期刊
HEMATOPOIETIC STEM CELLS IX
卷 1370, 期 -, 页码 119-125出版社
BLACKWELL SCIENCE PUBL
DOI: 10.1111/nyas.13097
关键词
severe congenital neutropenia; CSF3R mutations; deep sequencing
资金
- Madeleine-Schickedanz Kinderkrebsstiftung
- Excellence Initiative of Tubingen University
- European Network of Rare Diseases (E-Rare)
- Federal Ministry of Education and Research (German Network on Congenital Bone Marrow Failure Syndromes)
- Niedersachsenprofessur for Molecular Hematopoiesis at the Medical School, Hannover, Germany
Acquired mutations in the intracellular part of CSF3R (colony stimulating factor 3 receptor, granulocyte) have been detected with a frequency of more than 30% in severe congenital neutropenia (CN) patients. CN is a preleukemic syndrome with a risk of approximately 20% to develop leukemia. More than 80% of CN patients who develop acute myeloid leukemia or myelodysplastic syndrome reveal CSF3R mutations, suggesting that they are involved in leukemogenesis. Using deep-sequencing technology, we were able to analyze large cohorts of CN patients for the entire CSF3R sequence as well as to identify cell clones carrying mutations in the intracellular part of CSF3R with very high sensitivity. Acquisition of CSF3R mutations is a CN-specific phenomenon and is associated with inherited mutations causing CN or cyclic neutropenia, such as ELANE mutations. In the group of CN patients negative for known germ-linemutations, biallelic CSF3R mutations were identified. In addition, CSF3R mutant clones are highly dynamic and may disappear and reappear during continuous granulocyte colony-stimulating factor (G-CSF) therapy. The time between the first detection of CSF3R mutations and overt leukemia is highly variable.
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