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The transcriptomic landscape and directed chemical interrogation of MLL-rearranged acute myeloid leukemias

Nature Genetics volume 47, pages 10301037 (2015) | Download Citation

Abstract

Using next-generation sequencing of primary acute myeloid leukemia (AML) specimens, we identified to our knowledge the first unifying genetic network common to the two subgroups of KMT2A (MLL)-rearranged leukemia, namely having MLL fusions or partial tandem duplications. Within this network, we experimentally confirmed upregulation of the gene with the most subtype-specific increase in expression, LOC100289656, and identified cryptic MLL fusions, including a new MLL-ENAH fusion. We also identified a subset of MLL fusion specimens carrying mutations in SPI1 accompanied by inactivation of its transcriptional network, as well as frequent RAS pathway mutations, which sensitized the leukemias to synthetic lethal interactions between MEK and receptor tyrosine kinase inhibitors. This transcriptomics-based characterization and chemical interrogation of human MLL-rearranged AML was a valuable approach for identifying complementary features that define this disease.

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Acknowledgements

We thank M. Draoui for project coordination, S. Corneau for sample coordination and I. Boivin for data validation as well as M. Arteau and R. Lambert at the IRIC genomics platform for RNA sequencing. We acknowledge the dedicated work of the Quebec Leukemia Cell Bank (BCLQ) staff, namely G. d'Angelo for morphological diagnoses, C. Rondeau and S. Lavallée; M. Marquis for qRT-PCR validations, and H. Chaker for FISH analyses on AML samples. We thank J. Duchaine and D. Salois at the IRIC high-throughput screening platform. This work was mostly supported by Genome Canada and Génome Québec with supplementary funds from Amorchem and the Canadian Cancer Society Research Institute (CCSRI). Contribution was provided by Ministères de l'Economie, de l'Innovation et des Exportations du Québec and the Leukemia Lymphoma Society of Canada. G.S. and J.H. are recipients of research chairs from Industrielle-Alliance (Université de Montréal) and the Canada Research Chair program, respectively. BCLQ is supported by grants from the Cancer Research Network of the Fonds de Recherche du Québec–Santé. RNA sequencing read mapping and transcript quantification were performed on the supercomputer Briaree from Université de Montréal, managed by Calcul Québec and Compute Canada. The operation of this supercomputer is funded by the Canada Foundation for Innovation (CFI), NanoQuébec, RMGA and Fonds de Recherche du Québec–Nature et Technologies (FRQ-NT). V.P.L. is supported by a postdoctoral fellowship jointly supported by the Hôpital Maisonneuve-Rosemont Foundation and the Cole Foundation. I.B. is supported by a postdoctoral fellowship from the Human Frontier Science Program.

Author information

Affiliations

  1. The Leucegene Project at the Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.

    • Vincent-Philippe Lavallée
    • , Irène Baccelli
    • , Jana Krosl
    • , Brian Wilhelm
    • , Frédéric Barabé
    • , Patrick Gendron
    • , Geneviève Boucher
    • , Sébastien Lemieux
    • , Anne Marinier
    • , Josée Hébert
    •  & Guy Sauvageau
  2. Division of Hematology, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.

    • Vincent-Philippe Lavallée
    • , Josée Hébert
    •  & Guy Sauvageau
  3. Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.

    • Brian Wilhelm
    • , Josée Hébert
    •  & Guy Sauvageau
  4. Centre Hospitalier Universitaire de Québec, Centre de Recherche du Centre Hospitalier de l'Université Laval and Hôpital de l'Enfant-Jésus, Quebec City, Quebec, Canada.

    • Frédéric Barabé
  5. Department of Medicine, Université Laval, Quebec City, Quebec, Canada.

    • Frédéric Barabé
  6. Department of Computer Science and Operations Research, Université de Montréal, Montreal, Quebec, Canada.

    • Sébastien Lemieux
  7. Department of Chemistry, Université de Montréal, Montreal, Quebec, Canada.

    • Anne Marinier
  8. Department of Pharmacology, Université de Montréal, Montreal, Quebec, Canada.

    • Sylvain Meloche
  9. Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.

    • Sylvain Meloche
  10. Quebec Leukemia Cell Bank, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.

    • Josée Hébert
    •  & Guy Sauvageau

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Contributions

V.-P.L. analyzed the exomes and transcriptomes of all samples, generated the corresponding figures, tables and supplementary material, and co-wrote the manuscript. I.B. carried out and analyzed the chemical screens of the study, generated the corresponding figures and tables, and co-wrote the manuscript. G.S. contributed to project conception and coordination and co-wrote the manuscript. J.H. contributed to project conception, analyzed the cytogenetic, FISH and qRT-PCR studies, provided all the AML samples and edited the manuscript. J.K. carried out the combinatorial chemical screen. P.G. processed the raw next-generation sequencing data. G.B. co-developed the analytical pipeline. S.L. was responsible for supervision of the bioinformatics team and of statistical analyses. B.W. and F.B. generated the mouse MLL-AF9 model. A.M. is responsible for the chemistry team as part of the Leucegene project. S.M. contributed to the selection of compounds for the chemical screens and to data analysis.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Josée Hébert or Guy Sauvageau.

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DOI

https://doi.org/10.1038/ng.3371

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