A cellular hierarchy framework for understanding heterogeneity and predicting drug response in acute myeloid leukemia

Andy G X Zeng^{1

2}, Suraj Bansal^#¹, Liqing Jin^#¹, Amanda Mitchell¹, Weihsu Claire Chen^{1

3}, Hussein A Abbas⁴, Michelle Chan-Seng-Yue¹, Veronique Voisin⁵, Peter van Galen^{6

7

8

9}, Anne Tierens¹⁰, Meyling Cheok¹¹, Claude Preudhomme¹¹, Hervé Dombret¹², Naval Daver⁴, P Andrew Futreal¹³, Mark D Minden^{1

14

15

16}, James A Kennedy^{1

17}, Jean C Y Wang^{1

15

16}, John E Dick^{18

19}

Affiliations

¹ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
² Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
³ Biologics Discovery, Amgen British Columbia, Burnaby, BC, Canada.
⁴ Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁵ The Donnelly Centre, University of Toronto, Toronto, ON, Canada.
⁶ Division of Hematology, Brigham and Women's Hospital, Boston, MA, USA.
⁷ Department of Medicine, Harvard Medical School, Boston, MA, USA.
⁸ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁹ Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.
¹⁰ Laboratory Medicine Program, Hematopathology, University Health Network, Toronto, ON, Canada.
¹¹ University of Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France.
¹² Department of Hematology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris, France.
¹³ Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁴ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
¹⁵ Department of Medicine, University of Toronto, Toronto, ON, Canada.
¹⁶ Division of Medical Oncology and Hematology, University Health Network, Toronto, ON, Canada.
¹⁷ Division of Medical Oncology and Hematology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
¹⁸ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. john.dick@uhnresearch.ca.
¹⁹ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. john.dick@uhnresearch.ca.

^# Contributed equally.

PMID: 35618837
DOI: 10.1038/s41591-022-01819-x

A cellular hierarchy framework for understanding heterogeneity and predicting drug response in acute myeloid leukemia

Andy G X Zeng et al. Nat Med. 2022 Jun.

. 2022 Jun;28(6):1212-1223.

doi: 10.1038/s41591-022-01819-x. Epub 2022 May 26.

Authors

Affiliations

¹ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
² Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
³ Biologics Discovery, Amgen British Columbia, Burnaby, BC, Canada.
⁴ Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁵ The Donnelly Centre, University of Toronto, Toronto, ON, Canada.
⁶ Division of Hematology, Brigham and Women's Hospital, Boston, MA, USA.
⁷ Department of Medicine, Harvard Medical School, Boston, MA, USA.
⁸ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁹ Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.
¹⁰ Laboratory Medicine Program, Hematopathology, University Health Network, Toronto, ON, Canada.
¹¹ University of Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France.
¹² Department of Hematology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris, France.
¹³ Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁴ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
¹⁵ Department of Medicine, University of Toronto, Toronto, ON, Canada.
¹⁶ Division of Medical Oncology and Hematology, University Health Network, Toronto, ON, Canada.
¹⁷ Division of Medical Oncology and Hematology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
¹⁸ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. john.dick@uhnresearch.ca.
¹⁹ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. john.dick@uhnresearch.ca.

^# Contributed equally.

PMID: 35618837
DOI: 10.1038/s41591-022-01819-x

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.

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Comment in

Cellular hierarchies predict drug response in acute myeloid leukemia.
Raffel S, Velten L, Haas S. Raffel S, et al. Cancer Cell. 2022 Sep 12;40(9):917-919. doi: 10.1016/j.ccell.2022.08.019. Epub 2022 Sep 1. Cancer Cell. 2022. PMID: 36055227

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A cellular hierarchy framework for understanding heterogeneity and predicting drug response in acute myeloid leukemia

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A cellular hierarchy framework for understanding heterogeneity and predicting drug response in acute myeloid leukemia

Authors

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Abstract

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Grants and funding

LinkOut - more resources

Full Text Sources

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Medical

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