title: An acquired G-CSF receptor mutation results in increased proliferation of CMML cells from a patient with severe congenital neutropenia.
abstract: Severe congenital neutropenia (CN) is characterized by a maturation arrest of myelopoiesis at the promyelocyte stage. Treatment with pharmacological doses of recombinant human granulocyte colony-stimulating factor (rh-G-CSF) stimulates neutrophil production and decreases the risk of major infectious complications. However, approximately 15% of CN patients develop myeloid malignancies that have been associated with somatic mutations in the G-CSF receptor (G-CSFR) and RAS genes as well as with acquired monosomy 7. We report a CN patient with chronic myelomonocytic leukemia (CMML) who never received rh-G-CSF. Molecular analysis demonstrated a somatic G-CSFR mutation (C2390T), which led to expression of a truncated G-CSFR protein in the CMML. Normal G-CSFR expression was unexpectedly absent in primary and cultured CMML. In addition, CMML cells showed monosomy 7 and an oncogenic NRAS mutation. In vitro culture revealed a G-CSF-dependent proliferation of CMML cells, which subsequently differentiated along the monocytic/macrophage lineage. Our results provide direct evidence for the in vivo expression of a truncated G-CSFR in leukemic cells, which emerged in the absence of rh-G-CSF treatment and transduces proliferative signals.
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Germany. Germeshausen.Manuela@mh-hannover.de
authors.forename: M
authors.initials: M
authors.lastname: Germeshausen
authors.forename: H
authors.initials: H
authors.lastname: Schulze
authors.forename: C
authors.initials: C
authors.lastname: Kratz
authors.forename: L
authors.initials: L
authors.lastname: Wilkens
authors.forename: R
authors.initials: R
authors.lastname: Repp
authors.forename: K
authors.initials: K
authors.lastname: Shannon
authors.forename: K
authors.initials: K
authors.lastname: Welte
authors.forename: M
authors.initials: M
authors.lastname: Ballmaier
mesh_terms: D000293:Adolescent; D002455:Cell Division; D011905:Genes, ras / Q000235:genetics; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics* / Q000473:pathology*; D008297:Male; D009503:Neutropenia / Q000151:congenital / Q000235:genetics* / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D012333:RNA, Messenger; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016179:Granulocyte Colony-Stimulating Factor