A Cellular Hierarchy Framework for Understanding Heterogeneity and Predicting Drug Response in Acute Myeloid Leukemia

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2022 May 26

PMID 35618837

Authors

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

Herve Dombret

Naval Daver

P Andrew Futreal

Mark D Minden

James A Kennedy

Jean C Y Wang

John E Dick

Affiliations

Soon will be listed here.

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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