title: Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis.
abstract: 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.
authors: Department of Molecular Hematopoiesis, Hannover Medical School, Hannover, Germany;
authors: Julia
authors: J
authors: Skokowa
authors: Doris
authors: D
authors: Steinemann
authors: Jenny E
authors: JE
authors: Katsman-Kuipers
authors: Cornelia
authors: C
authors: Zeidler
authors: Olga
authors: O
authors: Klimenkova
authors: Maksim
authors: M
authors: Klimiankou
authors: Murat
authors: M
authors: Unalan
authors: Siarhei
authors: S
authors: Kandabarau
authors: Vahagn
authors: V
authors: Makaryan
authors: Renee
authors: R
authors: Beekman
authors: Kira
authors: K
authors: Behrens
authors: Carol
authors: C
authors: Stocking
authors: Julia
authors: J
authors: Obenauer
authors: Susanne
authors: S
authors: Schnittger
authors: Alexander
authors: A
authors: Kohlmann
authors: Marijke G
authors: MG
authors: Valkhof
authors: Remco
authors: R
authors: Hoogenboezem
authors: Gudrun
authors: G
authors: Göhring
authors: Dirk
authors: D
authors: Reinhardt
authors: Brigitte
authors: B
authors: Schlegelberger
authors: Martin
authors: M
authors: Stanulla
authors: Peter
authors: P
authors: Vandenberghe
authors: Jean
authors: J
authors: Donadieu
authors: C Michel
authors: CM
authors: Zwaan
authors: Ivo P
authors: IP
authors: Touw
authors: Marry M
authors: MM
authors: van den Heuvel-Eibrink
authors: David C
authors: DC
authors: Dale
authors: Karl
authors: K
authors: Welte
mesh_terms: D000293:Adolescent; D000328:Adult; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D000080984:Congenital Bone Marrow Failure Syndromes; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D020732:Cytogenetic Analysis; D005260:Female; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics*; D008297:Male; D009154:Mutation; D009503:Neutropenia / Q000151:congenital* / Q000235:genetics / Q000473:pathology; D016184:Receptors, Colony-Stimulating Factor / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D055815:Young Adult
chemical_list: C517047:CSF3R protein, human; D050676:Core Binding Factor Alpha 2 Subunit; C493728:RUNX1 protein, human; D016184:Receptors, Colony-Stimulating Factor