Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia

Daniel C. Link, Ghada Kunter, Yumi Kasai, Yu Zhao, Tracie Miner, Michael D. McLellan, Rhonda E. Ries, Deepak Kapur, Rakesh Nagarajan, David C. Dale, Audrey Anna Bolyard, Laurence A. Boxer, Karl Welte, Cornelia Zeidler, Jean Donadieu, Christine Bellanné-Chantelot, James W. Vardiman, Michael A. Caligiuri, Clara D. Bloomfield, John F. DiPersioMichael H. Tomasson, Timothy A. Graubert, Peter Westervelt, Mark Watson, William Shannon, Jack Baty, Elaine R. Mardis, Richard K. Wilson, Timothy J. Ley

Research output: Contribution to journalArticlepeer-review

83 Scopus citations


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.

Original languageEnglish
Pages (from-to)1648-1655
Number of pages8
Issue number5
StatePublished - Sep 1 2007


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