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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.
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Submitted March 21, 2007
Accepted April 23, 2007
Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia
Daniel C Link*, Ghada Kunter, Yumi Kasai, Yu Zhao, Tracie Miner, Michael D McLellan, Rhonda E Ries, Deepak Kapur, Rakesh Nagarajan, David C Dale, Audrey Anna Bolyard, Laurence A Boxer, Karl Welte, Cornelia Zeidler, Jean Donadieu, Christine Bellanne-Chantelot, James W Vardiman, Michael A Caligiuri, Clara D Bloomfield, John F DiPersio, Michael H Tomasson, Timothy A Graubert, Peter Westervelt, Mark Watson, William Shannon, Jack Baty, Elaine R Mardis, Richard K Wilson, and Timothy J Ley
Department of Medicine, Washington University, St. Louis, MO, United States
Genome Sequencing Center, Washington University, St. Louis, MO, United States
Department of Pathology and Immunology, Washington University, St. Louis, MO, United States
University of Washington, Seattle, WA, United States
Dept of Pediatrics, Div. of Pediatric Hematology/Oncology, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, MI, United States
Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany
Service d'Hemato Oncologie Pediatrique, Hopital Trousseau, Paris, France
Laboratoire de Cytogenetique, Hopital Saint-Antoine, Paris, France
University of Chicago, Chicago, IL, United States
The Cancer and Leukemia Group B, Chicago, IL, United States
Ohio State University Comprehensive Cancer Center and James Cancer Hospital, Columbus, OH, United States
Division of Biostatistics, Washington University, St. Louis, MO, United States
Dept of Genetics, Washington University, St. Louis, MO, United States
* Corresponding author; email: dlink{at}im.wustl.edu.
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 utilized high-throughput exon-based resequencing of whole-genome amplified genomic DNA with a semi-automated 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, CFS1R, 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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