@article{aeb809d4141e491696c41bb71984d118,
title = "A cellular hierarchy framework for understanding heterogeneity and predicting drug response in acute myeloid leukemia",
abstract = "The treatment landscape of acute myeloid leukemia (AML) is evolving, with promising therapies entering clinical translation, yet patient responses remain heterogeneous, and biomarkers for tailoring treatment are lacking. To understand how disease heterogeneity links with therapy response, we determined the leukemia cell hierarchy makeup from bulk transcriptomes of more than 1,000 patients through deconvolution using single-cell reference profiles of leukemia stem, progenitor and mature cell types. Leukemia hierarchy composition was associated with functional, genomic and clinical properties and converged into four overall classes, spanning Primitive, Mature, GMP and Intermediate. Critically, variation in hierarchy composition along the Primitive versus GMP or Primitive versus Mature axes were associated with response to chemotherapy or drug sensitivity profiles of targeted therapies, respectively. A seven-gene biomarker derived from the Primitive versus Mature axis was associated with response to 105 investigational drugs. Cellular hierarchy composition constitutes a novel framework for understanding disease biology and advancing precision medicine in AML.",
author = "Zeng, {Andy G.X.} and Suraj Bansal and Liqing Jin and Amanda Mitchell and Chen, {Weihsu Claire} and Abbas, {Hussein A.} and Michelle Chan-Seng-Yue and Veronique Voisin and {van Galen}, Peter and Anne Tierens and Meyling Cheok and Claude Preudhomme and Herv{\'e} Dombret and Naval Daver and Futreal, {P. Andrew} and Minden, {Mark D.} and Kennedy, {James A.} and Wang, {Jean C.Y.} and Dick, {John E.}",
note = "Funding Information: J.E.D. reports research funding from Celgene/Bristol Myers Squibb and advisory board/royalities from Trillium Therapeutics. All other authors declare no competing interests. Funding Information: We thank C. Jones, A. Tikhonova, N. Iscove, S. Chan, S. Abelson, B. Haibe-Kains, M. Anders and all members of the Dick Laboratory for valuable feedback on the manuscript. We thank P. Valk and the HOVON-SAKK trial group for providing the clinical annotations associated with GSE6891. A.G.X.Z. is supported by a CIHR Vanier scholarship. J.E.D. is supported by funds from the Ontario Institute for Cancer Research through funding provided by the Government of Ontario; the Canadian Institutes for Health Research (RN380110 - 409786); the International Development Research Centre Ottawa Canada; the Canadian Cancer Society (grant 703212 (end date 2019) and grant 706662 (end date 2025)); the Terry Fox New Frontiers Program Project Grant (Project 1106); University of Toronto{\textquoteright}s Medicine by Design initiative with funding from the Canada First Research Excellence Fund; a Canada Research Chair; Princess Margaret Cancer Centre; The Princess Margaret Cancer Foundation; and the Ontario Ministry of Health. The Leukemia Tissue Bank is supported by funds to M.D.M. from the Wendy Eisen Princess Margaret Hospital Foundation Account and the Philip Orsino Chair in Leukemia Research. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2022",
month = jun,
doi = "10.1038/s41591-022-01819-x",
language = "English (US)",
volume = "28",
pages = "1212--1223",
journal = "Nature medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "6",
}