The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions

Abstract

We present the molecular landscape of pediatric acute myeloid leukemia (AML) and characterize nearly 1,000 participants in Children's Oncology Group (COG) AML trials. The COG–National Cancer Institute (NCI) TARGET AML initiative assessed cases by whole-genome, targeted DNA, mRNA and microRNA sequencing and CpG methylation profiling. Validated DNA variants corresponded to diverse, infrequent mutations, with fewer than 40 genes mutated in >2% of cases. In contrast, somatic structural variants, including new gene fusions and focal deletions of MBNL1, ZEB2 and ELF1, were disproportionately prevalent in young individuals as compared to adults. Conversely, mutations in DNMT3A and TP53, which were common in adults, were conspicuously absent from virtually all pediatric cases. New mutations in GATA2, FLT3 and CBL and recurrent mutations in MYC-ITD, NRAS, KRAS and WT1 were frequent in pediatric AML. Deletions, mutations and promoter DNA hypermethylation convergently impacted Wnt signaling, Polycomb repression, innate immune cell interactions and a cluster of zinc finger–encoding genes associated with KMT2A rearrangements. These results highlight the need for and facilitate the development of age-tailored targeted therapies for the treatment of pediatric AML.

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Figure 1: An overview of the TARGET AML study.
Figure 2: Age-related differences in mutational and structural alterations in AML.
Figure 3: Biological and prognostic interactions between alterations of WT1 and NPM1, FLT3-ITD and NUP98-NSD1 fusions.
Figure 4: Chromosomal alterations in pediatric and adult subjects with AML.
Figure 5: Aberrant DNA methylation in adult and pediatric AML.
Figure 6: miRNAs differentially regulate distinct molecular and age subgroups in AML.

Change history

  • 01 January 2018

    In the version of this article initially published online, Figure 1a has two black boxes in the key that are labeled as 'Unknown'; these boxes should be white, matching the segments in the donut charts shown below the key. The error has been corrected in the print, PDF and HTML versions of this article.

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Acknowledgements

Dedicated to the memory of our colleague, mentor and friend, Dr. Robert Arceci, whose vision and perseverance set this effort in motion: “I may not have gone where I intended to go, but I think I have ended up where I needed to be” (Douglas Adams, The Long Dark Tea-Time of the Soul). The results published here are based on data generated by the TARGET initiative and TCGA. The TARGET initiative is supported by NCI Grant U10CA98543. Work performed under contracts from the NCI, US National Institutes of Health within HHSN261200800001E includes specimen processing (Children's Oncology Group Biopathology Center), WGS (Complete Genomics), and RNA-seq and TCS (British Columbia Cancer Agency). The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government. Computation for the work described in this paper was supported in part by Fred Hutchinson Scientific Computing, University of Southern California's Center for High-Performance Computing and National Science Foundation (NSF) award ACI-1341935. This work was additionally supported by COG Chairs U10CA180886 and U10CA98543; COG Statistics and Data Center U10CA098413 and U10CA180899; COG Specimen Banking U24CA114766; R01CA114563 (S.M.); St. Baldrick's Foundation (J.E.F., T.T. and S.M.); Alex's Lemonade Stand (S.M.); Target Pediatric AML (TpAML), P20GM121293 (J.E.F.); the Arkansas Biosciences Institute (J.E.F.); and the Jane Anne Nohl Hematology Research Fund (T.T.).

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M.A.S., D.S.G., S.M. and R.A. conceived and led the project. R.E.R., M.A.M., J.M.G.A., T.M.D., P.G., L.C.H., D.S.G. and S.M. managed the project. H.B., J.E.F., T.T., R.E.R., E.L.L., T.A.A., Y.M., R.M., A.J.M., M.A.M., J.Z., X.M., Yu Liu, Yanling Liu, T.M.D., A.C.H., B.S. and S.R.P. generated, processed and analyzed the data. S.C., G.R., C.M.Z., S.N., E.A.K. and A.S.G. shared critical data and reagents. H.B., J.E.F., T.T., R.E.R., E.L.L. and S.M. drafted the manuscript. All authors edited and approved the manuscript.

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Correspondence to Hamid Bolouri or Soheil Meshinchi.

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The authors declare no competing financial interests.

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Bolouri, H., Farrar, J., Triche, T. et al. The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions. Nat Med 24, 103–112 (2018). https://doi.org/10.1038/nm.4439

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