Single-cell mutation analysis of clonal evolution in myeloid malignancies

Linde A. Miles, Robert L. Bowman, Tiffany R. Merlinsky, Isabelle S. Csete, Aik T. Ooi, Robert Durruthy-Durruthy, Michael Bowman, Christopher Famulare, Minal A. Patel, Pedro Mendez, Chrysanthi Ainali, Benjamin Demaree, Cyrille L. Delley, Adam R. Abate, Manimozhi Manivannan, Sombeet Sahu, Aaron D. Goldberg, Kelly L. Bolton, Ahmet Zehir, Raajit Rampal, Martin P. Carroll, Sara E. Meyer, Aaron D. Viny and Ross L. Levine ()
Additional contact information
Linde A. Miles: Memorial Sloan Kettering Cancer Center
Robert L. Bowman: Memorial Sloan Kettering Cancer Center
Tiffany R. Merlinsky: Memorial Sloan Kettering Cancer Center
Isabelle S. Csete: Memorial Sloan Kettering Cancer Center
Aik T. Ooi: Mission Bio
Robert Durruthy-Durruthy: Mission Bio
Michael Bowman: Colorado School of Mines
Christopher Famulare: Memorial Sloan Kettering Cancer Center
Minal A. Patel: Memorial Sloan Kettering Cancer Center
Pedro Mendez: Mission Bio
Chrysanthi Ainali: Mission Bio
Benjamin Demaree: University of California
Cyrille L. Delley: University of California
Adam R. Abate: University of California
Manimozhi Manivannan: Mission Bio
Sombeet Sahu: Mission Bio
Aaron D. Goldberg: Memorial Sloan Kettering Cancer Center
Kelly L. Bolton: Memorial Sloan Kettering Cancer Center
Ahmet Zehir: Memorial Sloan Kettering Cancer Center
Raajit Rampal: Memorial Sloan Kettering Cancer Center
Martin P. Carroll: University of Pennsylvania
Sara E. Meyer: Thomas Jefferson University, Sidney Kimmel Cancer Center
Aaron D. Viny: Memorial Sloan Kettering Cancer Center
Ross L. Levine: Memorial Sloan Kettering Cancer Center

Nature, 2020, vol. 587, issue 7834, 477-482

Abstract: Abstract Myeloid malignancies, including acute myeloid leukaemia (AML), arise from the expansion of haematopoietic stem and progenitor cells that acquire somatic mutations. Bulk molecular profiling has suggested that mutations are acquired in a stepwise fashion: mutant genes with high variant allele frequencies appear early in leukaemogenesis, and mutations with lower variant allele frequencies are thought to be acquired later1–3. Although bulk sequencing can provide information about leukaemia biology and prognosis, it cannot distinguish which mutations occur in the same clone(s), accurately measure clonal complexity, or definitively elucidate the order of mutations. To delineate the clonal framework of myeloid malignancies, we performed single-cell mutational profiling on 146 samples from 123 patients. Here we show that AML is dominated by a small number of clones, which frequently harbour co-occurring mutations in epigenetic regulators. Conversely, mutations in signalling genes often occur more than once in distinct subclones, consistent with increasing clonal diversity. We mapped clonal trajectories for each sample and uncovered combinations of mutations that synergized to promote clonal expansion and dominance. Finally, we combined protein expression with mutational analysis to map somatic genotype and clonal architecture with immunophenotype. Our findings provide insights into the pathogenesis of myeloid transformation and how clonal complexity evolves with disease progression.

Date: 2020
References: Add references at CitEc
Citations: View citations in EconPapers (12)

Downloads: (external link)
https://www.nature.com/articles/s41586-020-2864-x Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:587:y:2020:i:7834:d:10.1038_s41586-020-2864-x

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-020-2864-x

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().