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Molecular targets for therapy

Patient-derived xenotransplants can recapitulate the genetic driver landscape of acute leukemias

Leukemia volume 31, pages 151–158 (2017)Cite this article

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Abstract

Genomic studies have identified recurrent somatic mutations in acute leukemias. However, current murine models do not sufficiently encompass the genomic complexity of human leukemias. To develop preclinical models, we transplanted 160 samples from patients with acute leukemia (acute myeloid leukemia, mixed lineage leukemia, B-cell acute lymphoblastic leukemia, T-cell ALL) into immunodeficient mice. Of these, 119 engrafted with expected immunophenotype. Targeted sequencing of 374 genes and 265 frequently rearranged RNAs detected recurrent and novel genetic lesions in 48 paired primary tumor (PT) and patient-derived xenotransplant (PDX) samples. Overall, the frequencies of 274 somatic variant alleles correlated between PT and PDX samples, although the data were highly variable for variant alleles present at 0–10%. Seventeen percent of variant alleles were detected in either PT or PDX samples only. Based on variant allele frequency changes, 24 PT-PDX pairs were classified as concordant while the other 24 pairs showed various degree of clonal discordance. There was no correlation of clonal concordance with clinical parameters of diseases. Significantly more bone marrow samples than peripheral blood samples engrafted discordantly. These data demonstrate the utility of developing PDX banks for modeling human leukemia, and emphasize the importance of genomic profiling of PDX and patient samples to ensure concordance before performing mechanistic or therapeutic studies.

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Acknowledgements

We thank Chun-Wei (David) Chen, Omar Abdel-Wahab and Alex Kentsis for critical discussion of the manuscript, Barb Every for editor help. Research funding was provided by the Kleberg Foundation and R01 CA176745/CA/NCI NIH.

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Author notes

  1. K Wang

    Present address: 4Current address: Department of Pathology & Cancer Research Institute, Zhejiang Cancer Hospital, Hangzhou 310022, China.,

  2. X Wang

    Present address: 6Current address: Cornell University, 1300 York Ave, New York, NY 10065, USA.,

  3. K Wang, M Sanchez-Martin and X Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Foundation Medicine, Cambridge, MA, USA

    K Wang, M K Nahas, J He, M Hadler, A L Donahue, G M Frampton, D Lipson, S Roels, P J Stephens, E M Sanford, T Brennan, G A Otto, R Yelensky & V A Miller

  2. Institute for Cancer Genetics Columbia University, New York, NY, USA

    M Sanchez-Martin & A Ferrando

  3. Center for Epigenetic Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    X Wang, K M Knapp, R Koche, L Vu, E M Stein, M S Tallman, M G Kharas, R L Levine, S A Armstrong & A V Krivtsov

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  1. K Wang
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Correspondence to A V Krivtsov.

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Competing interests

KW, MKN, JH, ALD, GMF, DL, SR, PJS, EMS, TB, GAO, RY, VAM are employees and equity holders, RLL is a consultant for Foundation Medicine, Inc.

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Wang, K., Sanchez-Martin, M., Wang, X. et al. Patient-derived xenotransplants can recapitulate the genetic driver landscape of acute leukemias. Leukemia 31, 151–158 (2017). https://doi.org/10.1038/leu.2016.166

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