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 RampalMartin P. Carroll, Sara E. Meyer, Aaron D. Viny, Ross L. Levine

Research output: Contribution to journalArticlepeer-review

238 Scopus citations


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.

Original languageEnglish
Pages (from-to)477-482
Number of pages6
Issue number7834
StatePublished - Nov 19 2020


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