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

Author:

Link Daniel C.1,Kunter Ghada1,Kasai Yumi2,Zhao Yu1,Miner Tracie2,McLellan Michael D.2,Ries Rhonda E.1,Kapur Deepak3,Nagarajan Rakesh4,Dale David C.3,Bolyard Audrey Anna3,Boxer Laurence A.5,Welte Karl6,Zeidler Cornelia6,Donadieu Jean7,Bellanné-Chantelot Christine8,Vardiman James W.910,Caligiuri Michael A.1110,Bloomfield Clara D.1110,DiPersio John F.1,Tomasson Michael H.1,Graubert Timothy A.1,Westervelt Peter1,Watson Mark4,Shannon William1,Baty Jack12,Mardis Elaine R.213,Wilson Richard K.213,Ley Timothy J.1

Affiliation:

1. Department of Medicine,

2. Genome Sequencing Center,

3. University of Washington, Seattle;

4. Department of Pathology and Immunology, Washington University, St Louis, MO;

5. Division of Pediatric Hematology/Oncology, Department of Pediatrics, C. S. Mott Children's Hospital, University of Michigan, Ann Arbor;

6. Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany;

7. Service d'Hémato Oncologie Pédiatrique, Hopital Trousseau, Paris, France;

8. Hôpital Saint-Antoine, Laboratoire de Cytogenetique, Paris, France;

9. University of Chicago, IL;

10. Ohio State University Comprehensive Cancer Center and James Cancer Hospital, Columbus, OH;

11. Cancer and Leukemia Group B, Chicago, IL;

12. Divisions ofBiostatistics and

13. Genetics, Washington University, St Louis, MO

Abstract

AbstractSevere 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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

Reference63 articles.

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