Nature. 2020 Nov;587(7834):477-482. doi: 10.1038/s41586-020-2864-x. | PubMed

Linde A Miles¹, Robert L Bowman¹, Tiffany R Merlinsky¹, Isabelle S Csete¹, Aik T Ooi², Robert Durruthy-Durruthy², Michael Bowman³, Christopher Famulare⁴, Minal A Patel⁴, Pedro Mendez², Chrysanthi Ainali², Benjamin Demaree^5,6, Cyrille L Delley⁵, Adam R Abate^5,6,7, Manimozhi Manivannan², Sombeet Sahu², Aaron D Goldberg^4,8, Kelly L Bolton^4,8, Ahmet Zehir⁹, Raajit Rampal^4,8, Martin P Carroll¹⁰, Sara E Meyer¹¹, Aaron D Viny^1,4,8, Ross L Levine^12,13,14

1. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
2. Mission Bio, San Francisco, CA, USA.
3. Department of Mechanical Engineering, Colorado School of Mines, Golden, CO, USA.
4. Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
5. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.
6. UC-Berkeley-UCSF Graduate Program in Bioengineering, University of California, San Francisco, CA, USA.
7. Chan Zuckerberg Biohub, San Francisco, CA, USA.
8. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
9. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
10. Department of Medicine, Perelman Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
11. Department of Cancer Biology, Thomas Jefferson University, Sidney Kimmel Cancer Center, Philadelphia, PA, USA.
12. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. leviner@mskcc.org.
13. Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA. leviner@mskcc.org.
14. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. leviner@mskcc.org.

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.

Presented By Linde Miles