Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia.
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.
Link
Daniel C
DC
Division of Oncology, Department of Medicine, Washington University, St Louis, MO 63110, USA. dlink@im.wustl.edu
Kunter
Ghada
G
Kasai
Yumi
Y
Zhao
Yu
Y
Miner
Tracie
T
McLellan
Michael D
MD
Ries
Rhonda E
RE
Kapur
Deepak
D
Nagarajan
Rakesh
R
Dale
David C
DC
Bolyard
Audrey Anna
AA
Boxer
Laurence A
LA
Welte
Karl
K
Zeidler
Cornelia
C
Donadieu
Jean
J
Bellanné-Chantelot
Christine
C
Vardiman
James W
JW
Caligiuri
Michael A
MA
Bloomfield
Clara D
CD
DiPersio
John F
JF
Tomasson
Michael H
MH
Graubert
Timothy A
TA
Westervelt
Peter
P
Watson
Mark
M
Shannon
William
W
Baty
Jack
J
Mardis
Elaine R
ER
Wilson
Richard K
RK
Ley
Timothy J
TJ
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*
C517047:CSF3R protein, human; D009363:Neoplasm Proteins; D016184:Receptors, Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases