Journal article
Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia
Blood, Vol.110(5), pp.1648-1655
Neoplasia
09/01/2007
DOI: 10.1182/blood-2007-03-081216
PMCID: PMC1975847
PMID: 17494858
Abstract
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.
Details
- Title: Subtitle
- Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia
- Creators
- Daniel C Link - Department of MedicineGhada Kunter - Department of MedicineYumi Kasai - Genome Sequencing CenterYu Zhao - Department of MedicineTracie Miner - Genome Sequencing CenterMichael D McLellan - Genome Sequencing CenterRhonda E Ries - Department of MedicineDeepak Kapur - University of Washington, SeattleRakesh Nagarajan - Department of Pathology and Immunology, Washington University, St Louis, MODavid C Dale - University of Washington, SeattleAudrey Anna Bolyard - University of Washington, SeattleLaurence A Boxer - Division of Pediatric Hematology/Oncology, Department of Pediatrics, C. S. Mott Children's Hospital, University of Michigan, Ann ArborKarl Welte - Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, GermanyCornelia Zeidler - Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, GermanyJean Donadieu - Service d'Hémato Oncologie Pédiatrique, Hopital Trousseau, Paris, FranceChristine Bellanné-Chantelot - Hôpital Saint-Antoine, Laboratoire de Cytogenetique, Paris, FranceJames W Vardiman - University of Chicago, ILMichael A Caligiuri - Cancer and Leukemia Group B, Chicago, ILClara D Bloomfield - Cancer and Leukemia Group B, Chicago, ILJohn F DiPersio - Department of MedicineMichael H Tomasson - Department of MedicineTimothy A Graubert - Department of MedicinePeter Westervelt - Department of MedicineMark Watson - Department of Pathology and Immunology, Washington University, St Louis, MOWilliam Shannon - Department of MedicineJack Baty - Divisions ofElaine R Mardis - Genome Sequencing CenterRichard K Wilson - Genome Sequencing CenterTimothy J Ley - Department of Medicine
- Resource Type
- Journal article
- Publication Details
- Blood, Vol.110(5), pp.1648-1655
- Publisher
- American Society of Hematology
- Series
- Neoplasia
- DOI
- 10.1182/blood-2007-03-081216
- PMID
- 17494858
- PMCID
- PMC1975847
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Language
- English
- Date published
- 09/01/2007
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984094386102771
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