Functional genomic landscape of acute myeloid leukaemia

Jeffrey W. Tyner; Cristina E. Tognon; Daniel Bottomly; Beth Wilmot; Stephen E. Kurtz; Samantha L. Savage; Nicola Long; Anna Reister Schultz; Elie Traer; Melissa Abel; Anupriya Agarwal; Aurora Blucher; Uma Borate; Jade Bryant; Russell Burke; Amy Carlos; Richie Carpenter; Joseph Carroll; Bill H. Chang; Cody Coblentz; Amanda d’Almeida; Rachel Cook; Alexey Danilov; Kim Hien T. Dao; Michie Degnin; Deirdre Devine; James Dibb; David K. Edwards; Christopher A. Eide; Isabel English; Jason Glover; Rachel Henson; Hibery Ho; Abdusebur Jemal; Kara Johnson; Ryan Johnson; Brian Junio; Andy Kaempf; Jessica Leonard; Chenwei Lin; Selina Qiuying Liu; Pierrette Lo; Marc M. Loriaux; Samuel Luty; Tara Macey; Jason MacManiman; Jacqueline Martinez; Motomi Mori; Dylan Nelson; Ceilidh Nichols; Jill Peters; Justin Ramsdill; Angela Rofelty; Robert Schuff; Robert Searles; Erik Segerdell; Rebecca L. Smith; Stephen E. Spurgeon; Tyler Sweeney; Aashis Thapa; Corinne Visser; Jake Wagner; Kevin Watanabe-Smith; Kristen Werth; Joelle Wolf; Libbey White; Amy Yates; Haijiao Zhang; Christopher R. Cogle; Robert H. Collins; Denise C. Connolly; Michael W. Deininger; Leylah Drusbosky; Christopher S. Hourigan; Craig T. Jordan; Patricia Kropf; Tara L. Lin; Micaela E. Martinez; Bruno C. Medeiros; Rachel R. Pallapati; Daniel A. Pollyea; Ronan T. Swords; Justin M. Watts; Scott J. Weir; David L. Wiest; Ryan M. Winters; Shannon K. McWeeney; Brian J. Druker

doi:10.1038/s41586-018-0623-z

Functional genomic landscape of acute myeloid leukaemia

Jeffrey W. Tyner, Cristina E. Tognon, Daniel Bottomly, Beth Wilmot, Stephen E. Kurtz, Samantha L. Savage, Nicola Long, Anna Reister Schultz, Elie Traer, Melissa Abel, Anupriya Agarwal, Aurora Blucher, Uma Borate, Jade Bryant, Russell Burke, Amy Carlos, Richie Carpenter, Joseph Carroll, Bill H. Chang, Cody CoblentzAmanda d’Almeida, Rachel Cook, Alexey Danilov, Kim Hien T. Dao, Michie Degnin, Deirdre Devine, James Dibb, David K. Edwards, Christopher A. Eide, Isabel English, Jason Glover, Rachel Henson, Hibery Ho, Abdusebur Jemal, Kara Johnson, Ryan Johnson, Brian Junio, Andy Kaempf, Jessica Leonard, Chenwei Lin, Selina Qiuying Liu, Pierrette Lo, Marc M. Loriaux, Samuel Luty, Tara Macey, Jason MacManiman, Jacqueline Martinez, Motomi Mori, Dylan Nelson, Ceilidh Nichols, Jill Peters, Justin Ramsdill, Angela Rofelty, Robert Schuff, Robert Searles, Erik Segerdell, Rebecca L. Smith, Stephen E. Spurgeon, Tyler Sweeney, Aashis Thapa, Corinne Visser, Jake Wagner, Kevin Watanabe-Smith, Kristen Werth, Joelle Wolf, Libbey White, Amy Yates, Haijiao Zhang, Christopher R. Cogle, Robert H. Collins, Denise C. Connolly, Michael W. Deininger, Leylah Drusbosky, Christopher S. Hourigan, Craig T. Jordan, Patricia Kropf, Tara L. Lin, Micaela E. Martinez, Bruno C. Medeiros, Rachel R. Pallapati, Daniel A. Pollyea, Ronan T. Swords, Justin M. Watts, Scott J. Weir, David L. Wiest, Ryan M. Winters, Shannon K. McWeeney, Brian J. Druker

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Abstract

The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML. We show that the response to drugs is associated with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA sequencing also revealed gene expression signatures, which predict a role for specific gene networks in the drug response. Collectively, we have generated a dataset—accessible through the Beat AML data viewer (Vizome)—that can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of AML.

Original language	English (US)
Pages (from-to)	526-531
Number of pages	6
Journal	Nature
Volume	562
Issue number	7728
DOIs	https://doi.org/10.1038/s41586-018-0623-z
State	Published - Oct 25 2018

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Tyner, J. W., Tognon, C. E., Bottomly, D., Wilmot, B., Kurtz, S. E., Savage, S. L., Long, N., Schultz, A. R., Traer, E., Abel, M., Agarwal, A., Blucher, A., Borate, U., Bryant, J., Burke, R., Carlos, A., Carpenter, R., Carroll, J., Chang, B. H., ... Druker, B. J. (2018). Functional genomic landscape of acute myeloid leukaemia. Nature, 562(7728), 526-531. https://doi.org/10.1038/s41586-018-0623-z

Tyner, JW, Tognon, CE, Bottomly, D, Wilmot, B, Kurtz, SE, Savage, SL, Long, N, Schultz, AR, Traer, E, Abel, M, Agarwal, A, Blucher, A, Borate, U, Bryant, J, Burke, R, Carlos, A, Carpenter, R, Carroll, J, Chang, BH, Coblentz, C, d’Almeida, A, Cook, R, Danilov, A, Dao, KHT, Degnin, M, Devine, D, Dibb, J, Edwards, DK, Eide, CA, English, I, Glover, J, Henson, R, Ho, H, Jemal, A, Johnson, K, Johnson, R, Junio, B, Kaempf, A, Leonard, J, Lin, C, Liu, SQ, Lo, P, Loriaux, MM, Luty, S, Macey, T, MacManiman, J, Martinez, J, Mori, M, Nelson, D, Nichols, C, Peters, J, Ramsdill, J, Rofelty, A, Schuff, R, Searles, R, Segerdell, E, Smith, RL, Spurgeon, SE, Sweeney, T, Thapa, A, Visser, C, Wagner, J, Watanabe-Smith, K, Werth, K, Wolf, J, White, L, Yates, A, Zhang, H, Cogle, CR, Collins, RH, Connolly, DC, Deininger, MW, Drusbosky, L, Hourigan, CS, Jordan, CT, Kropf, P, Lin, TL, Martinez, ME, Medeiros, BC, Pallapati, RR, Pollyea, DA, Swords, RT, Watts, JM, Weir, SJ, Wiest, DL, Winters, RM, McWeeney, SK & Druker, BJ 2018, 'Functional genomic landscape of acute myeloid leukaemia', Nature, vol. 562, no. 7728, pp. 526-531. https://doi.org/10.1038/s41586-018-0623-z

@article{6ff591964f414b0896840bb6204be5ec,

title = "Functional genomic landscape of acute myeloid leukaemia",

abstract = "The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML. We show that the response to drugs is associated with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA sequencing also revealed gene expression signatures, which predict a role for specific gene networks in the drug response. Collectively, we have generated a dataset—accessible through the Beat AML data viewer (Vizome)—that can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of AML.",

author = "Tyner, {Jeffrey W.} and Tognon, {Cristina E.} and Daniel Bottomly and Beth Wilmot and Kurtz, {Stephen E.} and Savage, {Samantha L.} and Nicola Long and Schultz, {Anna Reister} and Elie Traer and Melissa Abel and Anupriya Agarwal and Aurora Blucher and Uma Borate and Jade Bryant and Russell Burke and Amy Carlos and Richie Carpenter and Joseph Carroll and Chang, {Bill H.} and Cody Coblentz and Amanda d{\textquoteright}Almeida and Rachel Cook and Alexey Danilov and Dao, {Kim Hien T.} and Michie Degnin and Deirdre Devine and James Dibb and Edwards, {David K.} and Eide, {Christopher A.} and Isabel English and Jason Glover and Rachel Henson and Hibery Ho and Abdusebur Jemal and Kara Johnson and Ryan Johnson and Brian Junio and Andy Kaempf and Jessica Leonard and Chenwei Lin and Liu, {Selina Qiuying} and Pierrette Lo and Loriaux, {Marc M.} and Samuel Luty and Tara Macey and Jason MacManiman and Jacqueline Martinez and Motomi Mori and Dylan Nelson and Ceilidh Nichols and Jill Peters and Justin Ramsdill and Angela Rofelty and Robert Schuff and Robert Searles and Erik Segerdell and Smith, {Rebecca L.} and Spurgeon, {Stephen E.} and Tyler Sweeney and Aashis Thapa and Corinne Visser and Jake Wagner and Kevin Watanabe-Smith and Kristen Werth and Joelle Wolf and Libbey White and Amy Yates and Haijiao Zhang and Cogle, {Christopher R.} and Collins, {Robert H.} and Connolly, {Denise C.} and Deininger, {Michael W.} and Leylah Drusbosky and Hourigan, {Christopher S.} and Jordan, {Craig T.} and Patricia Kropf and Lin, {Tara L.} and Martinez, {Micaela E.} and Medeiros, {Bruno C.} and Pallapati, {Rachel R.} and Pollyea, {Daniel A.} and Swords, {Ronan T.} and Watts, {Justin M.} and Weir, {Scott J.} and Wiest, {David L.} and Winters, {Ryan M.} and McWeeney, {Shannon K.} and Druker, {Brian J.}",

note = "Publisher Copyright: {\textcopyright} 2018, Springer Nature Limited.",

year = "2018",

month = oct,

day = "25",

doi = "10.1038/s41586-018-0623-z",

language = "English (US)",

volume = "562",

pages = "526--531",

journal = "Nature",

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T1 - Functional genomic landscape of acute myeloid leukaemia

AU - Tyner, Jeffrey W.

AU - Tognon, Cristina E.

AU - Bottomly, Daniel

AU - Wilmot, Beth

AU - Kurtz, Stephen E.

AU - Savage, Samantha L.

AU - Long, Nicola

AU - Schultz, Anna Reister

AU - Traer, Elie

AU - Abel, Melissa

AU - Agarwal, Anupriya

AU - Blucher, Aurora

AU - Borate, Uma

AU - Bryant, Jade

AU - Burke, Russell

AU - Carlos, Amy

AU - Carpenter, Richie

AU - Carroll, Joseph

AU - Chang, Bill H.

AU - Coblentz, Cody

AU - d’Almeida, Amanda

AU - Cook, Rachel

AU - Danilov, Alexey

AU - Dao, Kim Hien T.

AU - Degnin, Michie

AU - Devine, Deirdre

AU - Dibb, James

AU - Edwards, David K.

AU - Eide, Christopher A.

AU - English, Isabel

AU - Glover, Jason

AU - Henson, Rachel

AU - Ho, Hibery

AU - Jemal, Abdusebur

AU - Johnson, Kara

AU - Johnson, Ryan

AU - Junio, Brian

AU - Kaempf, Andy

AU - Leonard, Jessica

AU - Lin, Chenwei

AU - Liu, Selina Qiuying

AU - Lo, Pierrette

AU - Loriaux, Marc M.

AU - Luty, Samuel

AU - Macey, Tara

AU - MacManiman, Jason

AU - Martinez, Jacqueline

AU - Mori, Motomi

AU - Nelson, Dylan

AU - Nichols, Ceilidh

AU - Peters, Jill

AU - Ramsdill, Justin

AU - Rofelty, Angela

AU - Schuff, Robert

AU - Searles, Robert

AU - Segerdell, Erik

AU - Smith, Rebecca L.

AU - Spurgeon, Stephen E.

AU - Sweeney, Tyler

AU - Thapa, Aashis

AU - Visser, Corinne

AU - Wagner, Jake

AU - Watanabe-Smith, Kevin

AU - Werth, Kristen

AU - Wolf, Joelle

AU - White, Libbey

AU - Yates, Amy

AU - Zhang, Haijiao

AU - Cogle, Christopher R.

AU - Collins, Robert H.

AU - Connolly, Denise C.

AU - Deininger, Michael W.

AU - Drusbosky, Leylah

AU - Hourigan, Christopher S.

AU - Jordan, Craig T.

AU - Kropf, Patricia

AU - Lin, Tara L.

AU - Martinez, Micaela E.

AU - Medeiros, Bruno C.

AU - Pallapati, Rachel R.

AU - Pollyea, Daniel A.

AU - Swords, Ronan T.

AU - Watts, Justin M.

AU - Weir, Scott J.

AU - Wiest, David L.

AU - Winters, Ryan M.

AU - McWeeney, Shannon K.

AU - Druker, Brian J.

PY - 2018/10/25

Y1 - 2018/10/25

N2 - The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML. We show that the response to drugs is associated with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA sequencing also revealed gene expression signatures, which predict a role for specific gene networks in the drug response. Collectively, we have generated a dataset—accessible through the Beat AML data viewer (Vizome)—that can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of AML.

AB - The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML. We show that the response to drugs is associated with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA sequencing also revealed gene expression signatures, which predict a role for specific gene networks in the drug response. Collectively, we have generated a dataset—accessible through the Beat AML data viewer (Vizome)—that can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of AML.

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DO - 10.1038/s41586-018-0623-z

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VL - 562

SP - 526

EP - 531

JO - Nature

JF - Nature

IS - 7728

ER -

Functional genomic landscape of acute myeloid leukaemia

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