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Vast population genetic diversity underlies the treatment dynamics of ETV6-RUNX1 acute lymphoblastic leukemia

Veronica Gonzalez-Pena, Matthew MacKay, View ORCID ProfileIwijn De Vlaminck, John Easton, View ORCID ProfileCharles Gawad
doi: https://doi.org/10.1101/117614
Veronica Gonzalez-Pena
1Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
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Matthew MacKay
2Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, 14850, USA
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Iwijn De Vlaminck
2Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, 14850, USA
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John Easton
3Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
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Charles Gawad
1Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
3Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
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  • ORCID record for Charles Gawad
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Abstract

Ensemble-averaged genome profiling of diagnostic samples suggests that acute leukemias harbor few somatic genetic alterations. We used single-cell exome and error-corrected sequencing to survey the genetic diversity underlying ETV6-RUNX1 acute lymphoblastic leukemia (ALL) at high resolution. The survey uncovered a vast range of low-frequency genetic variants that were undetected in conventional bulk assays, including additional clone-specific “driver” RAS mutations. Single-cell exome sequencing revealed APOBEC mutagenesis to be important in disease initiation but not in progression and identified many more mutations per cell than previously found. Using this data, we created a branching model of ETV6-RUNX1 ALL development that recapitulates the genetic features of patients. Exposure of leukemic populations to chemotherapy selected for specific clones in a dose-dependent manner. Together, these data have important implications for understanding the development and treatment response of childhood leukemia, and they provide a framework for using population genetics to deeply interrogate cancer clonal evolution.

One-Sentence Summary APOBEC and replication-associated mutagenesis contribute to the development of ETV6-RUNX1 ALL, creating massive leukemic population genetic diversity that results in clonal differences in susceptibilities to chemotherapy.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted March 16, 2017.
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Vast population genetic diversity underlies the treatment dynamics of ETV6-RUNX1 acute lymphoblastic leukemia
Veronica Gonzalez-Pena, Matthew MacKay, Iwijn De Vlaminck, John Easton, Charles Gawad
bioRxiv 117614; doi: https://doi.org/10.1101/117614
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Vast population genetic diversity underlies the treatment dynamics of ETV6-RUNX1 acute lymphoblastic leukemia
Veronica Gonzalez-Pena, Matthew MacKay, Iwijn De Vlaminck, John Easton, Charles Gawad
bioRxiv 117614; doi: https://doi.org/10.1101/117614

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