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

被引：0

作者：

Andy G. X. Zeng

Suraj Bansal

Liqing Jin

Amanda Mitchell

Weihsu Claire Chen

Hussein A. Abbas

Michelle Chan-Seng-Yue

Veronique Voisin

Peter van Galen

Anne Tierens

Meyling Cheok

Claude Preudhomme

Hervé Dombret

Naval Daver

P. Andrew Futreal

Mark D. Minden

James A. Kennedy

Jean C. Y. Wang

John E. Dick

机构：

[1] University Health Network,Princess Margaret Cancer Centre

[2] University of Toronto,Department of Molecular Genetics

[3] Department of Leukemia,The Donnelly Centre

[4] The University of Texas MD Anderson Cancer Center,Laboratory Medicine Program, Hematopathology

[5] University of Toronto,Department of Medical Biophysics

[6] Division of Hematology,Department of Medicine

[7] Brigham and Women’s Hospital,Division of Medical Oncology and Hematology

[8] Department of Medicine,undefined

[9] Harvard Medical School,undefined

[10] Broad Institute of MIT and Harvard,undefined

[11] Ludwig Center at Harvard,undefined

[12] Harvard Medical School,undefined

[13] University Health Network,undefined

[14] University of Lille,undefined

[15] CNRS,undefined

[16] Inserm,undefined

[17] CHU Lille,undefined

[18] UMR9020-U1277 - CANTHER – Cancer Heterogeneity Plasticity and Resistance to Therapies,undefined

[19] Department of Hematology,undefined

[20] Hôpital Saint-Louis,undefined

[21] Assistance Publique-Hôpitaux de Paris,undefined

[22] Université Paris Cité,undefined

[23] Department of Genomic Medicine,undefined

[24] The University of Texas MD Anderson Cancer Center,undefined

[25] University of Toronto,undefined

[26] University of Toronto,undefined

[27] University Health Network,undefined

[28] Division of Medical Oncology and Hematology,undefined

[29] Sunnybrook Health Sciences Centre,undefined

[30] Biologics Discovery,undefined

[31] Amgen British Columbia,undefined

来源：

Nature Medicine | 2022年 / 28卷

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摘要：

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.

引用

页码：1212 / 1223

页数：11

共 99 条

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