title: A truncation mutant of Csf3r cooperates with PML-RARα to induce acute myeloid leukemia in mice.
abstract: Severe congenital neutropenia is associated with a marked propensity to develop myelodysplasia or acute myeloid leukemia (AML). Truncation mutations of CSF3R, encoding the granulocyte colony-stimulating factor receptor (G-CSFR), are associated with development of myelodysplasia/AML in severe congenital neutropenia. However, a causal relationship between CSF3R mutations and leukemic transformation has not been established. Herein, we show that truncated G-CSFR cooperates with the PML-RARα oncogene to induce AML in mice. Expression of truncated G-CSFR significantly shortens the latency of AML in a G-CSF-dependent fashion and it is associated with a distinct AML presentation characterized by higher blast counts and more severe myelosuppression. Basal and G-CSF-induced signal transducer and activator of transcription 3, signal transducer and activator of transcription 5, and extracellular signal-regulated kinase 1/2 phosphorylation were highly variable but similar in leukemic blasts expressing wild-type and truncated G-CSFR. These data provide new evidence suggesting a causative role for CSF3R mutations in human AML.
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Mo., USA.
authors.forename: Ghada
authors.initials: G
authors.lastname: Kunter
authors.forename: Jill R
authors.initials: JR
authors.lastname: Woloszynek
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Link
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D018389:Codon, Nonsense; D003433:Crosses, Genetic; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D055879:Gene Knock-In Techniques; D005838:Genotype; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D010641:Phenotype; D011092:Polyethylene Glycols / Q000494:pharmacology / Q000633:toxicity; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D050791:STAT Transcription Factors / Q000502:physiology
chemical_list: D018389:Codon, Nonsense; D015514:Oncogene Proteins, Fusion; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D050791:STAT Transcription Factors; C486981:pegylated granulocyte colony-stimulating factor, human; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D016179:Granulocyte Colony-Stimulating Factor; D011092:Polyethylene Glycols; D048049:Extracellular Signal-Regulated MAP Kinases