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Blood, 1 September 2007, Vol. 110, No. 5, pp. 1648-1655. Prepublished online as a Blood First Edition Paper on May 9, 2007; DOI 10.1182/blood-2007-03-081216.
NEOPLASIA Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia1 Department of Medicine, 2 Genome Sequencing Center, 3 Department of Pathology and Immunology, Washington University, St Louis, MO; 4 University of Washington, Seattle; 5 Division of Pediatric Hematology/Oncology, Department of Pediatrics, C. S. Mott Children's Hospital, University of Michigan, Ann Arbor; 6 Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany; 7 Service d'Hémato Oncologie Pédiatrique, Hopital Trousseau, Paris, France; 8 Hôpital Saint-Antoine, Laboratoire de Cytogenetique, Paris, France; 9 University of Chicago, IL; 10 Cancer and Leukemia Group B, Chicago, IL; 11 Ohio State University Comprehensive Cancer Center and James Cancer Hospital, Columbus, OH; Divisions of12 Biostatistics and 13 Genetics, Washington University, St Louis, MO Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis. Like most other bone marrow failure syndromes, it is associated with a marked propensity to transform into a myelodysplastic syndrome (MDS) or acute leukemia, with a cumulative rate of transformation to MDS/leukemia that exceeds 20%. The genetic (and/or epigenetic) changes that contribute to malignant transformation in SCN are largely unknown. In this study, we performed mutational profiling of 14 genes previously implicated in leukemogenesis using 14 MDS/leukemia samples from patients with SCN. We used high-throughput exon-based resequencing of whole-genome–amplified genomic DNA with a semiautomated method to detect mutations. The sensitivity and specificity of the sequencing pipeline was validated by determining the frequency of mutations in these 14 genes using 188 de novo AML samples. As expected, mutations of tyrosine kinase genes (FLT3, KIT, and JAK2) were common in de novo AML, with a cumulative frequency of 30%. In contrast, no mutations in these genes were detected in the SCN samples; instead, mutations of CSF3R, encoding the G-CSF receptor, were common. These data support the hypothesis that mutations of CSF3R may provide the "activated tyrosine kinase signal" that is thought to be important for leukemogenesis.
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