Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia
Year: 2007
Type: article
Study design: Observational Study
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.
Source: Blood
Authors: 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. DiPersio, Michael H. Tomasson, Timothy A. Graubert, Peter Westervelt, Mark Watson, William Shannon, Jack Baty, Elaine R. Mardis, Richard K. Wilson, Timothy J. Ley
Institutions: University of Washington, Washington University in St. Louis, University of Michigan, C. S. Mott Children's Hospital, Medizinische Hochschule Hannover, Hôpital Armand-Trousseau, Hôpital Saint-Antoine, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Wexner Medical Center, University of Chicago, The Ohio State University
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2043277447