Integrative analysis of drug response and clinical outcome in acute myeloid leukemia

Daniel Bottomly; Nicola Long; Anna Reister Schultz; Stephen E. Kurtz; Cristina E. Tognon; Kara Johnson; Melissa Abel; Anupriya Agarwal; Sammantha Avaylon; Erik Benton; Aurora Blucher; Uma Borate; Theodore P. Braun; Jordana Brown; Jade Bryant; Russell Burke; Amy Carlos; Bill H. Chang; Hyun Jun Cho; Stephen Christy; Cody Coblentz; Aaron M. Cohen; Amanda d'Almeida; Rachel Cook; Alexey Danilov; Kim Hien T. Dao; Michie Degnin; James Dibb; Christopher A. Eide; Isabel English; Stuart Hagler; Heath Harrelson; Rachel Henson; Hibery Ho; Sunil K. Joshi; Brian Junio; Andy Kaempf; Yoko Kosaka; Ted Laderas; Matt Lawhead; Hyunjung Lee; Jessica T. Leonard; Chenwei Lin; Evan F. Lind; Selina Qiuying Liu; Pierrette Lo; Marc M. Loriaux; Samuel Luty; Julia E. Maxson; Tara Macey; Jacqueline Martinez; Jessica Minnier; Andrea Monteblanco; Motomi Mori; Quinlan Morrow; Dylan Nelson; Justin Ramsdill; Angela Rofelty; Alexandra Rogers; Kyle A. Romine; Peter Ryabinin; Jennifer N. Saultz; David A. Sampson; Samantha L. Savage; Robert Schuff; Robert Searles; Rebecca L. Smith; Stephen E. Spurgeon; Tyler Sweeney; Ronan T. Swords; Aashis Thapa; Karina Thiel-Klare; Elie Traer; Jake Wagner; Beth Wilmot; Joelle Wolf; Guanming Wu; Amy Yates; Haijiao Zhang; Christopher R. Cogle; Robert H. Collins; Michael W. Deininger; Christopher S. Hourigan; Craig T. Jordan; Tara L. Lin; Micaela E. Martinez; Rachel R. Pallapati; Daniel A. Pollyea; Anthony D. Pomicter; Justin M. Watts; Scott J. Weir; Brian J. Druker; Shannon K. McWeeney; Jeffrey W. Tyner

doi:10.1016/j.ccell.2022.07.002

Integrative analysis of drug response and clinical outcome in acute myeloid leukemia

Daniel Bottomly, Nicola Long, Anna Reister Schultz, Stephen E. Kurtz, Cristina E. Tognon, Kara Johnson, Melissa Abel, Anupriya Agarwal, Sammantha Avaylon, Erik Benton, Aurora Blucher, Uma Borate, Theodore P. Braun, Jordana Brown, Jade Bryant, Russell Burke, Amy Carlos, Bill H. Chang, Hyun Jun Cho, Stephen ChristyCody Coblentz, Aaron M. Cohen, Amanda d'Almeida, Rachel Cook, Alexey Danilov, Kim Hien T. Dao, Michie Degnin, James Dibb, Christopher A. Eide, Isabel English, Stuart Hagler, Heath Harrelson, Rachel Henson, Hibery Ho, Sunil K. Joshi, Brian Junio, Andy Kaempf, Yoko Kosaka, Ted Laderas, Matt Lawhead, Hyunjung Lee, Jessica T. Leonard, Chenwei Lin, Evan F. Lind, Selina Qiuying Liu, Pierrette Lo, Marc M. Loriaux, Samuel Luty, Julia E. Maxson, Tara Macey, Jacqueline Martinez, Jessica Minnier, Andrea Monteblanco, Motomi Mori, Quinlan Morrow, Dylan Nelson, Justin Ramsdill, Angela Rofelty, Alexandra Rogers, Kyle A. Romine, Peter Ryabinin, Jennifer N. Saultz, David A. Sampson, Samantha L. Savage, Robert Schuff, Robert Searles, Rebecca L. Smith, Stephen E. Spurgeon, Tyler Sweeney, Ronan T. Swords, Aashis Thapa, Karina Thiel-Klare, Elie Traer, Jake Wagner, Beth Wilmot, Joelle Wolf, Guanming Wu, Amy Yates, Haijiao Zhang, Christopher R. Cogle, Robert H. Collins, Michael W. Deininger, Christopher S. Hourigan, Craig T. Jordan, Tara L. Lin, Micaela E. Martinez, Rachel R. Pallapati, Daniel A. Pollyea, Anthony D. Pomicter, Justin M. Watts, Scott J. Weir, Brian J. Druker, Shannon K. McWeeney, Jeffrey W. Tyner

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

Abstract

Acute myeloid leukemia (AML) is a cancer of myeloid-lineage cells with limited therapeutic options. We previously combined ex vivo drug sensitivity with genomic, transcriptomic, and clinical annotations for a large cohort of AML patients, which facilitated discovery of functional genomic correlates. Here, we present a dataset that has been harmonized with our initial report to yield a cumulative cohort of 805 patients (942 specimens). We show strong cross-cohort concordance and identify features of drug response. Further, deconvoluting transcriptomic data shows that drug sensitivity is governed broadly by AML cell differentiation state, sometimes conditionally affecting other correlates of response. Finally, modeling of clinical outcome reveals a single gene, PEAR1, to be among the strongest predictors of patient survival, especially for young patients. Collectively, this report expands a large functional genomic resource, offers avenues for mechanistic exploration and drug development, and reveals tools for predicting outcome in AML.

Original language	English (US)
Pages (from-to)	850-864.e9
Journal	Cancer Cell
Volume	40
Issue number	8
DOIs	https://doi.org/10.1016/j.ccell.2022.07.002
State	Published - Aug 8 2022

Keywords

JEDI
LSC17
MEGF12
cell state
eigengene
hematologic malignancy
leukemia stem cell
monocyte
targeted therapy

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1016/j.ccell.2022.07.002

Cite this

Bottomly, D., Long, N., Schultz, A. R., Kurtz, S. E., Tognon, C. E., Johnson, K., Abel, M., Agarwal, A., Avaylon, S., Benton, E., Blucher, A., Borate, U., Braun, T. P., Brown, J., Bryant, J., Burke, R., Carlos, A., Chang, B. H., Cho, H. J., ... Tyner, J. W. (2022). Integrative analysis of drug response and clinical outcome in acute myeloid leukemia. Cancer Cell, 40(8), 850-864.e9. https://doi.org/10.1016/j.ccell.2022.07.002

Bottomly, D, Long, N, Schultz, AR, Kurtz, SE , Tognon, CE, Johnson, K, Abel, M, Agarwal, A, Avaylon, S, Benton, E, Blucher, A, Borate, U, Braun, TP, Brown, J, Bryant, J, Burke, R, Carlos, A, Chang, BH, Cho, HJ, Christy, S, Coblentz, C, Cohen, AM, d'Almeida, A, Cook, R, Danilov, A, Dao, KHT, Degnin, M, Dibb, J, Eide, CA, English, I, Hagler, S, Harrelson, H, Henson, R, Ho, H, Joshi, SK, Junio, B, Kaempf, A, Kosaka, Y, Laderas, T, Lawhead, M, Lee, H, Leonard, JT, Lin, C, Lind, EF, Liu, SQ, Lo, P, Loriaux, MM, Luty, S, Maxson, JE, Macey, T, Martinez, J, Minnier, J, Monteblanco, A, Mori, M, Morrow, Q, Nelson, D, Ramsdill, J, Rofelty, A, Rogers, A, Romine, KA, Ryabinin, P, Saultz, JN, Sampson, DA, Savage, SL, Schuff, R, Searles, R, Smith, RL, Spurgeon, SE, Sweeney, T, Swords, RT, Thapa, A, Thiel-Klare, K, Traer, E, Wagner, J, Wilmot, B, Wolf, J, Wu, G, Yates, A, Zhang, H, Cogle, CR, Collins, RH, Deininger, MW, Hourigan, CS, Jordan, CT, Lin, TL, Martinez, ME, Pallapati, RR, Pollyea, DA, Pomicter, AD, Watts, JM, Weir, SJ, Druker, BJ , McWeeney, SK & Tyner, JW 2022, 'Integrative analysis of drug response and clinical outcome in acute myeloid leukemia', Cancer Cell, vol. 40, no. 8, pp. 850-864.e9. https://doi.org/10.1016/j.ccell.2022.07.002

@article{f1cc556078454f03b289c648975ea52a,

title = "Integrative analysis of drug response and clinical outcome in acute myeloid leukemia",

abstract = "Acute myeloid leukemia (AML) is a cancer of myeloid-lineage cells with limited therapeutic options. We previously combined ex vivo drug sensitivity with genomic, transcriptomic, and clinical annotations for a large cohort of AML patients, which facilitated discovery of functional genomic correlates. Here, we present a dataset that has been harmonized with our initial report to yield a cumulative cohort of 805 patients (942 specimens). We show strong cross-cohort concordance and identify features of drug response. Further, deconvoluting transcriptomic data shows that drug sensitivity is governed broadly by AML cell differentiation state, sometimes conditionally affecting other correlates of response. Finally, modeling of clinical outcome reveals a single gene, PEAR1, to be among the strongest predictors of patient survival, especially for young patients. Collectively, this report expands a large functional genomic resource, offers avenues for mechanistic exploration and drug development, and reveals tools for predicting outcome in AML.",

keywords = "JEDI, LSC17, MEGF12, cell state, eigengene, hematologic malignancy, leukemia stem cell, monocyte, targeted therapy",

author = "Daniel Bottomly and Nicola Long and Schultz, {Anna Reister} and Kurtz, {Stephen E.} and Tognon, {Cristina E.} and Kara Johnson and Melissa Abel and Anupriya Agarwal and Sammantha Avaylon and Erik Benton and Aurora Blucher and Uma Borate and Braun, {Theodore P.} and Jordana Brown and Jade Bryant and Russell Burke and Amy Carlos and Chang, {Bill H.} and Cho, {Hyun Jun} and Stephen Christy and Cody Coblentz and Cohen, {Aaron M.} and Amanda d'Almeida and Rachel Cook and Alexey Danilov and Dao, {Kim Hien T.} and Michie Degnin and James Dibb and Eide, {Christopher A.} and Isabel English and Stuart Hagler and Heath Harrelson and Rachel Henson and Hibery Ho and Joshi, {Sunil K.} and Brian Junio and Andy Kaempf and Yoko Kosaka and Ted Laderas and Matt Lawhead and Hyunjung Lee and Leonard, {Jessica T.} and Chenwei Lin and Lind, {Evan F.} and Liu, {Selina Qiuying} and Pierrette Lo and Loriaux, {Marc M.} and Samuel Luty and Maxson, {Julia E.} and Tara Macey and Jacqueline Martinez and Jessica Minnier and Andrea Monteblanco and Motomi Mori and Quinlan Morrow and Dylan Nelson and Justin Ramsdill and Angela Rofelty and Alexandra Rogers and Romine, {Kyle A.} and Peter Ryabinin and Saultz, {Jennifer N.} and Sampson, {David A.} and Savage, {Samantha L.} and Robert Schuff and Robert Searles and Smith, {Rebecca L.} and Spurgeon, {Stephen E.} and Tyler Sweeney and Swords, {Ronan T.} and Aashis Thapa and Karina Thiel-Klare and Elie Traer and Jake Wagner and Beth Wilmot and Joelle Wolf and Guanming Wu and Amy Yates and Haijiao Zhang and Cogle, {Christopher R.} and Collins, {Robert H.} and Deininger, {Michael W.} and Hourigan, {Christopher S.} and Jordan, {Craig T.} and Lin, {Tara L.} and Martinez, {Micaela E.} and Pallapati, {Rachel R.} and Pollyea, {Daniel A.} and Pomicter, {Anthony D.} and Watts, {Justin M.} and Weir, {Scott J.} and Druker, {Brian J.} and McWeeney, {Shannon K.} and Tyner, {Jeffrey W.}",

note = "Funding Information: We thank all of our patients at all sites for donating precious time and tissue. DNA and RNA quality assessments, library creation, and short-read sequencing assays were performed by the OHSU Massively Parallel Sequencing Shared Resource. We thank Oscar Br{\"u}ck, Disha Malani, Olli Kallioniemi, and Kimmo Porkka for rapidly facilitating analysis of PEAR1 expression correlation with overall survival in their AML patient dataset ( Malani et al., 2022 ) and Oscar Br{\"u}ck for rapidly executing our analysis scripts from this study on those data. Funding for this project was provided in part by The Leukemia & Lymphoma Society (for the waves 1 + 2 dataset) and the Knight Cancer Research Institute ( OHSU ). Supported included grants from the National Cancer Institute ( U01CA217862 , U54CA224019 , U01CA214116 ) and NIH / NCATS CTSA UL1TR002369 (S.K.M., B.W.). C.E.T. receives grant support from the National Cancer Institute ( R01CA214428 ). A.A. is supported by grants from the National Cancer Institute ( R01CA229875 ), National Heart, Lung, and Blood Institute ( R01HL155426 ), American Cancer Society ( RSG-17-187-01-LIB ), Alex Lemonade/Babich RUNX1 Foundation , EvansMDS Foundation , and a V foundation Scholar award. Funding was provided to T.P.B. by an American Society of Hematology Research Restart Award, an American Society of Hematology Scholar Award, and one K08 CA245224 from NCI . S.K.J. is supported by the ARCS Scholar Foundation , The Paul & Daisy Soros Fellowship, and the National Cancer Institute ( F30CA239335 ). J.E.M. receives funding from the American Cancer Society ( RSG-19-184-01 – LIB ) and NIH /NCI ( R01 CA247943 ). H.Z. received grants from the National Cancer Institute ( R00 5K99CA237630 ) and the Oregon Medical Research Foundation New Investigator Award. Some patient samples used in this work were provided by the Division of Hematology Biorepository at Huntsman Cancer Institute, University of Utah, which is supported by the National Cancer Institute of the National Institutes of Health under award number P30CA042014 . Additional funding came from the Huntsman Center of Excellence in Hematologic Malignancies and Hematology at Huntsman Cancer Institute, University of Utah. C.R.C. received a Scholar in Clinical Research Award from The Leukemia & Lymphoma Society (2400-13), and was distinguished with a Pierre Chagnon Professorship in Stem Cell Biology and Blood & Marrow Transplant and a UF Research Foundation Professorship. This work was supported in part by the Intramural Research Program of the National Heart, Lung, and Blood Institute of the National Institutes of Health . B.J.D. received funding from the Howard Hughes Medical Institute . J.W.T. received grants from the V Foundation for Cancer Research , the Gabrielle's Angel Foundation for Cancer Research , the Mark Foundation For Cancer Research , the Silver Family Foundation , and the National Cancer Institute ( R01CA245002 , R01CA262758 ). Funding Information: We thank all of our patients at all sites for donating precious time and tissue. DNA and RNA quality assessments, library creation, and short-read sequencing assays were performed by the OHSU Massively Parallel Sequencing Shared Resource. We thank Oscar Br{\"u}ck, Disha Malani, Olli Kallioniemi, and Kimmo Porkka for rapidly facilitating analysis of PEAR1 expression correlation with overall survival in their AML patient dataset (Malani et al. 2022) and Oscar Br{\"u}ck for rapidly executing our analysis scripts from this study on those data. Funding for this project was provided in part by The Leukemia & Lymphoma Society (for the waves 1 + 2 dataset) and the Knight Cancer Research Institute (OHSU). Supported included grants from the National Cancer Institute (U01CA217862, U54CA224019, U01CA214116) and NIH/NCATS CTSA UL1TR002369 (S.K.M. B.W.). C.E.T. receives grant support from the National Cancer Institute (R01CA214428). A.A. is supported by grants from the National Cancer Institute (R01CA229875), National Heart, Lung, and Blood Institute (R01HL155426), American Cancer Society (RSG-17-187-01-LIB), Alex Lemonade/Babich RUNX1 Foundation, EvansMDS Foundation, and a V foundation Scholar award. Funding was provided to T.P.B. by an American Society of Hematology Research Restart Award, an American Society of Hematology Scholar Award, and one K08 CA245224 from NCI. S.K.J. is supported by the ARCS Scholar Foundation, The Paul & Daisy Soros Fellowship, and the National Cancer Institute (F30CA239335). J.E.M. receives funding from the American Cancer Society (RSG-19-184-01 – LIB) and NIH/NCI (R01 CA247943). H.Z. received grants from the National Cancer Institute (R00 5K99CA237630) and the Oregon Medical Research Foundation New Investigator Award. Some patient samples used in this work were provided by the Division of Hematology Biorepository at Huntsman Cancer Institute, University of Utah, which is supported by the National Cancer Institute of the National Institutes of Health under award number P30CA042014. Additional funding came from the Huntsman Center of Excellence in Hematologic Malignancies and Hematology at Huntsman Cancer Institute, University of Utah. C.R.C. received a Scholar in Clinical Research Award from The Leukemia & Lymphoma Society (2400-13), and was distinguished with a Pierre Chagnon Professorship in Stem Cell Biology and Blood & Marrow Transplant and a UF Research Foundation Professorship. This work was supported in part by the Intramural Research Program of the National Heart, Lung, and Blood Institute of the National Institutes of Health. B.J.D. received funding from the Howard Hughes Medical Institute. J.W.T. received grants from the V Foundation for Cancer Research, the Gabrielle's Angel Foundation for Cancer Research, the Mark Foundation For Cancer Research, the Silver Family Foundation, and the National Cancer Institute (R01CA245002, R01CA262758). D.B. N.L. A.R.S. S.E.K. C.E.T. K.J. B.J.D. S.K.M. and J.W.T. provided project oversight for experimental design, data management, integration, and data analysis and interpretation. D.B. co-led the modeling, analysis, and data visualizations; developed computational workflows for pre-processing, harmonization, and analysis of RNA-seq and Exome-seq; co-developed the workflow and extensions for ex vivo drug screening; assisted with clinical data curation; serves as co-developer and current maintainer of the Vizome platform; and led the dissemination efforts. N.L. led the management, curation, entry, quality assurance and quality control, validation, and analysis of patient clinical annotations. A.R.S. led patient sample processing; assisted with ex vivo drug screening, DNA/RNA extractions, and sequencing sample submissions; and managed sequencing mis-match findings. S.E.K. provided oversight for and assisted with collection of ex vivo drug response data and analysis and led the development of methodology for and collection of FLT3 and NPM1 in/del data. K.J. provided project oversight and management, and assisted with patient sample processing and ex vivo drug screening. C.E.T. and J.W.T. conceived the project and provided project oversight for sample accrual and collection as well as experimental methods development. B.J.D. conceived the project and provided project oversight. S.K.M. co-led the modeling, analysis, and visualizations, and provided oversight for computational methods development and the development of the Vizome platform as well as oversight for data governance and dissemination. T.P.B. U.B. B.H.C. R.C. A.D. K.-H.T.D. M.M.L. J.N.S. E.T. J.T. A.D.P. and S.E.S. assisted with patient sample acquisition. T.P.B. and A.D.P. assisted with patient sample coordination. E.T. assisted with clinical data structure, collection, and analysis. M.M.L. assisted with IRB protocol development and maintenance, clinical data structure, collection, and analysis. A.d'A. M.A. S.A. J.B. J. Bryant, R.B. C.C. H.J.C. S.C. M.D. I.E. H. Ho, S.K.J. Y.K. H.L. S.L. S. Luty, A.M. J.M. Q.M. A.R. A. Rogers, D.A.S. R.L.S. T.S. A.T. K.T.-K. J.W. and J. Wolf assisted with patient sample processing and ex vivo drug screening. M.A. I.E. and A.R. assisted with DNA/RNA extractions and sequencing sample submissions. B.J. and T.M. provided regulatory oversight. B.J. assisted with curation and entry of patient clinical annotations. P.L. assisted with technology transfer, project development, alliance management, and data management. A.K. and M.M. developed the original ex vivo drug screening workflow and A.K. co-developed the extensions of that workflow. J. Minnier contributed to extensions for the ex vivo drug screening workflow. D.N. assisted in the creation of the drug screening replicate plates. P.R. assisted with the ex vivo drug screening analysis. K.A.R. collected and analyzed PEAR1 flow cytometry data and helped design the graphical abstract. A.A. B.H.C. C.A.E. E.L. J.M. J.N.S. and H.Z. assisted with data analysis and interpretation. A.B. led the Targetome extensions. T.L. and G.W. assisted with data integration. B.W. assisted with project oversight and conceived the original Vizome platform. C.L. E.C. R.H. and R. Searles assisted with exome and RNA-seq library creation, sequencing, and data processing. A.M.C. and S.H. assisted with clinical curation and natural language processing. J.D. assisted with curation and entry of patient clinical annotations. E.B. H.H. J.R. M.L. R. Schuff, and A.Y. assisted with clinical data integration from the OHSU Research Data Warehouse. A.Y. integrated the ex vivo workflow in the Beat AML database. C.R.C. served as a co-investigator on the repository protocol, obtained consent and collected samples from patients, processed and shipped specimens, aided with clinical annotation, and edited and provided feedback on the manuscript. R.H.C. M.W.D. C.S.H. and T.L.L. served as local principal investigators for the repository protocols, consented patients and collected samples, aided with clinical annotation, and edited and provided feedback on the manuscript. R.T.S. served as a co-investigator on the repository protocol, assisted with data interpretation, and edited and provided feedback on the manuscript. C.T.J. and D.A.P. collected samples for the repository protocol and provided feedback on the manuscript. M.E.M. and R.R.P. consented patients and collected samples for the repository protocol and aided with clinical annotation. J.M.W. served as a local principal investigator for the repository protocol and edited and provided feedback on the manuscript. S.J.W. enabled, facilitated, and mentored basic, translational and clinical research activities arising from data generated by Beat AML at the University of Kansas Cancer Center site and participated in the Beat AML Symposia to share research and create research projects. C.E.T. receives research support from Notable Labs and serves as a scientific liaison for AstraZeneca. J.E.M. receives research funding from Gilead Pharmaceutical and serves on a scientific advisory board for Ionis Pharmaceuticals. M.W.D. serves on the advisory boards and/or as a consultant for Novartis, Incyte, and BMS and receives research funding from BMS and Gilead. C.S.H. receives research funding from Sellas. T.L.L. consults for Jazz Pharmaceuticals and receives research funding from Tolero, Gilead, Prescient, Ono, Bio-Path, Mateon, Genentech/Roche, Trovagene, AbbVie, Pfizer, Celgene, Imago, Astellas, Karyopharm, Seattle Genetics, and Incyte. D.A.P. receives research funding from Pfizer and Agios and served on advisory boards for Pfizer, Celyad, Agios, Celgene, AbbVie, Argenx, Takeda, and Servier. B.J.D. serves on the advisory boards for Aileron Therapeutics, Aptose, Blueprint Medicines, Cepheid, EnLiven Therapeutics, Gilead, GRAIL, Iterion Therapeutics, Nemucore Medical Innovations, the Novartis CML Molecular Monitoring Steering Committee, Recludix Pharma, the RUNX1 Research Program, ALLCRON Pharma, VB Therapeutics, Vincerx Pharma, and the Board of Directors for Amgen, and receives research funding from EnLiven and Recludix. B.J.D. is principal investigator or co-investigator on Novartis, BMS, and Pfizer clinical trials. His institution, OHSU, has contracts with these companies to pay for patient costs, nurse and data manager salaries, and institutional overhead, but he does not derive salary, nor does his laboratory receive funds, from these contracts. J.W.T. has received research support from Acerta, Agios, Aptose, Array, AstraZeneca, Constellation, Genentech, Gilead, Incyte, Janssen, Kronos, Meryx, Petra, Schrodinger, Seattle Genetics, Syros, Takeda, and Tolero and serves on the advisory board for Recludix Pharma. The authors certify that all compounds tested in this study were chosen without input from any of our industry partners. A subset of findings from this manuscript have been included in a pending patent application. Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = aug,

day = "8",

doi = "10.1016/j.ccell.2022.07.002",

language = "English (US)",

volume = "40",

pages = "850--864.e9",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "8",

}

TY - JOUR

T1 - Integrative analysis of drug response and clinical outcome in acute myeloid leukemia

AU - Bottomly, Daniel

AU - Long, Nicola

AU - Schultz, Anna Reister

AU - Kurtz, Stephen E.

AU - Tognon, Cristina E.

AU - Johnson, Kara

AU - Abel, Melissa

AU - Agarwal, Anupriya

AU - Avaylon, Sammantha

AU - Benton, Erik

AU - Blucher, Aurora

AU - Borate, Uma

AU - Braun, Theodore P.

AU - Brown, Jordana

AU - Bryant, Jade

AU - Burke, Russell

AU - Carlos, Amy

AU - Chang, Bill H.

AU - Cho, Hyun Jun

AU - Christy, Stephen

AU - Coblentz, Cody

AU - Cohen, Aaron M.

AU - d'Almeida, Amanda

AU - Cook, Rachel

AU - Danilov, Alexey

AU - Dao, Kim Hien T.

AU - Degnin, Michie

AU - Dibb, James

AU - Eide, Christopher A.

AU - English, Isabel

AU - Hagler, Stuart

AU - Harrelson, Heath

AU - Henson, Rachel

AU - Ho, Hibery

AU - Joshi, Sunil K.

AU - Junio, Brian

AU - Kaempf, Andy

AU - Kosaka, Yoko

AU - Laderas, Ted

AU - Lawhead, Matt

AU - Lee, Hyunjung

AU - Leonard, Jessica T.

AU - Lin, Chenwei

AU - Lind, Evan F.

AU - Liu, Selina Qiuying

AU - Lo, Pierrette

AU - Loriaux, Marc M.

AU - Luty, Samuel

AU - Maxson, Julia E.

AU - Macey, Tara

AU - Martinez, Jacqueline

AU - Minnier, Jessica

AU - Monteblanco, Andrea

AU - Mori, Motomi

AU - Morrow, Quinlan

AU - Nelson, Dylan

AU - Ramsdill, Justin

AU - Rofelty, Angela

AU - Rogers, Alexandra

AU - Romine, Kyle A.

AU - Ryabinin, Peter

AU - Saultz, Jennifer N.

AU - Sampson, David A.

AU - Savage, Samantha L.

AU - Schuff, Robert

AU - Searles, Robert

AU - Smith, Rebecca L.

AU - Spurgeon, Stephen E.

AU - Sweeney, Tyler

AU - Swords, Ronan T.

AU - Thapa, Aashis

AU - Thiel-Klare, Karina

AU - Traer, Elie

AU - Wagner, Jake

AU - Wilmot, Beth

AU - Wolf, Joelle

AU - Wu, Guanming

AU - Yates, Amy

AU - Zhang, Haijiao

AU - Cogle, Christopher R.

AU - Collins, Robert H.

AU - Deininger, Michael W.

AU - Hourigan, Christopher S.

AU - Jordan, Craig T.

AU - Lin, Tara L.

AU - Martinez, Micaela E.

AU - Pallapati, Rachel R.

AU - Pollyea, Daniel A.

AU - Pomicter, Anthony D.

AU - Watts, Justin M.

AU - Weir, Scott J.

AU - Druker, Brian J.

AU - McWeeney, Shannon K.

AU - Tyner, Jeffrey W.

N1 - Funding Information: We thank all of our patients at all sites for donating precious time and tissue. DNA and RNA quality assessments, library creation, and short-read sequencing assays were performed by the OHSU Massively Parallel Sequencing Shared Resource. We thank Oscar Brück, Disha Malani, Olli Kallioniemi, and Kimmo Porkka for rapidly facilitating analysis of PEAR1 expression correlation with overall survival in their AML patient dataset ( Malani et al., 2022 ) and Oscar Brück for rapidly executing our analysis scripts from this study on those data. Funding for this project was provided in part by The Leukemia & Lymphoma Society (for the waves 1 + 2 dataset) and the Knight Cancer Research Institute ( OHSU ). Supported included grants from the National Cancer Institute ( U01CA217862 , U54CA224019 , U01CA214116 ) and NIH / NCATS CTSA UL1TR002369 (S.K.M., B.W.). C.E.T. receives grant support from the National Cancer Institute ( R01CA214428 ). A.A. is supported by grants from the National Cancer Institute ( R01CA229875 ), National Heart, Lung, and Blood Institute ( R01HL155426 ), American Cancer Society ( RSG-17-187-01-LIB ), Alex Lemonade/Babich RUNX1 Foundation , EvansMDS Foundation , and a V foundation Scholar award. Funding was provided to T.P.B. by an American Society of Hematology Research Restart Award, an American Society of Hematology Scholar Award, and one K08 CA245224 from NCI . S.K.J. is supported by the ARCS Scholar Foundation , The Paul & Daisy Soros Fellowship, and the National Cancer Institute ( F30CA239335 ). J.E.M. receives funding from the American Cancer Society ( RSG-19-184-01 – LIB ) and NIH /NCI ( R01 CA247943 ). H.Z. received grants from the National Cancer Institute ( R00 5K99CA237630 ) and the Oregon Medical Research Foundation New Investigator Award. Some patient samples used in this work were provided by the Division of Hematology Biorepository at Huntsman Cancer Institute, University of Utah, which is supported by the National Cancer Institute of the National Institutes of Health under award number P30CA042014 . Additional funding came from the Huntsman Center of Excellence in Hematologic Malignancies and Hematology at Huntsman Cancer Institute, University of Utah. C.R.C. received a Scholar in Clinical Research Award from The Leukemia & Lymphoma Society (2400-13), and was distinguished with a Pierre Chagnon Professorship in Stem Cell Biology and Blood & Marrow Transplant and a UF Research Foundation Professorship. This work was supported in part by the Intramural Research Program of the National Heart, Lung, and Blood Institute of the National Institutes of Health . B.J.D. received funding from the Howard Hughes Medical Institute . J.W.T. received grants from the V Foundation for Cancer Research , the Gabrielle's Angel Foundation for Cancer Research , the Mark Foundation For Cancer Research , the Silver Family Foundation , and the National Cancer Institute ( R01CA245002 , R01CA262758 ). Funding Information: We thank all of our patients at all sites for donating precious time and tissue. DNA and RNA quality assessments, library creation, and short-read sequencing assays were performed by the OHSU Massively Parallel Sequencing Shared Resource. We thank Oscar Brück, Disha Malani, Olli Kallioniemi, and Kimmo Porkka for rapidly facilitating analysis of PEAR1 expression correlation with overall survival in their AML patient dataset (Malani et al. 2022) and Oscar Brück for rapidly executing our analysis scripts from this study on those data. Funding for this project was provided in part by The Leukemia & Lymphoma Society (for the waves 1 + 2 dataset) and the Knight Cancer Research Institute (OHSU). Supported included grants from the National Cancer Institute (U01CA217862, U54CA224019, U01CA214116) and NIH/NCATS CTSA UL1TR002369 (S.K.M. B.W.). C.E.T. receives grant support from the National Cancer Institute (R01CA214428). A.A. is supported by grants from the National Cancer Institute (R01CA229875), National Heart, Lung, and Blood Institute (R01HL155426), American Cancer Society (RSG-17-187-01-LIB), Alex Lemonade/Babich RUNX1 Foundation, EvansMDS Foundation, and a V foundation Scholar award. Funding was provided to T.P.B. by an American Society of Hematology Research Restart Award, an American Society of Hematology Scholar Award, and one K08 CA245224 from NCI. S.K.J. is supported by the ARCS Scholar Foundation, The Paul & Daisy Soros Fellowship, and the National Cancer Institute (F30CA239335). J.E.M. receives funding from the American Cancer Society (RSG-19-184-01 – LIB) and NIH/NCI (R01 CA247943). H.Z. received grants from the National Cancer Institute (R00 5K99CA237630) and the Oregon Medical Research Foundation New Investigator Award. Some patient samples used in this work were provided by the Division of Hematology Biorepository at Huntsman Cancer Institute, University of Utah, which is supported by the National Cancer Institute of the National Institutes of Health under award number P30CA042014. Additional funding came from the Huntsman Center of Excellence in Hematologic Malignancies and Hematology at Huntsman Cancer Institute, University of Utah. C.R.C. received a Scholar in Clinical Research Award from The Leukemia & Lymphoma Society (2400-13), and was distinguished with a Pierre Chagnon Professorship in Stem Cell Biology and Blood & Marrow Transplant and a UF Research Foundation Professorship. This work was supported in part by the Intramural Research Program of the National Heart, Lung, and Blood Institute of the National Institutes of Health. B.J.D. received funding from the Howard Hughes Medical Institute. J.W.T. received grants from the V Foundation for Cancer Research, the Gabrielle's Angel Foundation for Cancer Research, the Mark Foundation For Cancer Research, the Silver Family Foundation, and the National Cancer Institute (R01CA245002, R01CA262758). D.B. N.L. A.R.S. S.E.K. C.E.T. K.J. B.J.D. S.K.M. and J.W.T. provided project oversight for experimental design, data management, integration, and data analysis and interpretation. D.B. co-led the modeling, analysis, and data visualizations; developed computational workflows for pre-processing, harmonization, and analysis of RNA-seq and Exome-seq; co-developed the workflow and extensions for ex vivo drug screening; assisted with clinical data curation; serves as co-developer and current maintainer of the Vizome platform; and led the dissemination efforts. N.L. led the management, curation, entry, quality assurance and quality control, validation, and analysis of patient clinical annotations. A.R.S. led patient sample processing; assisted with ex vivo drug screening, DNA/RNA extractions, and sequencing sample submissions; and managed sequencing mis-match findings. S.E.K. provided oversight for and assisted with collection of ex vivo drug response data and analysis and led the development of methodology for and collection of FLT3 and NPM1 in/del data. K.J. provided project oversight and management, and assisted with patient sample processing and ex vivo drug screening. C.E.T. and J.W.T. conceived the project and provided project oversight for sample accrual and collection as well as experimental methods development. B.J.D. conceived the project and provided project oversight. S.K.M. co-led the modeling, analysis, and visualizations, and provided oversight for computational methods development and the development of the Vizome platform as well as oversight for data governance and dissemination. T.P.B. U.B. B.H.C. R.C. A.D. K.-H.T.D. M.M.L. J.N.S. E.T. J.T. A.D.P. and S.E.S. assisted with patient sample acquisition. T.P.B. and A.D.P. assisted with patient sample coordination. E.T. assisted with clinical data structure, collection, and analysis. M.M.L. assisted with IRB protocol development and maintenance, clinical data structure, collection, and analysis. A.d'A. M.A. S.A. J.B. J. Bryant, R.B. C.C. H.J.C. S.C. M.D. I.E. H. Ho, S.K.J. Y.K. H.L. S.L. S. Luty, A.M. J.M. Q.M. A.R. A. Rogers, D.A.S. R.L.S. T.S. A.T. K.T.-K. J.W. and J. Wolf assisted with patient sample processing and ex vivo drug screening. M.A. I.E. and A.R. assisted with DNA/RNA extractions and sequencing sample submissions. B.J. and T.M. provided regulatory oversight. B.J. assisted with curation and entry of patient clinical annotations. P.L. assisted with technology transfer, project development, alliance management, and data management. A.K. and M.M. developed the original ex vivo drug screening workflow and A.K. co-developed the extensions of that workflow. J. Minnier contributed to extensions for the ex vivo drug screening workflow. D.N. assisted in the creation of the drug screening replicate plates. P.R. assisted with the ex vivo drug screening analysis. K.A.R. collected and analyzed PEAR1 flow cytometry data and helped design the graphical abstract. A.A. B.H.C. C.A.E. E.L. J.M. J.N.S. and H.Z. assisted with data analysis and interpretation. A.B. led the Targetome extensions. T.L. and G.W. assisted with data integration. B.W. assisted with project oversight and conceived the original Vizome platform. C.L. E.C. R.H. and R. Searles assisted with exome and RNA-seq library creation, sequencing, and data processing. A.M.C. and S.H. assisted with clinical curation and natural language processing. J.D. assisted with curation and entry of patient clinical annotations. E.B. H.H. J.R. M.L. R. Schuff, and A.Y. assisted with clinical data integration from the OHSU Research Data Warehouse. A.Y. integrated the ex vivo workflow in the Beat AML database. C.R.C. served as a co-investigator on the repository protocol, obtained consent and collected samples from patients, processed and shipped specimens, aided with clinical annotation, and edited and provided feedback on the manuscript. R.H.C. M.W.D. C.S.H. and T.L.L. served as local principal investigators for the repository protocols, consented patients and collected samples, aided with clinical annotation, and edited and provided feedback on the manuscript. R.T.S. served as a co-investigator on the repository protocol, assisted with data interpretation, and edited and provided feedback on the manuscript. C.T.J. and D.A.P. collected samples for the repository protocol and provided feedback on the manuscript. M.E.M. and R.R.P. consented patients and collected samples for the repository protocol and aided with clinical annotation. J.M.W. served as a local principal investigator for the repository protocol and edited and provided feedback on the manuscript. S.J.W. enabled, facilitated, and mentored basic, translational and clinical research activities arising from data generated by Beat AML at the University of Kansas Cancer Center site and participated in the Beat AML Symposia to share research and create research projects. C.E.T. receives research support from Notable Labs and serves as a scientific liaison for AstraZeneca. J.E.M. receives research funding from Gilead Pharmaceutical and serves on a scientific advisory board for Ionis Pharmaceuticals. M.W.D. serves on the advisory boards and/or as a consultant for Novartis, Incyte, and BMS and receives research funding from BMS and Gilead. C.S.H. receives research funding from Sellas. T.L.L. consults for Jazz Pharmaceuticals and receives research funding from Tolero, Gilead, Prescient, Ono, Bio-Path, Mateon, Genentech/Roche, Trovagene, AbbVie, Pfizer, Celgene, Imago, Astellas, Karyopharm, Seattle Genetics, and Incyte. D.A.P. receives research funding from Pfizer and Agios and served on advisory boards for Pfizer, Celyad, Agios, Celgene, AbbVie, Argenx, Takeda, and Servier. B.J.D. serves on the advisory boards for Aileron Therapeutics, Aptose, Blueprint Medicines, Cepheid, EnLiven Therapeutics, Gilead, GRAIL, Iterion Therapeutics, Nemucore Medical Innovations, the Novartis CML Molecular Monitoring Steering Committee, Recludix Pharma, the RUNX1 Research Program, ALLCRON Pharma, VB Therapeutics, Vincerx Pharma, and the Board of Directors for Amgen, and receives research funding from EnLiven and Recludix. B.J.D. is principal investigator or co-investigator on Novartis, BMS, and Pfizer clinical trials. His institution, OHSU, has contracts with these companies to pay for patient costs, nurse and data manager salaries, and institutional overhead, but he does not derive salary, nor does his laboratory receive funds, from these contracts. J.W.T. has received research support from Acerta, Agios, Aptose, Array, AstraZeneca, Constellation, Genentech, Gilead, Incyte, Janssen, Kronos, Meryx, Petra, Schrodinger, Seattle Genetics, Syros, Takeda, and Tolero and serves on the advisory board for Recludix Pharma. The authors certify that all compounds tested in this study were chosen without input from any of our industry partners. A subset of findings from this manuscript have been included in a pending patent application. Publisher Copyright: © 2022 The Author(s)

PY - 2022/8/8

Y1 - 2022/8/8

N2 - Acute myeloid leukemia (AML) is a cancer of myeloid-lineage cells with limited therapeutic options. We previously combined ex vivo drug sensitivity with genomic, transcriptomic, and clinical annotations for a large cohort of AML patients, which facilitated discovery of functional genomic correlates. Here, we present a dataset that has been harmonized with our initial report to yield a cumulative cohort of 805 patients (942 specimens). We show strong cross-cohort concordance and identify features of drug response. Further, deconvoluting transcriptomic data shows that drug sensitivity is governed broadly by AML cell differentiation state, sometimes conditionally affecting other correlates of response. Finally, modeling of clinical outcome reveals a single gene, PEAR1, to be among the strongest predictors of patient survival, especially for young patients. Collectively, this report expands a large functional genomic resource, offers avenues for mechanistic exploration and drug development, and reveals tools for predicting outcome in AML.

AB - Acute myeloid leukemia (AML) is a cancer of myeloid-lineage cells with limited therapeutic options. We previously combined ex vivo drug sensitivity with genomic, transcriptomic, and clinical annotations for a large cohort of AML patients, which facilitated discovery of functional genomic correlates. Here, we present a dataset that has been harmonized with our initial report to yield a cumulative cohort of 805 patients (942 specimens). We show strong cross-cohort concordance and identify features of drug response. Further, deconvoluting transcriptomic data shows that drug sensitivity is governed broadly by AML cell differentiation state, sometimes conditionally affecting other correlates of response. Finally, modeling of clinical outcome reveals a single gene, PEAR1, to be among the strongest predictors of patient survival, especially for young patients. Collectively, this report expands a large functional genomic resource, offers avenues for mechanistic exploration and drug development, and reveals tools for predicting outcome in AML.

KW - JEDI

KW - LSC17

KW - MEGF12

KW - cell state

KW - eigengene

KW - hematologic malignancy

KW - leukemia stem cell

KW - monocyte

KW - targeted therapy

UR - http://www.scopus.com/inward/record.url?scp=85135439194&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85135439194&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2022.07.002

DO - 10.1016/j.ccell.2022.07.002

M3 - Article

C2 - 35868306

AN - SCOPUS:85135439194

SN - 1535-6108

VL - 40

SP - 850-864.e9

JO - Cancer Cell

JF - Cancer Cell

IS - 8

ER -

Integrative analysis of drug response and clinical outcome in acute myeloid leukemia

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