Dissecting the clonal origins of childhood acute lymphoblastic leukemia by single-cell genomics
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- 25 November 2014
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 111 (50), 17947-17952
- https://doi.org/10.1073/pnas.1420822111
Abstract
Many cancers have substantial genomic heterogeneity within a given tumor, and to fully understand that diversity requires the ability to perform single cell analysis. We performed targeted sequencing of a panel of single nucleotide variants (SNVs), deletions, and IgH sequences in 1,479 single tumor cells from six acute lymphoblastic leukemia (ALL) patients. By accurately segregating groups of cooccurring mutations into distinct clonal populations, we identified codominant clones in the majority of patients. Evaluation of intraclonal mutation patterns identified clone-specific punctuated cytosine mutagenesis events, showed that most structural variants are acquired before SNVs, determined that KRAS mutations occur late in disease development but are not sufficient for clonal dominance, and identified clones within the same patient that are arrested at varied stages in B-cell development. Taken together, these data order the sequence of genetic events that underlie childhood ALL and provide a framework for understanding the development of the disease at single-cell resolution.Funding Information
- American Society of Hematology (ASH) (Scholar)
- Leukemia and Lymphoma Society (Special Fellow)
- Howard Hughes Medical Institute (Investigator)
- A*STAR, Agency of Science, Technology, and Research, Singapore (National Science Scholar)
- Spectrum Child Health Research Institute (Pilot Grant)
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