Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2019 May 21;116(21):10494-10503. doi: 10.1073/pnas.1902375116. Epub 2019 May 7.

Heterogeneity in refractory acute myeloid leukemia.

Author information

1
Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; sachi.horibata@nih.gov mgottesman@nih.gov hourigan@nih.gov.
2
Laboratory of Myeloid Malignancies, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20814.
3
NIAID Collaborative Bioinformatics Resource, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
4
Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD 21702.
5
Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814.
6
Laboratory of Myeloid Malignancies, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20814; sachi.horibata@nih.gov mgottesman@nih.gov hourigan@nih.gov.

Abstract

Successful clinical remission to therapy for acute myeloid leukemia (AML) is required for long-term survival to be achieved. Despite trends in improved survival due to better supportive care, up to 40% of patients will have refractory disease, which has a poorly understood biology and carries a dismal prognosis. The development of effective treatment strategies has been hindered by a general lack of knowledge about mechanisms of chemotherapy resistance. Here, through transcriptomic analysis of 154 cases of treatment-naive AML, three chemorefractory patient groups with distinct expression profiles are identified. A classifier, four key refractory gene signatures (RG4), trained based on the expression profile of the highest risk refractory patients, validated in an independent cohort (n = 131), was prognostic for overall survival (OS) and refined an established 17-gene stemness score. Refractory subpopulations have differential expression in pathways involved in cell cycle, transcription, translation, metabolism, and/or stem cell properties. Ex vivo drug sensitivity to 122 small-molecule inhibitors revealed effective group-specific targeting of pathways among these three refractory groups. Gene expression profiling by RNA sequencing had a suboptimal ability to correctly predict those individuals resistant to conventional cytotoxic induction therapy, but could risk-stratify for OS and identify subjects most likely to have superior responses to a specific alternative therapy. Such personalized therapy may be studied prospectively in clinical trials.

KEYWORDS:

acute myeloid leukemia; cancer heterogeneity; drug resistance

PMID:
31064876
PMCID:
PMC6535032
[Available on 2019-11-07]
DOI:
10.1073/pnas.1902375116

Conflict of interest statement

Conflict of interest statement: C.S.H. receives laboratory research funding from the Merck Sharp & Dohme and SELLAS Life Sciences Group AG.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center