Alternative transcription initiation leads to expression of a novel ALK isoform in cancer

Activation of oncogenes by mechanisms other than genetic aberrations such as mutations, translocations, or amplifications is largely undefined. Here we report a novel isoform of the anaplastic lymphoma kinase (ALK) that is expressed in ~11% of melanomas and sporadically in other human cancer types,...
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Gespeichert in:

Autor*in:	Julia Button [verfasserIn] James A Fagin Nathalie Lailler Leili Ran Thomas Wiesner Anna C Obenauf Zhen Cao Shipra Shukla Charlotte E Ariyan Yu Chen Marc Ladanyi Andrea Sboner Taha Merghoub Michael F Berger Rajmohan Murali William Lee Laetitia Borsu Gary K Schwartz Ronak H Shah Elissa W P Wong Qi Fan Zhang Michael A Postow Sasinya N Scott Iñigo Landa Wenhuo Hu Deyou Zheng Travis J Hollmann Klaus J Busam Lu Wang Ping Chi Devan A Murphy Dong Gao

Format:	Artikel
Sprache:	Englisch

Erschienen:	2015

Schlagwörter:	Kinases Genes Phosphorylation Cancer therapies Tumorigenesis Binding sites Proteins Tumors Thyroid cancer Metastasis Melanoma Oncogenes Development and progression Health aspects Cancer Genetic transcription Genetic aspects

Übergeordnetes Werk:	Enthalten in: Nature - London : Macmillan Publishers Limited, part of Springer Nature, 1869, 526(2015), 7573, Seite 453-457
Übergeordnetes Werk:	volume:526 ; year:2015 ; number:7573 ; pages:453-457

Links:	Volltext Link aufrufen Link aufrufen

DOI / URN:	10.1038/nature15258

Katalog-ID:	OLC1969670789

Internformat


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520			\|a Activation of oncogenes by mechanisms other than genetic aberrations such as mutations, translocations, or amplifications is largely undefined. Here we report a novel isoform of the anaplastic lymphoma kinase (ALK) that is expressed in ~11% of melanomas and sporadically in other human cancer types, but not in normal tissues. The novelALK transcript initiates from a de novo alternative transcription initiation (ATI) site in ALK intron 19, and was termed ALK^sup ATI^. In ALK^sup ATI^-expressing tumours, the ATI site is enriched for H3K4me3 and RNA polymerase II, chromatin marks characteristic of active transcription initiation sites. ALK^sup ATI^ is expressed from both ALK alleles, and no recurrent genetic aberrations are found at the ALK locus, indicating that the transcriptional activation is independent of genetic aberrations at the ALK locus. The ALK^sup ATI^ transcript encodes three proteins with molecular weights of 61.1, 60.8 and 58.7 kilodaltons, consisting primarily of the intracellular tyrosine kinase domain. ALK^sup ATI^ stimulates multiple oncogenic signalling pathways, drives growthfactor- independent cell proliferation in vitro, and promotes tumorigenesis in vivo in mouse models. ALK inhibitors can suppress the kinase activity of ALK^sup ATI^, suggesting that patients with ALK^sup ATI^-expressing tumours may benefit from ALK inhibitors. Our findings suggest a novel mechanism of oncogene activation in cancer through de novo alternative transcription initiation.
650		4	\|a Kinases
650		4	\|a Genes
650		4	\|a Phosphorylation
650		4	\|a Cancer therapies
650		4	\|a Tumorigenesis
650		4	\|a Binding sites
650		4	\|a Proteins
650		4	\|a Tumors
650		4	\|a Thyroid cancer
650		4	\|a Metastasis
650		4	\|a Melanoma
650		4	\|a Oncogenes
650		4	\|a Development and progression
650		4	\|a Health aspects
650		4	\|a Cancer
650		4	\|a Genetic transcription
650		4	\|a Genetic aspects
700	0		\|a James A Fagin \|4 oth
700	0		\|a Nathalie Lailler \|4 oth
700	0		\|a Leili Ran \|4 oth
700	0		\|a Thomas Wiesner \|4 oth
700	0		\|a Anna C Obenauf \|4 oth
700	0		\|a Zhen Cao \|4 oth
700	0		\|a Shipra Shukla \|4 oth
700	0		\|a Charlotte E Ariyan \|4 oth
700	0		\|a Yu Chen \|4 oth
700	0		\|a Marc Ladanyi \|4 oth
700	0		\|a Andrea Sboner \|4 oth
700	0		\|a Taha Merghoub \|4 oth
700	0		\|a Michael F Berger \|4 oth
700	0		\|a Rajmohan Murali \|4 oth
700	0		\|a William Lee \|4 oth
700	0		\|a Laetitia Borsu \|4 oth
700	0		\|a Gary K Schwartz \|4 oth
700	0		\|a Ronak H Shah \|4 oth
700	0		\|a Elissa W P Wong \|4 oth
700	0		\|a Qi Fan Zhang \|4 oth
700	0		\|a Michael A Postow \|4 oth
700	0		\|a Sasinya N Scott \|4 oth
700	0		\|a Iñigo Landa \|4 oth
700	0		\|a Wenhuo Hu \|4 oth
700	0		\|a Deyou Zheng \|4 oth
700	0		\|a Travis J Hollmann \|4 oth
700	0		\|a Klaus J Busam \|4 oth
700	0		\|a Lu Wang \|4 oth
700	0		\|a Ping Chi \|4 oth
700	0		\|a Devan A Murphy \|4 oth
700	0		\|a Dong Gao \|4 oth
773	0	8	\|i Enthalten in \|t Nature \|d London : Macmillan Publishers Limited, part of Springer Nature, 1869 \|g 526(2015), 7573, Seite 453-457 \|w (DE-627)129292834 \|w (DE-600)120714-3 \|w (DE-576)014473941 \|x 0028-0836 \|7 nnns
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856	4	1	\|u http://dx.doi.org/10.1038/nature15258 \|3 Volltext
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matchkey_str	article:00280836:2015----::lentvtasrpinntainedtepesooao
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publishDate	2015
allfields	10.1038/nature15258 doi PQ20160211 (DE-627)OLC1969670789 (DE-599)GBVOLC1969670789 (PRQ)c2226-253279c9f9552e66d8a67529a6e6822b2e2d431d4220a51dcaa20ea4f9358cff0 (KEY)0072945020150000526757300453alternativetranscriptioninitiationleadstoexpressio DE-627 ger DE-627 rakwb eng 070 500 DNB 500 AVZ BIODIV fid Julia Button verfasserin aut Alternative transcription initiation leads to expression of a novel ALK isoform in cancer 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Activation of oncogenes by mechanisms other than genetic aberrations such as mutations, translocations, or amplifications is largely undefined. Here we report a novel isoform of the anaplastic lymphoma kinase (ALK) that is expressed in ~11% of melanomas and sporadically in other human cancer types, but not in normal tissues. The novelALK transcript initiates from a de novo alternative transcription initiation (ATI) site in ALK intron 19, and was termed ALK^sup ATI^. In ALK^sup ATI^-expressing tumours, the ATI site is enriched for H3K4me3 and RNA polymerase II, chromatin marks characteristic of active transcription initiation sites. ALK^sup ATI^ is expressed from both ALK alleles, and no recurrent genetic aberrations are found at the ALK locus, indicating that the transcriptional activation is independent of genetic aberrations at the ALK locus. The ALK^sup ATI^ transcript encodes three proteins with molecular weights of 61.1, 60.8 and 58.7 kilodaltons, consisting primarily of the intracellular tyrosine kinase domain. ALK^sup ATI^ stimulates multiple oncogenic signalling pathways, drives growthfactor- independent cell proliferation in vitro, and promotes tumorigenesis in vivo in mouse models. ALK inhibitors can suppress the kinase activity of ALK^sup ATI^, suggesting that patients with ALK^sup ATI^-expressing tumours may benefit from ALK inhibitors. Our findings suggest a novel mechanism of oncogene activation in cancer through de novo alternative transcription initiation. Kinases Genes Phosphorylation Cancer therapies Tumorigenesis Binding sites Proteins Tumors Thyroid cancer Metastasis Melanoma Oncogenes Development and progression Health aspects Cancer Genetic transcription Genetic aspects James A Fagin oth Nathalie Lailler oth Leili Ran oth Thomas Wiesner oth Anna C Obenauf oth Zhen Cao oth Shipra Shukla oth Charlotte E Ariyan oth Yu Chen oth Marc Ladanyi oth Andrea Sboner oth Taha Merghoub oth Michael F Berger oth Rajmohan Murali oth William Lee oth Laetitia Borsu oth Gary K Schwartz oth Ronak H Shah oth Elissa W P Wong oth Qi Fan Zhang oth Michael A Postow oth Sasinya N Scott oth Iñigo Landa oth Wenhuo Hu oth Deyou Zheng oth Travis J Hollmann oth Klaus J Busam oth Lu Wang oth Ping Chi oth Devan A Murphy oth Dong Gao oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 526(2015), 7573, Seite 453-457 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:526 year:2015 number:7573 pages:453-457 http://dx.doi.org/10.1038/nature15258 Volltext http://www.ncbi.nlm.nih.gov/pubmed/26444240 http://search.proquest.com/docview/1723755802 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_21 GBV_ILN_22 GBV_ILN_30 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_100 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_154 GBV_ILN_160 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_267 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2015 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2173 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4046 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 GBV_ILN_4700 AR 526 2015 7573 453-457
spelling	10.1038/nature15258 doi PQ20160211 (DE-627)OLC1969670789 (DE-599)GBVOLC1969670789 (PRQ)c2226-253279c9f9552e66d8a67529a6e6822b2e2d431d4220a51dcaa20ea4f9358cff0 (KEY)0072945020150000526757300453alternativetranscriptioninitiationleadstoexpressio DE-627 ger DE-627 rakwb eng 070 500 DNB 500 AVZ BIODIV fid Julia Button verfasserin aut Alternative transcription initiation leads to expression of a novel ALK isoform in cancer 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Activation of oncogenes by mechanisms other than genetic aberrations such as mutations, translocations, or amplifications is largely undefined. Here we report a novel isoform of the anaplastic lymphoma kinase (ALK) that is expressed in ~11% of melanomas and sporadically in other human cancer types, but not in normal tissues. The novelALK transcript initiates from a de novo alternative transcription initiation (ATI) site in ALK intron 19, and was termed ALK^sup ATI^. In ALK^sup ATI^-expressing tumours, the ATI site is enriched for H3K4me3 and RNA polymerase II, chromatin marks characteristic of active transcription initiation sites. ALK^sup ATI^ is expressed from both ALK alleles, and no recurrent genetic aberrations are found at the ALK locus, indicating that the transcriptional activation is independent of genetic aberrations at the ALK locus. The ALK^sup ATI^ transcript encodes three proteins with molecular weights of 61.1, 60.8 and 58.7 kilodaltons, consisting primarily of the intracellular tyrosine kinase domain. ALK^sup ATI^ stimulates multiple oncogenic signalling pathways, drives growthfactor- independent cell proliferation in vitro, and promotes tumorigenesis in vivo in mouse models. ALK inhibitors can suppress the kinase activity of ALK^sup ATI^, suggesting that patients with ALK^sup ATI^-expressing tumours may benefit from ALK inhibitors. Our findings suggest a novel mechanism of oncogene activation in cancer through de novo alternative transcription initiation. Kinases Genes Phosphorylation Cancer therapies Tumorigenesis Binding sites Proteins Tumors Thyroid cancer Metastasis Melanoma Oncogenes Development and progression Health aspects Cancer Genetic transcription Genetic aspects James A Fagin oth Nathalie Lailler oth Leili Ran oth Thomas Wiesner oth Anna C Obenauf oth Zhen Cao oth Shipra Shukla oth Charlotte E Ariyan oth Yu Chen oth Marc Ladanyi oth Andrea Sboner oth Taha Merghoub oth Michael F Berger oth Rajmohan Murali oth William Lee oth Laetitia Borsu oth Gary K Schwartz oth Ronak H Shah oth Elissa W P Wong oth Qi Fan Zhang oth Michael A Postow oth Sasinya N Scott oth Iñigo Landa oth Wenhuo Hu oth Deyou Zheng oth Travis J Hollmann oth Klaus J Busam oth Lu Wang oth Ping Chi oth Devan A Murphy oth Dong Gao oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 526(2015), 7573, Seite 453-457 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:526 year:2015 number:7573 pages:453-457 http://dx.doi.org/10.1038/nature15258 Volltext http://www.ncbi.nlm.nih.gov/pubmed/26444240 http://search.proquest.com/docview/1723755802 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_21 GBV_ILN_22 GBV_ILN_30 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_100 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_154 GBV_ILN_160 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_267 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2015 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2173 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4046 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 GBV_ILN_4700 AR 526 2015 7573 453-457
allfields_unstemmed	10.1038/nature15258 doi PQ20160211 (DE-627)OLC1969670789 (DE-599)GBVOLC1969670789 (PRQ)c2226-253279c9f9552e66d8a67529a6e6822b2e2d431d4220a51dcaa20ea4f9358cff0 (KEY)0072945020150000526757300453alternativetranscriptioninitiationleadstoexpressio DE-627 ger DE-627 rakwb eng 070 500 DNB 500 AVZ BIODIV fid Julia Button verfasserin aut Alternative transcription initiation leads to expression of a novel ALK isoform in cancer 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Activation of oncogenes by mechanisms other than genetic aberrations such as mutations, translocations, or amplifications is largely undefined. Here we report a novel isoform of the anaplastic lymphoma kinase (ALK) that is expressed in ~11% of melanomas and sporadically in other human cancer types, but not in normal tissues. The novelALK transcript initiates from a de novo alternative transcription initiation (ATI) site in ALK intron 19, and was termed ALK^sup ATI^. In ALK^sup ATI^-expressing tumours, the ATI site is enriched for H3K4me3 and RNA polymerase II, chromatin marks characteristic of active transcription initiation sites. ALK^sup ATI^ is expressed from both ALK alleles, and no recurrent genetic aberrations are found at the ALK locus, indicating that the transcriptional activation is independent of genetic aberrations at the ALK locus. The ALK^sup ATI^ transcript encodes three proteins with molecular weights of 61.1, 60.8 and 58.7 kilodaltons, consisting primarily of the intracellular tyrosine kinase domain. ALK^sup ATI^ stimulates multiple oncogenic signalling pathways, drives growthfactor- independent cell proliferation in vitro, and promotes tumorigenesis in vivo in mouse models. ALK inhibitors can suppress the kinase activity of ALK^sup ATI^, suggesting that patients with ALK^sup ATI^-expressing tumours may benefit from ALK inhibitors. Our findings suggest a novel mechanism of oncogene activation in cancer through de novo alternative transcription initiation. Kinases Genes Phosphorylation Cancer therapies Tumorigenesis Binding sites Proteins Tumors Thyroid cancer Metastasis Melanoma Oncogenes Development and progression Health aspects Cancer Genetic transcription Genetic aspects James A Fagin oth Nathalie Lailler oth Leili Ran oth Thomas Wiesner oth Anna C Obenauf oth Zhen Cao oth Shipra Shukla oth Charlotte E Ariyan oth Yu Chen oth Marc Ladanyi oth Andrea Sboner oth Taha Merghoub oth Michael F Berger oth Rajmohan Murali oth William Lee oth Laetitia Borsu oth Gary K Schwartz oth Ronak H Shah oth Elissa W P Wong oth Qi Fan Zhang oth Michael A Postow oth Sasinya N Scott oth Iñigo Landa oth Wenhuo Hu oth Deyou Zheng oth Travis J Hollmann oth Klaus J Busam oth Lu Wang oth Ping Chi oth Devan A Murphy oth Dong Gao oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 526(2015), 7573, Seite 453-457 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:526 year:2015 number:7573 pages:453-457 http://dx.doi.org/10.1038/nature15258 Volltext http://www.ncbi.nlm.nih.gov/pubmed/26444240 http://search.proquest.com/docview/1723755802 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_21 GBV_ILN_22 GBV_ILN_30 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_100 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_154 GBV_ILN_160 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_267 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2015 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2173 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4046 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 GBV_ILN_4700 AR 526 2015 7573 453-457
allfieldsGer	10.1038/nature15258 doi PQ20160211 (DE-627)OLC1969670789 (DE-599)GBVOLC1969670789 (PRQ)c2226-253279c9f9552e66d8a67529a6e6822b2e2d431d4220a51dcaa20ea4f9358cff0 (KEY)0072945020150000526757300453alternativetranscriptioninitiationleadstoexpressio DE-627 ger DE-627 rakwb eng 070 500 DNB 500 AVZ BIODIV fid Julia Button verfasserin aut Alternative transcription initiation leads to expression of a novel ALK isoform in cancer 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Activation of oncogenes by mechanisms other than genetic aberrations such as mutations, translocations, or amplifications is largely undefined. Here we report a novel isoform of the anaplastic lymphoma kinase (ALK) that is expressed in ~11% of melanomas and sporadically in other human cancer types, but not in normal tissues. The novelALK transcript initiates from a de novo alternative transcription initiation (ATI) site in ALK intron 19, and was termed ALK^sup ATI^. In ALK^sup ATI^-expressing tumours, the ATI site is enriched for H3K4me3 and RNA polymerase II, chromatin marks characteristic of active transcription initiation sites. ALK^sup ATI^ is expressed from both ALK alleles, and no recurrent genetic aberrations are found at the ALK locus, indicating that the transcriptional activation is independent of genetic aberrations at the ALK locus. The ALK^sup ATI^ transcript encodes three proteins with molecular weights of 61.1, 60.8 and 58.7 kilodaltons, consisting primarily of the intracellular tyrosine kinase domain. ALK^sup ATI^ stimulates multiple oncogenic signalling pathways, drives growthfactor- independent cell proliferation in vitro, and promotes tumorigenesis in vivo in mouse models. ALK inhibitors can suppress the kinase activity of ALK^sup ATI^, suggesting that patients with ALK^sup ATI^-expressing tumours may benefit from ALK inhibitors. Our findings suggest a novel mechanism of oncogene activation in cancer through de novo alternative transcription initiation. Kinases Genes Phosphorylation Cancer therapies Tumorigenesis Binding sites Proteins Tumors Thyroid cancer Metastasis Melanoma Oncogenes Development and progression Health aspects Cancer Genetic transcription Genetic aspects James A Fagin oth Nathalie Lailler oth Leili Ran oth Thomas Wiesner oth Anna C Obenauf oth Zhen Cao oth Shipra Shukla oth Charlotte E Ariyan oth Yu Chen oth Marc Ladanyi oth Andrea Sboner oth Taha Merghoub oth Michael F Berger oth Rajmohan Murali oth William Lee oth Laetitia Borsu oth Gary K Schwartz oth Ronak H Shah oth Elissa W P Wong oth Qi Fan Zhang oth Michael A Postow oth Sasinya N Scott oth Iñigo Landa oth Wenhuo Hu oth Deyou Zheng oth Travis J Hollmann oth Klaus J Busam oth Lu Wang oth Ping Chi oth Devan A Murphy oth Dong Gao oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 526(2015), 7573, Seite 453-457 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:526 year:2015 number:7573 pages:453-457 http://dx.doi.org/10.1038/nature15258 Volltext http://www.ncbi.nlm.nih.gov/pubmed/26444240 http://search.proquest.com/docview/1723755802 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_21 GBV_ILN_22 GBV_ILN_30 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_100 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_154 GBV_ILN_160 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_267 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2015 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2173 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4046 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 GBV_ILN_4700 AR 526 2015 7573 453-457
allfieldsSound	10.1038/nature15258 doi PQ20160211 (DE-627)OLC1969670789 (DE-599)GBVOLC1969670789 (PRQ)c2226-253279c9f9552e66d8a67529a6e6822b2e2d431d4220a51dcaa20ea4f9358cff0 (KEY)0072945020150000526757300453alternativetranscriptioninitiationleadstoexpressio DE-627 ger DE-627 rakwb eng 070 500 DNB 500 AVZ BIODIV fid Julia Button verfasserin aut Alternative transcription initiation leads to expression of a novel ALK isoform in cancer 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Activation of oncogenes by mechanisms other than genetic aberrations such as mutations, translocations, or amplifications is largely undefined. Here we report a novel isoform of the anaplastic lymphoma kinase (ALK) that is expressed in ~11% of melanomas and sporadically in other human cancer types, but not in normal tissues. The novelALK transcript initiates from a de novo alternative transcription initiation (ATI) site in ALK intron 19, and was termed ALK^sup ATI^. In ALK^sup ATI^-expressing tumours, the ATI site is enriched for H3K4me3 and RNA polymerase II, chromatin marks characteristic of active transcription initiation sites. ALK^sup ATI^ is expressed from both ALK alleles, and no recurrent genetic aberrations are found at the ALK locus, indicating that the transcriptional activation is independent of genetic aberrations at the ALK locus. The ALK^sup ATI^ transcript encodes three proteins with molecular weights of 61.1, 60.8 and 58.7 kilodaltons, consisting primarily of the intracellular tyrosine kinase domain. ALK^sup ATI^ stimulates multiple oncogenic signalling pathways, drives growthfactor- independent cell proliferation in vitro, and promotes tumorigenesis in vivo in mouse models. ALK inhibitors can suppress the kinase activity of ALK^sup ATI^, suggesting that patients with ALK^sup ATI^-expressing tumours may benefit from ALK inhibitors. Our findings suggest a novel mechanism of oncogene activation in cancer through de novo alternative transcription initiation. Kinases Genes Phosphorylation Cancer therapies Tumorigenesis Binding sites Proteins Tumors Thyroid cancer Metastasis Melanoma Oncogenes Development and progression Health aspects Cancer Genetic transcription Genetic aspects James A Fagin oth Nathalie Lailler oth Leili Ran oth Thomas Wiesner oth Anna C Obenauf oth Zhen Cao oth Shipra Shukla oth Charlotte E Ariyan oth Yu Chen oth Marc Ladanyi oth Andrea Sboner oth Taha Merghoub oth Michael F Berger oth Rajmohan Murali oth William Lee oth Laetitia Borsu oth Gary K Schwartz oth Ronak H Shah oth Elissa W P Wong oth Qi Fan Zhang oth Michael A Postow oth Sasinya N Scott oth Iñigo Landa oth Wenhuo Hu oth Deyou Zheng oth Travis J Hollmann oth Klaus J Busam oth Lu Wang oth Ping Chi oth Devan A Murphy oth Dong Gao oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 526(2015), 7573, Seite 453-457 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:526 year:2015 number:7573 pages:453-457 http://dx.doi.org/10.1038/nature15258 Volltext http://www.ncbi.nlm.nih.gov/pubmed/26444240 http://search.proquest.com/docview/1723755802 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_21 GBV_ILN_22 GBV_ILN_30 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_100 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_154 GBV_ILN_160 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_267 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2015 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2173 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4046 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 GBV_ILN_4700 AR 526 2015 7573 453-457
language	English
source	Enthalten in Nature 526(2015), 7573, Seite 453-457 volume:526 year:2015 number:7573 pages:453-457
sourceStr	Enthalten in Nature 526(2015), 7573, Seite 453-457 volume:526 year:2015 number:7573 pages:453-457
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Kinases Genes Phosphorylation Cancer therapies Tumorigenesis Binding sites Proteins Tumors Thyroid cancer Metastasis Melanoma Oncogenes Development and progression Health aspects Cancer Genetic transcription Genetic aspects
dewey-raw	070
isfreeaccess_bool	false
container_title	Nature
authorswithroles_txt_mv	Julia Button @@aut@@ James A Fagin @@oth@@ Nathalie Lailler @@oth@@ Leili Ran @@oth@@ Thomas Wiesner @@oth@@ Anna C Obenauf @@oth@@ Zhen Cao @@oth@@ Shipra Shukla @@oth@@ Charlotte E Ariyan @@oth@@ Yu Chen @@oth@@ Marc Ladanyi @@oth@@ Andrea Sboner @@oth@@ Taha Merghoub @@oth@@ Michael F Berger @@oth@@ Rajmohan Murali @@oth@@ William Lee @@oth@@ Laetitia Borsu @@oth@@ Gary K Schwartz @@oth@@ Ronak H Shah @@oth@@ Elissa W P Wong @@oth@@ Qi Fan Zhang @@oth@@ Michael A Postow @@oth@@ Sasinya N Scott @@oth@@ Iñigo Landa @@oth@@ Wenhuo Hu @@oth@@ Deyou Zheng @@oth@@ Travis J Hollmann @@oth@@ Klaus J Busam @@oth@@ Lu Wang @@oth@@ Ping Chi @@oth@@ Devan A Murphy @@oth@@ Dong Gao @@oth@@
publishDateDaySort_date	2015-01-01T00:00:00Z
hierarchy_top_id	129292834
dewey-sort	270
id	OLC1969670789
language_de	englisch
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author	Julia Button
spellingShingle	Julia Button ddc 070 ddc 500 fid BIODIV misc Kinases misc Genes misc Phosphorylation misc Cancer therapies misc Tumorigenesis misc Binding sites misc Proteins misc Tumors misc Thyroid cancer misc Metastasis misc Melanoma misc Oncogenes misc Development and progression misc Health aspects misc Cancer misc Genetic transcription misc Genetic aspects Alternative transcription initiation leads to expression of a novel ALK isoform in cancer
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topic_title	070 500 DNB 500 AVZ BIODIV fid Alternative transcription initiation leads to expression of a novel ALK isoform in cancer Kinases Genes Phosphorylation Cancer therapies Tumorigenesis Binding sites Proteins Tumors Thyroid cancer Metastasis Melanoma Oncogenes Development and progression Health aspects Cancer Genetic transcription Genetic aspects
topic	ddc 070 ddc 500 fid BIODIV misc Kinases misc Genes misc Phosphorylation misc Cancer therapies misc Tumorigenesis misc Binding sites misc Proteins misc Tumors misc Thyroid cancer misc Metastasis misc Melanoma misc Oncogenes misc Development and progression misc Health aspects misc Cancer misc Genetic transcription misc Genetic aspects
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title	Alternative transcription initiation leads to expression of a novel ALK isoform in cancer
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title_full	Alternative transcription initiation leads to expression of a novel ALK isoform in cancer
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title_sort	alternative transcription initiation leads to expression of a novel alk isoform in cancer
title_auth	Alternative transcription initiation leads to expression of a novel ALK isoform in cancer
abstract	Activation of oncogenes by mechanisms other than genetic aberrations such as mutations, translocations, or amplifications is largely undefined. Here we report a novel isoform of the anaplastic lymphoma kinase (ALK) that is expressed in ~11% of melanomas and sporadically in other human cancer types, but not in normal tissues. The novelALK transcript initiates from a de novo alternative transcription initiation (ATI) site in ALK intron 19, and was termed ALK^sup ATI^. In ALK^sup ATI^-expressing tumours, the ATI site is enriched for H3K4me3 and RNA polymerase II, chromatin marks characteristic of active transcription initiation sites. ALK^sup ATI^ is expressed from both ALK alleles, and no recurrent genetic aberrations are found at the ALK locus, indicating that the transcriptional activation is independent of genetic aberrations at the ALK locus. The ALK^sup ATI^ transcript encodes three proteins with molecular weights of 61.1, 60.8 and 58.7 kilodaltons, consisting primarily of the intracellular tyrosine kinase domain. ALK^sup ATI^ stimulates multiple oncogenic signalling pathways, drives growthfactor- independent cell proliferation in vitro, and promotes tumorigenesis in vivo in mouse models. ALK inhibitors can suppress the kinase activity of ALK^sup ATI^, suggesting that patients with ALK^sup ATI^-expressing tumours may benefit from ALK inhibitors. Our findings suggest a novel mechanism of oncogene activation in cancer through de novo alternative transcription initiation.
abstractGer	Activation of oncogenes by mechanisms other than genetic aberrations such as mutations, translocations, or amplifications is largely undefined. Here we report a novel isoform of the anaplastic lymphoma kinase (ALK) that is expressed in ~11% of melanomas and sporadically in other human cancer types, but not in normal tissues. The novelALK transcript initiates from a de novo alternative transcription initiation (ATI) site in ALK intron 19, and was termed ALK^sup ATI^. In ALK^sup ATI^-expressing tumours, the ATI site is enriched for H3K4me3 and RNA polymerase II, chromatin marks characteristic of active transcription initiation sites. ALK^sup ATI^ is expressed from both ALK alleles, and no recurrent genetic aberrations are found at the ALK locus, indicating that the transcriptional activation is independent of genetic aberrations at the ALK locus. The ALK^sup ATI^ transcript encodes three proteins with molecular weights of 61.1, 60.8 and 58.7 kilodaltons, consisting primarily of the intracellular tyrosine kinase domain. ALK^sup ATI^ stimulates multiple oncogenic signalling pathways, drives growthfactor- independent cell proliferation in vitro, and promotes tumorigenesis in vivo in mouse models. ALK inhibitors can suppress the kinase activity of ALK^sup ATI^, suggesting that patients with ALK^sup ATI^-expressing tumours may benefit from ALK inhibitors. Our findings suggest a novel mechanism of oncogene activation in cancer through de novo alternative transcription initiation.
abstract_unstemmed	Activation of oncogenes by mechanisms other than genetic aberrations such as mutations, translocations, or amplifications is largely undefined. Here we report a novel isoform of the anaplastic lymphoma kinase (ALK) that is expressed in ~11% of melanomas and sporadically in other human cancer types, but not in normal tissues. The novelALK transcript initiates from a de novo alternative transcription initiation (ATI) site in ALK intron 19, and was termed ALK^sup ATI^. In ALK^sup ATI^-expressing tumours, the ATI site is enriched for H3K4me3 and RNA polymerase II, chromatin marks characteristic of active transcription initiation sites. ALK^sup ATI^ is expressed from both ALK alleles, and no recurrent genetic aberrations are found at the ALK locus, indicating that the transcriptional activation is independent of genetic aberrations at the ALK locus. The ALK^sup ATI^ transcript encodes three proteins with molecular weights of 61.1, 60.8 and 58.7 kilodaltons, consisting primarily of the intracellular tyrosine kinase domain. ALK^sup ATI^ stimulates multiple oncogenic signalling pathways, drives growthfactor- independent cell proliferation in vitro, and promotes tumorigenesis in vivo in mouse models. ALK inhibitors can suppress the kinase activity of ALK^sup ATI^, suggesting that patients with ALK^sup ATI^-expressing tumours may benefit from ALK inhibitors. Our findings suggest a novel mechanism of oncogene activation in cancer through de novo alternative transcription initiation.
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title_short	Alternative transcription initiation leads to expression of a novel ALK isoform in cancer
url	http://dx.doi.org/10.1038/nature15258 http://www.ncbi.nlm.nih.gov/pubmed/26444240 http://search.proquest.com/docview/1723755802
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doi_str	10.1038/nature15258
up_date	2024-07-04T06:03:48.581Z
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Alternative transcription initiation leads to expression of a novel ALK isoform in cancer

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