Thank you! Your submission has been received!
Oops! Something went wrong while submitting the form.

Single-cell mutation analysis of clonal evolution in myeloid malignancies.

Miles, L. A. et al.
Nature (2020)

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.


Miles, L. A., Bowman, R. L., Merlinsky, T. R., Csete, I. S., Ooi, A., Durruthy-Durruthy, R., Bowman, M., Famulare, C., Patel, M. A., Mendez, P., Ainali, C., Manivannan, M., Sahu, S., Goldberg, A. D., Bolton, K., ZEHIR, A., Rampal, R., Carroll, M. P., Meyer, S. E., Viny, A. D., Levine, R. L.


Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia
Wang, F.
BioRxiv (2020)
Personalized Single-Cell Proteogenomics to Distinguish Acute Myeloid Leukemia from Non-Malignant Clonal Hematopoiesis
Laura W. Dillon
MedRxiv (2020)
Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics.
Morita, K.
Nature Communications (2020)
High throughput single-cell detection of multiplex CRISPR-edited gene modifications.
Ten Hacken, E.
Genome Biology (2020)