title: Sequencing a mouse acute promyelocytic leukemia genome reveals genetic events relevant for disease progression.
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.
authors: Department of Internal Medicine, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA.
authors: Lukas D
authors: LD
authors: Wartman
authors: David E
authors: DE
authors: Larson
authors: Zhifu
authors: Z
authors: Xiang
authors: Li
authors: L
authors: Ding
authors: Ken
authors: K
authors: Chen
authors: Ling
authors: L
authors: Lin
authors: Patrick
authors: P
authors: Cahan
authors: Jeffery M
authors: JM
authors: Klco
authors: John S
authors: JS
authors: Welch
authors: Cheng
authors: C
authors: Li
authors: Jacqueline E
authors: JE
authors: Payton
authors: Geoffrey L
authors: GL
authors: Uy
authors: Nobish
authors: N
authors: Varghese
authors: Rhonda E
authors: RE
authors: Ries
authors: Mieke
authors: M
authors: Hoock
authors: Daniel C
authors: DC
authors: Koboldt
authors: Michael D
authors: MD
authors: McLellan
authors: Heather
authors: H
authors: Schmidt
authors: Robert S
authors: RS
authors: Fulton
authors: Rachel M
authors: RM
authors: Abbott
authors: Lisa
authors: L
authors: Cook
authors: Sean D
authors: SD
authors: McGrath
authors: Xian
authors: X
authors: Fan
authors: Adam F
authors: AF
authors: Dukes
authors: Tammi
authors: T
authors: Vickery
authors: Joelle
authors: J
authors: Kalicki
authors: Tamara L
authors: TL
authors: Lamprecht
authors: Timothy A
authors: TA
authors: Graubert
authors: Michael H
authors: MH
authors: Tomasson
authors: Elaine R
authors: ER
authors: Mardis
authors: Richard K
authors: RK
authors: Wilson
authors: Timothy J
authors: TJ
authors: Ley
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D006801:Humans; D053613:Janus Kinase 1 / Q000235:genetics; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics; D007942:Leukemia, Experimental / Q000235:genetics; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics*; D051379:Mice; D057507:Mice, 129 Strain; D008969:Molecular Sequence Data; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid
chemical_list: D004273:DNA, Neoplasm; D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D056484:Jumonji Domain-Containing Histone Demethylases; C523761:Kdm6b protein, mouse; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1