Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: A unique pathway in myeloid leukemogenesis

Julia Skokowa, Doris Steinemann, Jenny E. Katsman-Kuipers, Cornelia Zeidler, Olga Klimenkova, Maksim Klimiankou, Murat Ünalan, Siarhei Kandabarau, Vahagn Makaryan, Renee Beekman, Kira Behrens, Carol Stocking, Julia Obenauer, Susanne Schnittger, Alexander Kohlmann, Marijke G. Valkhof, Remco Hoogenboezem, Gudrun Göhring, Dirk Reinhardt, Brigitte SchlegelbergerMartin Stanulla, Peter Vandenberghe, Jean Donadieu, C. Michel Zwaan, Ivo P. Touw, Marry M. Van Den Heuvel-Eibrink, David C. Dale, Karl Welte

Research output: Contribution to journalArticlepeer-review

124 Citations (Scopus)


Severe congenital neutropenia (CN) is a preleukemic bone marrow failure syndrome with a 20% risk of evolving into leukemia or myelodysplastic syndrome (MDS). Patterns of acquisition of leukemia-associated mutations were investigated using next-generation deep-sequencing in 31 CN patients who developed leukemia or MDS. Twenty (64.5%) of the 31 patients had mutations in RUNX1. A majority of patients with RUNX1 mutations (80.5%) also had acquired CSF3R mutations. In contrast to their high frequency in CN patients who developed leukemia or MDS, RUNX1 mutations were found in only 9 of 307 (2.9%) patients with de novo pediatric acute myeloid leukemia. A sequential analysis at stages prior to overt leukemia revealed RUNX1 mutations to be late events in leukemic transformation. Single-cell analyses in 2 patients showed that RUNX1 and CSF3R mutations were present in the same malignant clone. Functional studies demonstrated elevated granulocyte colony-stimulating factor (G-CSF)-induced proliferation with diminished myeloid differentiation of hematopoietic CD34 + cells coexpressing mutated forms of RUNX1 and CSF3R. The high frequency of cooperating RUNX1 and CSF3R mutations in CN patients suggests a novel molecular pathway of leukemogenesis: mutations in the hematopoietic cytokine receptor (G-CSFR) in combination with the second mutations in the downstream hematopoietic transcription fator (RUNX1). The detection of both RUNX1 and CSF3R mutations could be used as a marker for identifying CN patients with a high risk of progressing to leukemia or MDS.

Original languageEnglish
Pages (from-to)2229-2237
Number of pages9
Issue number14
Publication statusPublished - 3 Apr 2014
Externally publishedYes


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