Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics

Kiyomi Morita,Jorge Cortes,Curtis Gumbs,Marina Konopleva,Katharina Jahn,Daisuke Nakada,Feng Wang,Tomoyuki Tanaka,Sanam Loghavi,P Andrew Futreal,Farhad Ravandi,Niko Beerenwinkel,Erika J Thompson ,Keyur P Patel,Jairo Matthews,Carlos E Bueso‐Ramos ,Hagop M Kantarjian ,Michael Andreeff,Nicholas Navin ,Courtney D Dinardo,Sa A Wang,Xingzhi Song,Kapil N Bhalla ,Guillermo Garcia‐Manero ,Yuanqing Yan,Latasha Little,Yuya Sasaki,Jack Kuipers,Elias Jabbour,Tianyuan Hu,Jianhua Zhang,Ken Furudate,Koichi Takahashi

doi:10.1038/s41467-020-19119-8

Kiyomi Morita, Jorge Cortes + Show 31 more

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https://doi.org/10.1038/s41467-020-19119-8

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Clonal diversity is a consequence of cancer cell evolution driven by Darwinian selection. Precise characterization of clonal architecture is essential to understand the evolutionary history of tumor development and its association with treatment resistance. Here, using a single-cell DNA sequencing, we report the clonal architecture and mutational histories of 123 acute myeloid leukemia (AML) patients. The single-cell data reveals cell-level mutation co-occurrence and enables reconstruction of mutational histories characterized by linear and branching patterns of clonal evolution, with the latter including convergent evolution. Through xenotransplantion, we show leukemia initiating capabilities of individual subclones evolving in parallel. Also, by simultaneous single-cell DNA and cell surface protein analysis, we illustrate both genetic and phenotypic evolution in AML. Lastly, single-cell analysis of longitudinal samples reveals underlying evolutionary process of therapeutic resistance. Together, these data unravel clonal diversity and evolution patterns of AML, and highlight their clinical relevance in the era of precision medicine.

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Clonal diversity is a consequence of cancer cell evolution driven by Darwinian selection
The amplicons covering guanine–cytosine (GC)-rich sequences, such as GATA2, SRSF2, and parts of RUNX1 and TP53, had lower coverage compared with other regions, such that relatively large numbers of cells had inconclusive genotype information for the mutations covered by these amplicons (Supplementary Fig. 2)
Cell-level mutation co-occurrence and mutual exclusivity data obtained from this study provide a validation for the clonal relationship among acute myeloid leukemia (AML) driver mutations previously inferred by bulk-sequencing studies, and revealed novel clonal relationships, such as between TP53 and PPM1D that was previously mischaracterized by the population-based analysis[14,15]

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Clonal diversity is a consequence of cancer cell evolution driven by Darwinian selection. Using a single-cell DNA sequencing, we report the clonal architecture and mutational histories of 123 acute myeloid leukemia (AML) patients. By simultaneous single-cell DNA and cell surface protein analysis, we illustrate both genetic and phenotypic evolution in AML. Single-cell analysis of longitudinal samples reveals underlying evolutionary process of therapeutic resistance. Together, these data unravel clonal diversity and evolution patterns of AML, and highlight their clinical relevance in the era of precision medicine. We previously described the performance and feasibility of a scDNA-seq platform (Tapestri®, Mission Bio, Inc.) in primary samples from two patients with acute myeloid leukemia (AML)[11]. We reconstructed the mutational history of driver genes and demonstrated linear as well as branching clonal evolution patterns in AML. ScDNA-seq of longitudinal samples in 15 patients allowed illustration of clonal evolution in response to therapeutic selective pressures

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