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CSF3R mutations have a high degree of overlap with CEBPA mutations in pediatric AML

Blood. Volume 127, Issue 24 p.3094-3098, 3 May 2016 10.1182/blood-2016-04-709899

Childhood cancers represent distinct clinical entities, often with unique genomic alterations and therapeutic responses that differ from cancers arising in adults. Our limited understanding of the genetic alterations in pediatric AML has hindered development of targeted therapeutic strategies. Given that AML is primarily an adult disease, until recently, our understanding of pediatric AML had been informed by data generated in adults. Yet, some newly discovered mutations in adult AML are rare or entirely lacking in pediatric AML, thus validating critical differences in the pathogenesis. The Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative (, a collaboration between the Children’s Oncology Group (COG) and the National Institutes of Health National Cancer Institute, has addressed this issue by large-scale genomic analysis of pediatric AML. For the first time, “pediatric-specific” genomic lesions are being defined that may alter the therapeutic options in childhood AML.

Through the TARGET initiative, comprehensive genomic analysis was performed on 186 cases of pediatric AML, 95 with matched relapse and all with matched remission samples in the discovery phase. Samples were marrow or peripheral blood. The analysis included whole genome (WGS) and exome sequencing from which a custom capture panel of ∼200 genes of interest was generated. A total of 787 samples were then deep sequenced using this custom capture panel, including samples from the discovery cohort. Through these efforts, we have identified oncogenic colony-stimulating factor 3 receptor (CSF3R) mutations in pediatric AML. This study identifies a distinct molecular subtype of pediatric AML defined by CSF3R mutations. The CSF3R mutations found in pediatric AML are either the same point mutations or similar truncation mutations that are observed in adult CNL, suggesting that other cooperating mutations contribute to the distinct pathobiology of these 2 diseases. The majority of patients with CSF3R mutations have either a mutation in CEBPA or CBF translocations. Strikingly, CEPBA mutations are approximately eightfold more frequent in patients with transforming CSF3R mutations than in those patients without transforming CSF3R mutations.

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