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. AbbottLisa 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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1445-1455
Number of pages11
JournalJournal of Clinical Investigation
Volume121
Issue number4
DOIs
StatePublished - Apr 1 2011
Externally publishedYes

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Acute Promyelocytic Leukemia
Disease Progression
Genome
Oncogene Fusion
Mutation
Leukemia
Acute Myeloid Leukemia
Genetic Translocation
Retinoic Acid Receptors
Myeloid Cells
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Lysine

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Wartman, L. D., Larson, D. E., Xiang, Z., Ding, L., Chen, K., Lin, L., ... Ley, T. J. (2011). Sequencing a mouse acute promyelocytic leukemia genome reveals genetic events relevant for disease progression. Journal of Clinical Investigation, 121(4), 1445-1455. https://doi.org/10.1172/JCI45284

Sequencing a mouse acute promyelocytic leukemia genome reveals genetic events relevant for disease progression. / Wartman, Lukas D.; Larson, David E.; Xiang, Zhifu; Ding, Li; Chen, Ken; Lin, Ling; Cahan, Patrick; Klco, Jeffery M.; Welch, John S.; Li, Cheng; 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.; Cook, Lisa; McGrath, Sean D.; Fan, Xian; Dukes, Adam F.; Vickery, Tammi; Kalicki, Joelle; Lamprecht, Tamara L.; Graubert, Timothy A.; Tomasson, Michael H.; Mardis, Elaine R.; Wilson, Richard K.; Ley, Timothy J.

In: Journal of Clinical Investigation, Vol. 121, No. 4, 01.04.2011, p. 1445-1455.

Research output: Contribution to journalArticle

Wartman, LD, Larson, DE, Xiang, Z, Ding, L, Chen, K, Lin, L, Cahan, P, Klco, JM, Welch, JS, Li, C, Payton, JE, Uy, GL, Varghese, N, Ries, RE, Hoock, M, Koboldt, DC, McLellan, MD, Schmidt, H, Fulton, RS, Abbott, RM, Cook, L, McGrath, SD, Fan, X, Dukes, AF, Vickery, T, Kalicki, J, Lamprecht, TL, Graubert, TA, Tomasson, MH, Mardis, ER, Wilson, RK & Ley, TJ 2011, 'Sequencing a mouse acute promyelocytic leukemia genome reveals genetic events relevant for disease progression', Journal of Clinical Investigation, vol. 121, no. 4, pp. 1445-1455. https://doi.org/10.1172/JCI45284
Wartman, Lukas D. ; Larson, David E. ; Xiang, Zhifu ; Ding, Li ; Chen, Ken ; Lin, Ling ; Cahan, Patrick ; Klco, Jeffery M. ; Welch, John S. ; Li, Cheng ; 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. ; Cook, Lisa ; McGrath, Sean D. ; Fan, Xian ; Dukes, Adam F. ; Vickery, Tammi ; Kalicki, Joelle ; Lamprecht, Tamara L. ; Graubert, Timothy A. ; Tomasson, Michael H. ; Mardis, Elaine R. ; Wilson, Richard K. ; Ley, Timothy J. / Sequencing a mouse acute promyelocytic leukemia genome reveals genetic events relevant for disease progression. In: Journal of Clinical Investigation. 2011 ; Vol. 121, No. 4. pp. 1445-1455.
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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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AU - Wartman, Lukas D.

AU - Larson, David E.

AU - Xiang, Zhifu

AU - Ding, Li

AU - Chen, Ken

AU - Lin, Ling

AU - Cahan, Patrick

AU - Klco, Jeffery M.

AU - Welch, John S.

AU - Li, Cheng

AU - Payton, Jacqueline E.

AU - Uy, Geoffrey L.

AU - Varghese, Nobish

AU - Ries, Rhonda E.

AU - Hoock, Mieke

AU - Koboldt, Daniel C.

AU - McLellan, Michael D.

AU - Schmidt, Heather

AU - Fulton, Robert S.

AU - Abbott, Rachel M.

AU - Cook, Lisa

AU - McGrath, Sean D.

AU - Fan, Xian

AU - Dukes, Adam F.

AU - Vickery, Tammi

AU - Kalicki, Joelle

AU - Lamprecht, Tamara L.

AU - Graubert, Timothy A.

AU - Tomasson, Michael H.

AU - Mardis, Elaine R.

AU - Wilson, Richard K.

AU - Ley, Timothy J.

PY - 2011/4/1

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N2 - 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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