Genotype-immunophenotype relationships in <i>NPM1</i> -mutated AML clonal evolution uncovered by single-cell multiomic analysis
Abstract
Abstract Acute myeloid leukemia (AML) is a multiclonal disease, existing as a milieu of clones with unique but related genotypes as initiating clones acquire subsequent mutations. However, bulk sequencing cannot fully capture AML clonal architecture or the clonal evolution that occurs as patients undergo therapy. To interrogate clonal evolution, we performed simultaneous single-cell molecular profiling and immunophenotyping on 43 samples from 32 patients with NPM1 (nucleophosmin 1)–mutated AML at different time points in disease progression. Here, we show that diagnosis and relapse AML samples display similar clonal architecture patterns, but signaling mutations drive increased clonal complexity, specifically at relapse, which correlates with overall survival. We uncovered unique genotype-immunophenotype relationships regardless of disease state, suggesting leukemic lineage trajectories can be hard-wired by the mutations present. Analysis of longitudinal samples from patients on front-line AML therapy identified dynamic clonal and immunophenotypic changes consistent with the genotype-immunophenotype relationships we identified.
Article Details
Authors (22)
Morgan Drucker
1Division of Oncology, Cancer and Blood Disease Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
Darren Lee
Michael Bowman
4Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
Xuan Zhang
Bailee N. Kain
5Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
Deedra Nicolet
6The Ohio State University Comprehensive Cancer Center, Columbus, OH
Roopsha Bandopadhyay
4Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
Varsha Singh
Zhe Wang
Richard M. Stone
8Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
Caner Saygin
9Department of Medicine, University of Chicago, Chicago, IL
Krzysztof Mrózek
6The Ohio State University Comprehensive Cancer Center, Columbus, OH
Andrew J. Carroll
Department of Genetics, University of Alabama at Birmingham, Birmingham
Daniel T. Starczynowski
Ross L. Levine
John C. Byrd
Nathan Salomonis
2Department of Pediatrics, University of Cincinnati, Cincinnati, OH
Sarah J. Skuli
12University of Cincinnati Cancer Center, Cincinnati, OH
H. Leighton Grimes
Ann-Kathrin Eisfeld
6The Ohio State University Comprehensive Cancer Center, Columbus, OH
Robert L. Bowman
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Linde A. Miles
2Department of Pediatrics, University of Cincinnati, Cincinnati, OH