Acute Myeloid Leukemia

TARGET investigators are analyzing tumors from pediatric patients, many who have relapsed, to identify biomarkers that correlate with poor clinical outcome and/or new therapeutic approaches to treat childhood AML. The tissues used in this study were collected from patients enrolled in Children's Oncology Group (COG) biology studies and clinical trials.

The AML project team members (like other TARGET researchers) are generating data in two phases: Discovery and Validation. Visit the TARGET Research page to learn more.

Discovery Dataset

The TARGET AML project has produced comprehensive genomic profiles of nearly 200 relapse-enriched, clinically annotated patient cases in the discovery dataset. This cohort includes ~100 patients with adequate relapse specimens to study as trios (see three sample types below). Each fully-characterized TARGET AML case includes data from nucleic acid samples extracted from peripheral blood or bone marrow tissues as follows:

• Primary tumor sample collected at diagnosis
• Case-matched tissue sample collected at remission (<5% blasts detected following standard induction therapy)
• Relapsed tumor sample (case-matched) when available; ~50% cases have 3^rd sample (those cases are considered a “trio”)

Additional cases with partial molecular characterization and/or sequencing data are available to the research community.

Case Selection Criteria

Tissues and clinical data used for the TARGET AML project were obtained from patients enrolled on biology studies and clinical trials managed through the Children’s Oncology Group (COG). Patient samples with full characterization were chosen based on the following criteria:

• Patients achieved a remission following a standard two rounds of induction therapy (fewer than 5% blasts)
• Bone marrow and peripheral blood blast counts of >50% in tumor specimens
• Adequate amount of high-quality nucleic acids for comprehensive genomic profiling
• 3 or fewer clinically-relevant cytogenetic findings (majority of cases)

Molecular Characterization

The TARGET AML project team relied on a variety of platforms to obtain a fully characterized dataset of ~200 relapse-enriched cases. The COG AML Statistics and Data Center provided clinical annotations and outcome data for all cases. Visit the TARGET Project Experimental Methods page for detailed information and protocols.

Verification of Discovery Variants

The TARGET AML project team utilized a variety of sequencing approaches to confirm candidate variants identified in the discovery sample cohort as somatic. For example, mRNA-seq results are being used to determine variants which were expressed and originally identified through whole genome or exome sequencing. These verified variants will be made available as open-access data. The TARGET AML project team has additionally employed the same targeted capture sequencing approach described in the validation strategy below to verify variants seen in a variety of tumor, remission and/or relapse samples from a majority of fully-characterized patient cases in the TARGET AML discovery cohort.

Validation Strategy

Some sequence mutations identified in the relapse-enriched discovery cohort, along with some previously published variants in adult AML, were further analyzed in an additional 600-plus cases. The TARGET AML project team employed targeted capture sequencing to look at the presence and frequency of alterations in 400 gene variants. This validation effort was performed in an unbiased cohort that was randomly selected from patients enrolled on a single COG protocol, which allowed for determination of the frequency of these changes across a broader spectrum of AML subtypes.

All data from the discovery and validation efforts are made available as specified in the Using TARGET Data and TARGET Publication Guidelines pages. The TARGET Data Matrix provides an overview of the data generated and described above.

TARGET includes comprehensive genomic characterization of some highly aggressive subtypes of pediatric cancers, including acute myeloid leukemia “induction failures” (AML-IF). Upon diagnosis, AML patients without high-risk genetic markers undergo standard chemotherapy regimen, called the primary induction phase to eliminate most cancer cells and induce a remission state. Successful treatment reduces the percentage of myeloblasts (immature white blood cells) detected in the patient following primary induction chemotherapy to less than 15%. Patients with greater than 15% myeloblasts did not sufficiently respond to standard therapy and are “induction failures.” Currently, these patients have few clinical options for further treatment.

Discovery Dataset

The TARGET AML-IF subproject has produced comprehensive genomic profiles of 30 clinically annotated patient cases. Each fully-characterized TARGET AML-IF case consists of data generated from nucleic acid samples extracted from case-matched tumor and normal tissues as follows:

• Primary tumor sample collected at diagnosis
• Control fibroblast sample grown from the patient’s bone marrow (case-matched)
• Tumor obtained at the end of induction phase of treatment (2 rounds)

Case Selection Criteria

Tissues and clinical data used for the TARGET AML-IF project were obtained from patients enrolled on biology studies and clinical trials managed through the Children’s Oncology Group (COG). Patient samples with full characterization were chosen based on the following criteria:

• Patients failed to achieve remission following a standard two rounds of induction therapy (>15% blasts)
• Adequate amount of high-quality nucleic acids for comprehensive genomic profiling

Molecular Characterization

The TARGET AML project team relied on a variety of platforms to obtain a fully characterized dataset of 30 AML-IF cases. The COG AML Statistics and Data Center provided clinical annotations and outcome data for all cases. Visit the TARGET Project Experimental Methods page for detailed information and protocols.

Verification of Discovery Variants

The TARGET AML project team utilized a variety of sequencing approaches to confirm candidate variants identified in the discovery sample cohort as somatic. For example, mRNA-seq results are being used to determine variants which were expressed and originally identified through whole genome sequencing. These verified variants will be made available as open-access data.

The following AML-IF cases were part of the validation cohort using “TARGET-20-” prefixes and were also included in the AML discovery cohort using ‘TARGET-21’ prefixes:

All data generated through the AML-IF subproject are made available as specified in the Using TARGET Data and TARGET Publication Guidelines pages. The TARGET Data Matrix provides an overview of the data generated and described above.

The TARGET AML project team consists of multiple COG investigators at various institutions. The AML team works with the scientists, analysts, project managers and technicians from the COG (Biorepository, Data and Statistics Core) and NCI offices (Office of Cancer Genomics, Clinical Therapy Evaluation Program, and Center for Bioinformatics and Information Technology). This collaborative network is led by:

Principal Investigators

• Soheil Meshinchi, M.D., Ph.D.
  • Fred Hutchinson Cancer Research Center
• Robert Arceci, M.D., Ph.D. (2009 - 2015)
  • Phoenix Children's Hospital

• Brunner AM, Graubert TA. (2018) Genomics in childhood acute myeloid leukemia comes of age. Nature Medicine 24(1):7-9. (PMID: 29315296) View PubMed abstract
• Bolouri H, Farrar JE, Triche T Jr, et al. (2018) The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions. Nature Medicine 24(1):103-112. (PMID: 29227476) View PubMed abstract  View GDC Publication Page
• Lim EL, Trinh DL, Ries RE, et al. (2017) MicroRNA Expression-Based Model Indicates Event-Free Survival in Pediatric Acute Myeloid Leukemia. Journal of Clinical Oncology 35(35):3964-3977. (PMID: 29068783) View PubMed abstract
• Maxson JE, Ries RE, Wang YC, et al. (2016) CSF3R mutations have a high degree of overlap with CEBPA mutations in pediatric AML. Blood 127(24):3094-8. (PMID: 27143256) View PubMed abstract
• Farrar JE, Schuback HL, Ries RE, et al. (2016) Genomic Profiling of Pediatric Acute Myeloid Leukemia Reveals a Changing Mutational Landscape from Disease Diagnosis to Relapse. Cancer Research 76(8):2197-205. (PMID: 26941285) View PubMed abstract