Deletion / Sequence Homology, Amino Acid / Stem cells / Technical Advance