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

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

doi:10.1172/JCI45284

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

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

Lukas D Wartman, David E Larson, Zhifu Xiang, Li Ding, Ken Chen, Ling Lin, Patrick Cahan, Jeffery M Klco, John S Welch, Cheng Li, …

The Journal of clinical investigation, Vol.121(4), pp.1445-1455

04/01/2011

DOI: 10.1172/JCI45284

PMCID: PMC3069786

PMID: 21436584

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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.

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Title: Subtitle: Sequencing a mouse acute promyelocytic leukemia genome reveals genetic events relevant for disease progression
Creators: Lukas D Wartman - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
David E Larson - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Zhifu Xiang - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Li Ding - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Ken Chen - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Ling Lin - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Patrick Cahan - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Jeffery M Klco - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
John S Welch - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Cheng Li - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Jacqueline E Payton - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Geoffrey L Uy - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Nobish Varghese - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Rhonda E Ries - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Mieke Hoock - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Daniel C Koboldt - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Michael D McLellan - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Heather Schmidt - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Robert S Fulton - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Rachel M Abbott - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Lisa Cook - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Sean D McGrath - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Xian Fan - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Adam F Dukes - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Tammi Vickery - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Joelle Kalicki - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Tamara L Lamprecht - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Timothy A Graubert - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Michael H Tomasson - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Elaine R Mardis - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Richard K Wilson - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Timothy J Ley - Departments of Internal Medicine and Genetics, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.121(4), pp.1445-1455
DOI: 10.1172/JCI45284
PMID: 21436584
PMCID: PMC3069786
NLM abbreviation: J Clin Invest
ISSN: 0021-9738
eISSN: 1558-8238
Publisher: American Society for Clinical Investigation
Language: English
Date published: 04/01/2011
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984094389302771

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