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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. This Article Full Text Full Text (PDF) Supplemental Table and Figure All Versions of this Article: blood-2007-03-081216v1 110/5/1648    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Link, D. C. Articles by Ley, T. J. Search for Related Content PubMed PubMed Citation Articles by Link, D. C. Articles by Ley, T. J. Related Collections Hematopoiesis and Stem Cells Neoplasia Phagocytes Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia Daniel C. Link1, Ghada Kunter1, Yumi Kasai2, Yu Zhao1, Tracie Miner2, Michael D. McLellan2, Rhonda E. Ries1, Deepak Kapur4, Rakesh Nagarajan3, David C. Dale4, Audrey Anna Bolyard4, Laurence A. Boxer5, Karl Welte6, Cornelia Zeidler6, Jean Donadieu7, Christine Bellanné-Chantelot8, James W. Vardiman9,11, Michael A. Caligiuri10,11, Clara D. Bloomfield10,11, John F. DiPersio1, Michael H. Tomasson1, Timothy A. Graubert1, Peter Westervelt1, Mark Watson3, William Shannon1, Jack Baty12, Elaine R. Mardis2,13, Richard K. Wilson2,13, and Timothy J. Ley1 1 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Germeshausen, C. P. Kratz, M. Ballmaier, and K. Welte RAS and CSF3R mutations in severe congenital neutropenia Blood, October 15, 2009; 114(16): 3504 - 3505. [Full Text] [PDF] E. R. Mardis, L. Ding, D. J. Dooling, D. E. Larson, M. D. McLellan, K. Chen, D. C. Koboldt, R. S. Fulton, K. D. Delehaunty, S. D. McGrath, et al. Recurring Mutations Found by Sequencing an Acute Myeloid Leukemia Genome N. Engl. J. Med., September 10, 2009; 361(11): 1058 - 1066. [Abstract] [Full Text] [PDF] M. J. Walter, J. E. Payton, R. E. Ries, W. D. Shannon, H. Deshmukh, Y. Zhao, J. Baty, S. Heath, P. Westervelt, M. A. Watson, et al. Acquired copy number alterations in adult acute myeloid leukemia genomes PNAS, August 4, 2009; 106(31): 12950 - 12955. [Abstract] [Full Text] [PDF] Z. Xiang, Y. Zhao, V. Mitaksov, D. H. Fremont, Y. Kasai, A. Molitoris, R. E. Ries, T. L. Miner, M. D. McLellan, J. F. DiPersio, et al. Identification of somatic JAK1 mutations in patients with acute myeloid leukemia Blood, May 1, 2008; 111(9): 4809 - 4812. [Abstract] [Full Text] [PDF] M. H. Tomasson, Z. Xiang, R. Walgren, Y. Zhao, Y. Kasai, T. Miner, R. E. Ries, O. Lubman, D. H. Fremont, M. D. McLellan, et al. Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia Blood, May 1, 2008; 111(9): 4797 - 4808. [Abstract] [Full Text] [PDF]

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