TY - JOUR
T1 - Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia
AU - Link, Daniel C.
AU - Kunter, Ghada
AU - Kasai, Yumi
AU - Zhao, Yu
AU - Miner, Tracie
AU - McLellan, Michael D.
AU - Ries, Rhonda E.
AU - Kapur, Deepak
AU - Nagarajan, Rakesh
AU - Dale, David C.
AU - Bolyard, Audrey Anna
AU - Boxer, Laurence A.
AU - Welte, Karl
AU - Zeidler, Cornelia
AU - Donadieu, Jean
AU - Bellanné-Chantelot, Christine
AU - Vardiman, James W.
AU - Caligiuri, Michael A.
AU - Bloomfield, Clara D.
AU - DiPersio, John F.
AU - Tomasson, Michael H.
AU - Graubert, Timothy A.
AU - Westervelt, Peter
AU - Watson, Mark
AU - Shannon, William
AU - Baty, Jack
AU - Mardis, Elaine R.
AU - Wilson, Richard K.
AU - Ley, Timothy J.
PY - 2007/9/1
Y1 - 2007/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=34548820699&partnerID=8YFLogxK
U2 - 10.1182/blood-2007-03-081216
DO - 10.1182/blood-2007-03-081216
M3 - Article
C2 - 17494858
AN - SCOPUS:34548820699
SN - 0006-4971
VL - 110
SP - 1648
EP - 1655
JO - Blood
JF - Blood
IS - 5
ER -