title: Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia.
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.
authors.affiliation: Division of Oncology, Department of Medicine, Washington University, St Louis, MO 63110, USA. dlink@im.wustl.edu
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Link
authors.forename: Ghada
authors.initials: G
authors.lastname: Kunter
authors.forename: Yumi
authors.initials: Y
authors.lastname: Kasai
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.forename: Tracie
authors.initials: T
authors.lastname: Miner
authors.forename: Michael D
authors.initials: MD
authors.lastname: McLellan
authors.forename: Rhonda E
authors.initials: RE
authors.lastname: Ries
authors.forename: Deepak
authors.initials: D
authors.lastname: Kapur
authors.forename: Rakesh
authors.initials: R
authors.lastname: Nagarajan
authors.forename: David C
authors.initials: DC
authors.lastname: Dale
authors.forename: Audrey Anna
authors.initials: AA
authors.lastname: Bolyard
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Boxer
authors.forename: Karl
authors.initials: K
authors.lastname: Welte
authors.forename: Cornelia
authors.initials: C
authors.lastname: Zeidler
authors.forename: Jean
authors.initials: J
authors.lastname: Donadieu
authors.forename: Christine
authors.initials: C
authors.lastname: Bellanné-Chantelot
authors.forename: James W
authors.initials: JW
authors.lastname: Vardiman
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
authors.forename: John F
authors.initials: JF
authors.lastname: DiPersio
authors.forename: Michael H
authors.initials: MH
authors.lastname: Tomasson
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Graubert
authors.forename: Peter
authors.initials: P
authors.lastname: Westervelt
authors.forename: Mark
authors.initials: M
authors.lastname: Watson
authors.forename: William
authors.initials: W
authors.lastname: Shannon
authors.forename: Jack
authors.initials: J
authors.lastname: Baty
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Ley
mesh_terms: D000328:Adult; D004252:DNA Mutational Analysis; D004789:Enzyme Activation / Q000235:genetics; D044127:Epigenesis, Genetic; D030342:Genetic Diseases, Inborn / Q000150:complications / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics*; D009190:Myelodysplastic Syndromes / Q000209:etiology / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics*; D009503:Neutropenia / Q000150:complications / Q000151:congenital / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D016184:Receptors, Colony-Stimulating Factor / Q000235:genetics*
chemical_list: C517047:CSF3R protein, human; D009363:Neoplasm Proteins; D016184:Receptors, Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases