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- Title
Sequencing a mouse acute promyelocytic leukemia genome reveals genetic events relevant for disease progression.
- Authors
Wartman, Lukas D.; Larson, David E.; Zhifu Xiang; Li Ding; Ken Chen; Ling Lin; Cahan, Patrick; Klco, Jeffery M.; Welch, John S.; Cheng Li; Payton, Jacqueline E.; Uy, Geoffrey L.; Varghese, Nobish; Ries, Rhonda E.; Hoock, Mieke; Koboldt, Daniel C.; McLellan, Michael D.; Schmidt, Heather; Fulton, Robert S.; Abbott, Rachel M.
- Abstract
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.
- Subjects
ACUTE myeloid leukemia; DISEASE progression; NUCLEOTIDE sequence; CELL proliferation; CARCINOGENESIS; LABORATORY mice; GENETICS; AMINO acids; ANIMAL experimentation; COMPARATIVE studies; DNA; DOCUMENTATION; GENETIC polymorphisms; LEUKEMIA; RESEARCH methodology; MEDICAL cooperation; MICE; GENETIC mutation; NUCLEOTIDES; OXIDOREDUCTASES; PROTEINS; RESEARCH; EVALUATION research; ACUTE promyelocytic leukemia
- Publication
Journal of Clinical Investigation, 2011, Vol 121, Issue 4, p1445
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI45284