Genetic mechanisms of primary chemotherapy resistance in pediatric acute myeloid leukemia

Leukemia. Volume 33, Issue 8: p.1934-1943, 13 February 2019

10.1038/s41375-019-0402-3

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.

In order to access Controlled TARGET AML data using the links below, users must submit an application for Authorized Access via dbGaP as described on dbGaP’s TARGET Study Page. To begin the application process, please view the information and instructions provided on the dbGaP Authorized Access Login Page under “dbGaP Data Download”.

Supplemental Data

• GDC Manifests
  • Controlled-Access Data Download Manifest (8 Files)
  • Open-Access Data Download Manifest (25 Files)
  • WGS CGI Files Download Manifest (209 Files)
• Copy Number Array
  • TARGET AML Copy Number Array Level 1 Data (Controlled)
  • TARGET AML Copy Number Array Level 2 Data (Controlled)
  • TARGET AML Copy Number Array Level 3 Data
  • TARGET AML Copy Number Array Data Metadata
• Gene Expression Array
  • TARGET AML Gene Expression Array Level 1 Data
  • TARGET AML Gene Expression Array Level 2 Data
  • TARGET AML Gene Expression Array Level 3 Data
  • TARGET AML Gene Expression Array Metadata
• mRNA-Seq
  • TARGET AML RNA-Seq Level 3 Data
  • TARGET AML RNA-Seq Level 3 Data (Controlled)
  • TARGET AML RNA-Seq Metadata
• miRNA-Seq
  • TARGET AML miRNA-Seq Level 3 Data
  • TARGET AML miRNA-Seq Level 4 Data
  • TARGET AML miRNA-Seq Metadata
• WXS
  • TARGET AML WXS Level 3 Data
  • TARGET AML WXS Level 3 Data (Controlled)
  • TARGET AML WXS Design
  • TARGET AML WXS Metadata
• Methylation Array
  • TARGET AML Methylation Array Level 1 Data (Controlled)
  • TARGET AML Methylation Array Level 2 Data
  • TARGET AML Methylation Array Level 3 Data
  • TARGET AML Methylation Array Level 4 Data
  • TARGET AML Methylation Array Metadata
• WGS
  • TARGET AML WGS Level 3 Data
  • TARGET AML WGS Level 3 Data (Controlled)
  • TARGET AML WGS Level 4 Data
  • TARGET AML WGS Metadata
• Targeted Capture Sequencing
  • TARGET AML Targeted Capture Sequencing Level 3 Data (Controlled)
  • TARGET AML Targeted Capture Sequencing Design
  • TARGET AML Targeted Capture Sequencing Metadata
• Miscellaneous Files
  • TARGET AML Sample Matrices
  • TARGET AML CGI Requested Reports (Controlled)

Additional Resources

• SRA - SRP012000 (link is external) NCBI

Instructions for Data Download

Open Access Data

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   • GDC DTT (Download, User's Guide)
   • GDC API (User’s Guide)

Controlled Access Data

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2. Download a token from the GDC Data Portal
   • GDC Data Portal (Launch, User’s Guide)
3. Use the manifest file and token to download data using the GDC DTT or the GDC API
   • GDC DTT (Download, User’s Guide)
   • GDC API (User’s Guide)

For assistance, please contact the GDC Help Desk: support@nci-gdc.datacommons.io.