Role of CSF3R mutations in the pathomechanism of congenital neutropenia and secondary acute myeloid leukemia.
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-line mutations, 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.
Department of Hematology, Oncology, Immunology, Rheumatology and Pulmonology, University Hospital Tübingen, Tübingen, Germany.
Maksim
M
Klimiankou
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
Sabine
S
Mellor-Heineke
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
Cornelia
C
Zeidler
Department of Pediatric Hematology and Oncology, University Children's Hospital, Tübingen, Germany.
Karl
K
Welte
Department of Hematology, Oncology, Immunology, Rheumatology and Pulmonology, University Hospital Tübingen, Tübingen, Germany.
Julia
J
Skokowa
D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009503:Neutropenia / Q000150:complications / Q000151:congenital* / Q000235:genetics* / Q000378:metabolism; D016184:Receptors, Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism
C517047:CSF3R protein, human; D016184:Receptors, Colony-Stimulating Factor
CSF3R mutations; deep sequencing; severe congenital neutropenia