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Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is a cancer of the white blood cells, the cells in the body that normally fight infections. It is the most common cancer in children. Over the last several decades, advances in the treatment and supportive care of pediatric ALL have dramatically increased its 5-year survival rates to almost 90%. Despite these improvements, a considerable number of children with ALL continue to relapse following standardized treatment. Accurately diagnosing those patients who are high-risk (HR) for relapse and treating them upfront with more targeted therapies can greatly enhance their outcomes.

Pilot Phase (Phase I) – TARGET ALL Project

The TARGET ALL pilot project (Phase I) focused on the most common type of the disease: precursor B-cell ALL. The project team used an integrated genome-wide approach to analyze tumors from HR precursor B-cell ALL patients enrolled in clinical trial 9906 of the Pediatric Oncology Group (POG), now the Children's Oncology Group (COG). The POG 9906 clinical trial was composed of a selected group of children diagnosed with ALL predicted to have a high risk for relapse. Clinically annotated tumor and normal tissues from the same patient were obtained for this study.

Genome-wide analysis

  • Gene expression (Affymetrix U133 +2.0 platform)
  • Copy number analyses, paired tumor & normal (Affymetrix SNP 500K arrays)
  • Targeted Sequencing (Sanger)
    • 125 selected genes
    • Kinome sequencing
  • 2nd and 3rd Generation Sequencing
    • Whole Genome Sequencing
    • Transcriptome Sequencing

The types of data on 230 clinically annotated patient cases

  • 189 fully characterized (gene expression, copy number analysis, and sequencing)
  • 41 partially characterized

The Phase I ALL project has published a number of significant biological and clinical findings to date (see Publications list below). The complete dataset is currently available to the research community through the TARGET Data Matrix.

Expansion Phase (Phase II) – TARGET ALL Project

The success of the ALL pilot project served as a catalyst for the expansion of the TARGET initiative into its current structure. Additional funding, largely through the American Recovery and Reinvestment Act (ARRA) of 2009, has allowed for investigation of additional pediatric cancers, as well as further studies within HR ALL. In the current phase (Phase II) of this project, the TARGET ALL project team is characterizing a separate group of childhood B-precursor ALL cases, focusing on those with early relapse of the disease (within 48 months from diagnosis) in order to identify genomic changes associated with treatment failure and novel therapeutic targets for these patients. Matched tumor and normal tissues from patients enrolled on COG clinical trial AALL03B1 are being analyzed, along with a relapse sample when available, to produce a highly informative dataset.

Genome-wide analysis of matched tumor and normal samples (relapse sample when available)

  • Gene expression (Affymetrix U133 +2.0 platform)
  • Copy number analyses and loss of heterozygosity (Affymetrix SNP 6.0 arrays)
  • DNA Methylation (HpaII tiny fragment-Enrichment by Ligation-mediated PCR (HELP) methylation assay)
  • 2nd and 3rd Generation Sequencing
    • Whole Genome Sequencing
    • Whole Exome Sequencing

Data generated for this project will be made available to the research community through the TARGET Data Matrix rapidly upon completion of validation.

Investigators

The TARGET ALL project team consists of COG investigators at various institutions who work together 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, Center for Cancer Research and Center for Bioinformatics and Information Technology). This collaborative network is led by the following:

Principal Investigator – University of Colorado Cancer Center

  • Stephen P. Hunger

Lead Scientific Investigators

  • Mignon Loh, MD. – University of California San Francisco Benioff Children's Hospital
  • Charles G. Mullighan, MD., MSc. – St. Jude Children's Research Hospital
  • Cheryl Willman, MD. – University of New Mexico Cancer Center

Project Publications

Below is a list of all publications resulting from the high-risk ALL TARGET pilot phase project.

  • Roberts, K., Morin, R., Zhang, J., Hirst, M., Zhao, Y.,  Su, X., Chen, S.,  Payne-Turner, D., Churchman, M., Harvey, R., Chen, X., et al. (2012) Genetic Alterations Activating Kinase and Cytokine Receptor Signaling in High-Risk Acute Lymphoblastic Leukemia. Cancer Cell 22(2):153-66 (PMID: 22897847) View PubMed abstract.
  • Zhang J., Mullighan C.G., Harvey R.C., Wu G., Chen X., Edmonson M., Buetow K.H., Carroll W.L., Chen I.M., Devidas M., Gerhard D.S. et al. (2011) Key pathways are frequently mutated in high risk childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood 118(11): 3080-7 (PMID: 21680795). View PubMed abstract.
  • Harvey, R.C., Mullighan, C.G., Wang, X., Dobbin, K.K., Davidson, G.S., Bedrick, E.J., Chen, I.M., Atlas, S.R., Kang, H., Ar, K., et al. (2010) Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome. Blood 116(23):4874-4884 (PMID: 20699438). View PubMed abstract.
  • Harvey, R.C., Mullighan, C.G., Chen, I.M., Wharton, W., Mikhail, F.M., Carroll, A.J., Kang, H., Liu, W., Dobbin, K.K., Smith, M.A., et al. (2010) Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia. Blood 115(26): 5312-5321 (PMID: 20139093). View PubMed abstract.
  • Kang, H., Chen, I.M., Wilson, C.S., Bedrick, E.J., Harvey, R.C., Atlas, S.R., Devidas, M., Mullighan, C.G., Wang, X., Murphy, M., et al. (2010) Gene expression classifiers for relapse-free survival and minimal residual disease improve risk classification and outcome prediction in pediatric B-precursor acute lymphoblastic leukemia. Blood 115(7): 1394-1405 (PMID: 19880498). View PubMed abstract.
  • Mullighan, C.G., Zhang, J., Harvey, R.C., Collins-Underwood, J.R., Schulman, B.A., Phillips, L.A., Tasian, S.K., Loh, M.L., Su, X., Liu, W., et al. (2009) JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci USA 106(23):9414-9418 (PMID: 19470474). View PubMed abstract.
  • Mullighan, C.G., Su, X., Zhang, J., Radtke, I., Phillips, L.A., Miller, C.B., Ma, J., Liu, W., Cheng, C., Schulman, B.A., et al. (2009) Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med 360(5):470-480 (PMID: 19129520). View PubMed abstract.