Clonal Evolution of Acute Myeloid Leukemia Revealed by High-throughput Single-cell Genomics

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Oct 22

PMID 33087716

Citations 175

Authors

Kiyomi Morita

Feng Wang

Katharina Jahn

Tianyuan Hu

Tomoyuki Tanaka

Yuya Sasaki

Jack Kuipers

Sanam Loghavi

Sa A Wang

Yuanqing Yan

Ken Furudate

Jairo Matthews

Latasha Little

Curtis Gumbs

Jianhua Zhang

Xingzhi Song

Erika Thompson

Keyur P Patel

Carlos E Bueso-Ramos

Courtney D DiNardo

Farhad Ravandi

Elias Jabbour

Michael Andreeff

Jorge Cortes

Kapil Bhalla

Guillermo Garcia-Manero

Hagop Kantarjian

Marina Konopleva

Daisuke Nakada

Nicholas Navin

Niko Beerenwinkel

P Andrew Futreal

Koichi Takahashi

Affiliations

Soon will be listed here.

Abstract

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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Single-cell DNA sequencing reveals pervasive positive selection throughout preleukemic evolution.

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References

Nam A, Kim K, Chaligne R, Izzo F, Ang C, Taylor J . Somatic mutations and cell identity linked by Genotyping of Transcriptomes. Nature. 2019; 571(7765):355-360. PMC: 6782071. DOI: 10.1038/s41586-019-1367-0. View

McGranahan N, Swanton C . Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future. Cell. 2017; 168(4):613-628. DOI: 10.1016/j.cell.2017.01.018. View

Welch J, Ley T, Link D, Miller C, Larson D, Koboldt D . The origin and evolution of mutations in acute myeloid leukemia. Cell. 2012; 150(2):264-78. PMC: 3407563. DOI: 10.1016/j.cell.2012.06.023. View

Lindsley R, Saber W, Mar B, Redd R, Wang T, Haagenson M . Prognostic Mutations in Myelodysplastic Syndrome after Stem-Cell Transplantation. N Engl J Med. 2017; 376(6):536-547. PMC: 5438571. DOI: 10.1056/NEJMoa1611604. View

Gerlinger M, Rowan A, Horswell S, Math M, Larkin J, Endesfelder D . Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012; 366(10):883-892. PMC: 4878653. DOI: 10.1056/NEJMoa1113205. View

Ho P, Zeng R, Alonzo T, Gerbing R, Miller K, Pollard J . Prevalence and prognostic implications of WT1 mutations in pediatric acute myeloid leukemia (AML): a report from the Children's Oncology Group. Blood. 2010; 116(5):702-10. PMC: 2918327. DOI: 10.1182/blood-2010-02-268953. View

Kanda Y . Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant. 2012; 48(3):452-8. PMC: 3590441. DOI: 10.1038/bmt.2012.244. View

Eirew P, Steif A, Khattra J, Ha G, Yap D, Farahani H . Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution. Nature. 2014; 518(7539):422-6. PMC: 4864027. DOI: 10.1038/nature13952. View

Wang Y, Navin N . Advances and applications of single-cell sequencing technologies. Mol Cell. 2015; 58(4):598-609. PMC: 4441954. DOI: 10.1016/j.molcel.2015.05.005. View

10.

Zafar H, Wang Y, Nakhleh L, Navin N, Chen K . Monovar: single-nucleotide variant detection in single cells. Nat Methods. 2016; 13(6):505-7. PMC: 4887298. DOI: 10.1038/nmeth.3835. View

11.

Nik-Zainal S, Van Loo P, Wedge D, Alexandrov L, Greenman C, Lau K . The life history of 21 breast cancers. Cell. 2012; 149(5):994-1007. PMC: 3428864. DOI: 10.1016/j.cell.2012.04.023. View

12.

Chou W, Lei W, Ko B, Hou H, Chen C, Tang J . The prognostic impact and stability of Isocitrate dehydrogenase 2 mutation in adult patients with acute myeloid leukemia. Leukemia. 2010; 25(2):246-53. DOI: 10.1038/leu.2010.267. View

13.

Campbell P, Yachida S, Mudie L, Stephens P, Pleasance E, Stebbings L . The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature. 2010; 467(7319):1109-13. PMC: 3137369. DOI: 10.1038/nature09460. View

14.

McMahon C, Ferng T, Canaani J, Wang E, Morrissette J, Eastburn D . Clonal Selection with RAS Pathway Activation Mediates Secondary Clinical Resistance to Selective FLT3 Inhibition in Acute Myeloid Leukemia. Cancer Discov. 2019; 9(8):1050-1063. DOI: 10.1158/2159-8290.CD-18-1453. View

15.

Klco J, Spencer D, Miller C, Griffith M, Lamprecht T, OLaughlin M . Functional heterogeneity of genetically defined subclones in acute myeloid leukemia. Cancer Cell. 2014; 25(3):379-92. PMC: 3983786. DOI: 10.1016/j.ccr.2014.01.031. View

16.

Van Loo P, Nordgard S, Lingjaerde O, Russnes H, Rye I, Sun W . Allele-specific copy number analysis of tumors. Proc Natl Acad Sci U S A. 2010; 107(39):16910-5. PMC: 2947907. DOI: 10.1073/pnas.1009843107. View

17.

Anderson K, Lutz C, van Delft F, Bateman C, Guo Y, Colman S . Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature. 2010; 469(7330):356-61. DOI: 10.1038/nature09650. View

18.

Potter N, Miraki-Moud F, Ermini L, Titley I, Vijayaraghavan G, Papaemmanuil E . Single cell analysis of clonal architecture in acute myeloid leukaemia. Leukemia. 2018; 33(5):1113-1123. PMC: 6451634. DOI: 10.1038/s41375-018-0319-2. View

19.

Yang L, Rau R, Goodell M . DNMT3A in haematological malignancies. Nat Rev Cancer. 2015; 15(3):152-65. PMC: 5814392. DOI: 10.1038/nrc3895. View

20.

Pellegrino M, Sciambi A, Treusch S, Durruthy-Durruthy R, Gokhale K, Jacob J . High-throughput single-cell DNA sequencing of acute myeloid leukemia tumors with droplet microfluidics. Genome Res. 2018; 28(9):1345-1352. PMC: 6120635. DOI: 10.1101/gr.232272.117. View