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Integrative Analysis of Drug Response and Clinical Outcome in Acute Myeloid Leukemia

57 Pages Posted: 22 Feb 2022 Publication Status: Accepted

See all articles by Daniel Bottomly

Daniel Bottomly

affiliation not provided to SSRN

Nicola Long

Oregon Health and Science University

Anna Reister Schultz

Oregon Health and Science University

Stephen E. Kurtz

Oregon Health and Science University

Cristina E. Tognon

Oregon Health and Science University

Kara Johnson

Oregon Health and Science University

Melissa Abel

Oregon Health and Science University

Anupriya Agarwal

Oregon Health and Science University

Sammantha Avaylan

Oregon Health and Science University

Erik Benton

Oregon Health and Science University

Aurora Blucher

Oregon Health and Science University

Uma Borate

affiliation not provided to SSRN

Theodore Braun

Oregon Health and Science University

Jordana Brown

Oregon Health and Science University

Jade Bryant

Oregon Health and Science University

Russell Burke

Oregon Health and Science University

Amy Carlos

Oregon Health and Science University

Bill H. Chang

Oregon Health and Science University

Hyun Jun Cho

Oregon Health and Science University

Stephen Christy

Oregon Health and Science University

Cody Coblentz

Oregon Health and Science University

Aaron M. Cohen

Oregon Health and Science University

Amanda d’Almeida

Oregon Health and Science University

Rachel Cook

Oregon Health and Science University

Alexey Danilov

City of Hope

Kim-Hien T. Dao

affiliation not provided to SSRN

Michie Degnin

Oregon Health and Science University

James Dibb

Oregon Health and Science University

Christopher A. Eide

Oregon Health and Science University

Isabel A. English

Oregon Health and Science University - Department of Molecular and Medical Genetics

Stuart Hagler

Oregon Health & Science University

Heath Harrelson

Oregon Health and Science University

Rachel Henson

Oregon Health and Science University

Hibery Ho

Oregon Health and Science University

Sunil Joshi

Oregon Health and Science University - OHSU Knight Cancer Center Institute

Brian Junio

Oregon Health and Science University

Andy Kaempf

Oregon Health and Science University

Yoko Kosaka

Oregon Health and Science University

Ted Laderas

affiliation not provided to SSRN

Matt Lawhead

Oregon Health and Science University

Hyunjung Lee

Oregon Health and Science University

Jessica T. Leonard

Oregon Health and Science University

Chenwei Lin

Oregon Health and Science University

Evan F. Lind

Oregon Health and Science University

Selina Qiuying Liu

Oregon Health and Science University

Pierrette Lo

Oregon Health and Science University

Marc M. Loriaux

Oregon Health and Science University

Samuel Luty

Oregon Health and Science University

Julia E. Maxson

Oregon Health and Science University

Tara Macey

Oregon Health and Science University

Jacqueline Martinez

Oregon Health and Science University

Jessica Minnier

Oregon Health and Science University

Andrea Monteblanco

Oregon Health and Science University

Motomi Mori

Oregon Health and Science University

Quinlan Morrow

Oregon Health and Science University

Dylan Nelson

Oregon State University

Justin Ramsdill

Oregon Health and Science University

Angela Rofelty

Oregon Health and Science University

Alexandra Rogers

Oregon Health and Science University

Peter Ryabinin

Oregon Health and Science University

Jennifer N. Saultz

Oregon Health and Science University

David A. Sampson

Oregon Health and Science University

Samantha L. Savage

Oregon Health and Science University

Robert Schuff

Oregon Health and Science University

Robert Searles

Oregon Health and Science University

Rebecca L. Smith

Oregon Health and Science University

Stephen E. Spurgeon

Oregon Health and Science University

Tyler Sweeney

Oregon Health and Science University

Ronan T. Swords

Oregon Health and Science University

Aashis Thapa

Oregon Health and Science University

Karina Thiel-Klare

Oregon Health and Science University

Elie Traer

Oregon Health and Science University - OHSU Knight Cancer Center Institute

Jake Wagner

Oregon Health and Science University

Beth Wilmot

Oregon Health and Science University

Joelle Wolf

Oregon Health and Science University

Guanming Wu

Oregon Health and Science University

Amy Yates

Oregon Health and Science University

Haijiao Zhang

Oregon Health and Science University

Christopher Cogle

University of Florida - Division of Hematology/Oncology

Robert H. Collins

affiliation not provided to SSRN

Michael W. Deininger

affiliation not provided to SSRN

Christopher S. Hourigan

University of North Carolina (UNC) at Chapel Hill - National Institute of Health

Craig T. Jordan

University of Colorado Denver

Tara L. Lin

affiliation not provided to SSRN

Micaela E. Martinez

University of Miami

Rachel R. Pallapati

University of Miami

Daniel Pollyea

University of Colorado at Denver - Division of Hematology

Tony Pomicter

University of Utah

Justin M. Watts

University of Miami

Scott Weir

University of Kansas Medical Center

Brian J. Druker

Oregon Health and Science University

Shannon K. McWeeney

Oregon Health and Science University

Jeffrey W. Tyner

Oregon Health and Science University - Division of Bioinformatics and Computational Biology

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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 new dataset, which has been harmonized with our initial report to yield a cumulative cohort of 805 patients (942 specimens). We show strong cross-cohort validation and identify new features of drug response. Further, deconvoluting transcriptomic data shows that drug sensitivity is governed broadly by AML cell differentiation state, sometimes conditionally impacting 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 new avenues for mechanistic exploration and drug development, and reveals new tools for predicting outcome in AML.

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

Suggested Citation

Bottomly, Daniel and Long, Nicola and Schultz, Anna Reister and Kurtz, Stephen E. and Tognon, Cristina E. and Johnson, Kara and Abel, Melissa and Agarwal, Anupriya and Avaylan, Sammantha and Benton, Erik and Blucher, Aurora and Borate, Uma and Braun, Theodore and Brown, Jordana and Bryant, Jade and Burke, Russell and Carlos, Amy and Chang, Bill H. and Cho, Hyun Jun and Christy, Stephen and Coblentz, Cody and Cohen, Aaron M. and d’Almeida, Amanda and Cook, Rachel and Danilov, Alexey and Dao, Kim-Hien T. and Degnin, Michie and Dibb, James and Eide, Christopher A. and English, Isabel A. and Hagler, Stuart and Harrelson, Heath and Henson, Rachel and Ho, Hibery and Joshi, Sunil and Junio, Brian and Kaempf, Andy and Kosaka, Yoko and Laderas, Ted and Lawhead, Matt and Lee, Hyunjung and Leonard, Jessica T. and Lin, Chenwei and Lind, Evan F. and Liu, Selina Qiuying and Lo, Pierrette and Loriaux, Marc M. and Luty, Samuel and Maxson, Julia E. and Macey, Tara and Martinez, Jacqueline and Minnier, Jessica and Monteblanco, Andrea and Mori, Motomi and Morrow, Quinlan and Nelson, Dylan and Ramsdill, Justin and Rofelty, Angela and Rogers, Alexandra and Ryabinin, Peter and Saultz, Jennifer N. and Sampson, David A. and Savage, Samantha L. and Schuff, Robert and Searles, Robert and Smith, Rebecca L. and Spurgeon, Stephen E. and Sweeney, Tyler and Swords, Ronan T. and Thapa, Aashis and Thiel-Klare, Karina and Traer, Elie and Wagner, Jake and Wilmot, Beth and Wolf, Joelle and Wu, Guanming and Yates, Amy and Zhang, Haijiao and Cogle, Christopher 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 and Pomicter, Tony and Watts, Justin M. and Weir, Scott and Druker, Brian J. and McWeeney, Shannon K. and Tyner, Jeffrey W., Integrative Analysis of Drug Response and Clinical Outcome in Acute Myeloid Leukemia. Available at SSRN: https://ssrn.com/abstract=4041405 or http://dx.doi.org/10.2139/ssrn.4041405
This version of the paper has not been formally peer reviewed.

Daniel Bottomly

affiliation not provided to SSRN ( email )

No Address Available

Nicola Long

Oregon Health and Science University ( email )

Portland, OR
United States

Anna Reister Schultz

Oregon Health and Science University ( email )

Portland, OR
United States

Stephen E. Kurtz

Oregon Health and Science University ( email )

Portland, OR
United States

Cristina E. Tognon

Oregon Health and Science University ( email )

Portland, OR
United States

Kara Johnson

Oregon Health and Science University ( email )

Portland, OR
United States

Melissa Abel

Oregon Health and Science University ( email )

Portland, OR
United States

Anupriya Agarwal

Oregon Health and Science University ( email )

Portland, OR
United States

Sammantha Avaylan

Oregon Health and Science University ( email )

Portland, OR
United States

Erik Benton

Oregon Health and Science University ( email )

Portland, OR
United States

Aurora Blucher

Oregon Health and Science University ( email )

Portland, OR
United States

Uma Borate

affiliation not provided to SSRN ( email )

No Address Available

Theodore Braun

Oregon Health and Science University ( email )

Jordana Brown

Oregon Health and Science University ( email )

Portland, OR
United States

Jade Bryant

Oregon Health and Science University ( email )

Portland, OR
United States

Russell Burke

Oregon Health and Science University ( email )

Portland, OR
United States

Amy Carlos

Oregon Health and Science University ( email )

Portland, OR
United States

Bill H. Chang

Oregon Health and Science University ( email )

Portland, OR
United States

Hyun Jun Cho

Oregon Health and Science University ( email )

Portland, OR
United States

Stephen Christy

Oregon Health and Science University ( email )

Portland, OR
United States

Cody Coblentz

Oregon Health and Science University ( email )

Portland, OR
United States

Aaron M. Cohen

Oregon Health and Science University ( email )

Portland, OR
United States

Amanda D’Almeida

Oregon Health and Science University ( email )

Portland, OR
United States

Rachel Cook

Oregon Health and Science University ( email )

Portland, OR
United States

Alexey Danilov

City of Hope ( email )

1500 E. Duarte Rd.
Duarte, CA 91010
United States

Kim-Hien T. Dao

affiliation not provided to SSRN ( email )

No Address Available

Michie Degnin

Oregon Health and Science University ( email )

Portland, OR
United States

James Dibb

Oregon Health and Science University ( email )

Portland, OR
United States

Christopher A. Eide

Oregon Health and Science University ( email )

Portland, OR
United States

Isabel A. English

Oregon Health and Science University - Department of Molecular and Medical Genetics ( email )

United States

Stuart Hagler

Oregon Health & Science University ( email )

3181 S.W. Sam Jackson Park Rd.
Portland, OR 97201
United States

Heath Harrelson

Oregon Health and Science University ( email )

Portland, OR
United States

Rachel Henson

Oregon Health and Science University ( email )

Portland, OR
United States

Hibery Ho

Oregon Health and Science University ( email )

Portland, OR
United States

Sunil Joshi

Oregon Health and Science University - OHSU Knight Cancer Center Institute ( email )

3181 S.W. Sam Jackson Park Rd.
Portland, OR 97201
United States

Brian Junio

Oregon Health and Science University ( email )

Portland, OR
United States

Andy Kaempf

Oregon Health and Science University ( email )

Portland, OR
United States

Yoko Kosaka

Oregon Health and Science University ( email )

Portland, OR
United States

Ted Laderas

affiliation not provided to SSRN ( email )

No Address Available

Matt Lawhead

Oregon Health and Science University ( email )

Portland, OR
United States

Hyunjung Lee

Oregon Health and Science University ( email )

Portland, OR
United States

Jessica T. Leonard

Oregon Health and Science University ( email )

Portland, OR
United States

Chenwei Lin

Oregon Health and Science University ( email )

Portland, OR
United States

Evan F. Lind

Oregon Health and Science University ( email )

Portland, OR
United States

Selina Qiuying Liu

Oregon Health and Science University ( email )

Portland, OR
United States

Pierrette Lo

Oregon Health and Science University ( email )

Portland, OR
United States

Marc M. Loriaux

Oregon Health and Science University ( email )

Portland, OR
United States

Samuel Luty

Oregon Health and Science University ( email )

Portland, OR
United States

Julia E. Maxson

Oregon Health and Science University ( email )

Portland, OR
United States

Tara Macey

Oregon Health and Science University ( email )

Portland, OR
United States

Jacqueline Martinez

Oregon Health and Science University ( email )

Portland, OR
United States

Jessica Minnier

Oregon Health and Science University ( email )

Portland, OR
United States

Andrea Monteblanco

Oregon Health and Science University ( email )

Portland, OR
United States

Motomi Mori

Oregon Health and Science University ( email )

Portland, OR
United States

Quinlan Morrow

Oregon Health and Science University ( email )

Portland, OR
United States

Dylan Nelson

Oregon State University ( email )

Bexell Hall 200
Corvallis, OR 97331
United States

Justin Ramsdill

Oregon Health and Science University ( email )

Portland, OR
United States

Angela Rofelty

Oregon Health and Science University ( email )

Portland, OR
United States

Alexandra Rogers

Oregon Health and Science University ( email )

Portland, OR
United States

Peter Ryabinin

Oregon Health and Science University ( email )

Portland, OR
United States

Jennifer N. Saultz

Oregon Health and Science University ( email )

Portland, OR
United States

David A. Sampson

Oregon Health and Science University ( email )

Portland, OR
United States

Samantha L. Savage

Oregon Health and Science University ( email )

Portland, OR
United States

Robert Schuff

Oregon Health and Science University ( email )

Portland, OR
United States

Robert Searles

Oregon Health and Science University ( email )

Portland, OR
United States

Rebecca L. Smith

Oregon Health and Science University ( email )

Portland, OR
United States

Stephen E. Spurgeon

Oregon Health and Science University ( email )

Portland, OR
United States

Tyler Sweeney

Oregon Health and Science University ( email )

Portland, OR
United States

Ronan T. Swords

Oregon Health and Science University ( email )

Portland, OR
United States

Aashis Thapa

Oregon Health and Science University ( email )

Portland, OR
United States

Karina Thiel-Klare

Oregon Health and Science University ( email )

Portland, OR
United States

Elie Traer

Oregon Health and Science University - OHSU Knight Cancer Center Institute ( email )

3181 S.W. Sam Jackson Park Rd.
Portland, OR 97201
United States

Jake Wagner

Oregon Health and Science University ( email )

Portland, OR
United States

Beth Wilmot

Oregon Health and Science University ( email )

Portland, OR
United States

Joelle Wolf

Oregon Health and Science University ( email )

Portland, OR
United States

Guanming Wu

Oregon Health and Science University ( email )

Portland, OR
United States

Amy Yates

Oregon Health and Science University ( email )

Portland, OR
United States

Haijiao Zhang

Oregon Health and Science University ( email )

Portland, OR
United States

Christopher Cogle

University of Florida - Division of Hematology/Oncology ( email )

PO Box 117165, 201 Stuzin Hall
Gainesville, FL 32610-0496
United States

Robert H. Collins

affiliation not provided to SSRN ( email )

No Address Available

Michael W. Deininger

affiliation not provided to SSRN ( email )

No Address Available

Christopher S. Hourigan

University of North Carolina (UNC) at Chapel Hill - National Institute of Health ( email )

Chapel Hill, NC
United States

Craig T. Jordan

University of Colorado Denver ( email )

1475 Lawrence St
Denver, CO 80238-3363
United States

Tara L. Lin

affiliation not provided to SSRN ( email )

No Address Available

Micaela E. Martinez

University of Miami ( email )

Coral Gables, FL 33124
United States

Rachel R. Pallapati

University of Miami ( email )

Coral Gables, FL 33124
United States

Daniel Pollyea

University of Colorado at Denver - Division of Hematology ( email )

13001 E 17th Pl
Aurora, CO 80045
United States

Tony Pomicter

University of Utah ( email )

1645 E. Campus Center
Salt Lake City, UT 84112
United States

Justin M. Watts

University of Miami ( email )

Coral Gables, FL 33124
United States

Scott Weir

University of Kansas Medical Center ( email )

3901 Rainbow Boulevard
Kansas City, KS 66160
United States

HOME PAGE: http://www.kumc.edu/school-of-medicine/pharmacology-toxicology-and-therapeutics/faculty/scott-weir-p

Brian J. Druker

Oregon Health and Science University ( email )

Portland, OR
United States

Shannon K. McWeeney

Oregon Health and Science University ( email )

Portland, OR
United States

Jeffrey W. Tyner (Contact Author)

Oregon Health and Science University - Division of Bioinformatics and Computational Biology ( email )

3181 S.W. Sam Jackson Park Rd.
Portland, OR 97201
United States

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