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Acute myeloid leukemia

Genetic mechanisms of primary chemotherapy resistance in pediatric acute myeloid leukemia

Leukemia volume 33, pages 1934–1943 (2019)Cite this article

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Abstract

Acute myeloid leukemias (AML) are characterized by mutations of tumor suppressor and oncogenes, involving distinct genes in adults and children. While certain mutations have been associated with the increased risk of AML relapse, the genomic landscape of primary chemotherapy-resistant AML is not well defined. As part of the TARGET initiative, we performed whole-genome DNA and transcriptome RNA and miRNA sequencing analysis of pediatric AML with failure of induction chemotherapy. We identified at least three genetic groups of patients with induction failure, including those with NUP98 rearrangements, somatic mutations of WT1 in the absence of apparent NUP98 mutations, and additional recurrent variants including those in KMT2C and MLLT10. Comparison of specimens before and after chemotherapy revealed distinct and invariant gene expression programs. While exhibiting overt therapy resistance, these leukemias nonetheless showed diverse forms of clonal evolution upon chemotherapy exposure. This included selection for mutant alleles of FRMD8, DHX32, PIK3R1, SHANK3, MKLN1, as well as persistence of WT1 and TP53 mutant clones, and elimination of FLT3, PTPN11, and NRAS mutant clones. These findings delineate genetic mechanisms of primary chemotherapy resistance in pediatric AML, which should inform improved approaches for its diagnosis and therapy.

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Acknowledgements

This paper is dedicated to the memory of Dr. Robert Arceci. This work was supported by the NCI U10 CA98543 (TARGET), U24 CA114766 (COG), U10 CA180886, U10 CA098413, U10 CA180899, P30 CA008748, R01 CA204396, by the Damon Runyon-Richard Lumsden Foundation Clinical Investigator and St. Baldrick’s Foundation Arceci Innovation Awards (to AK), and the Charles E. Trobman Scholarship (to NM). We thank T. Davidsen and P. Gesuwan for their support of the TARGET Data Coordinating Center and Alejandro Gutierrez, Gila Spitzer, and Maria Luisa Sulis for comments on the manuscript.

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  1. These authors contributed equally: Nicole A. McNeer, John Philip

Authors and Affiliations

  1. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Nicole A. McNeer, John Philip, Michael Walsh & Alex Kentsis

  2. New York Genome Center, New York, NY, USA

    Heather Geiger, Minita Shah, Kanika Arora, Anne-Katrin Emde & Nicolas Robine

  3. Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Rhonda E. Ries & Soheil Meshinchi

  4. Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Vincent-Philippe Lavallée

  5. Department of Biostatistics, University of Southern California, Los Angeles, CA, USA

    Todd A. Alonzo

  6. Nemours Center for Cancer and Blood Disorders, Nemours/Alfred Dupont Hospital for Children, Wilmington, DE, USA

    E. Anders Kolb

  7. University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA

    Alan S. Gamis

  8. National Cancer Institute, Rockville, MD, USA

    Malcolm Smith, Daniela Se Gerhard & Jaime Guidry-Auvil

  9. Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Alex Kentsis

  10. Department of Pediatrics, Pharmacology, and Physiology & Biophysics, Weill Medical College of Cornell University, New York, NY, USA

    Alex Kentsis

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Correspondence to Soheil Meshinchi or Alex Kentsis.

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AK is a consultant for Novartis. The other authors declare that they have no conflict of interest.

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McNeer, N.A., Philip, J., Geiger, H. et al. Genetic mechanisms of primary chemotherapy resistance in pediatric acute myeloid leukemia. Leukemia 33, 1934–1943 (2019). https://doi.org/10.1038/s41375-019-0402-3

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