Sustained receptor activation and hyperproliferation in response to granulocyte colony-stimulating factor (G-CSF) in mice with a severe congenital neutropenia/acute myeloid leukemia-derived mutation in the G-CSF receptor gene
journal contributionposted on 1999-02-15, 00:00 authored by M H Hermans, C Antonissen, Alister WardAlister Ward, A E Mayen, R E Ploemacher, I P Touw
In approximately 20% of cases of severe congenital neutropenia (SCN), mutations are found in the gene encoding the granulocyte colony-stimulating factor receptor (G-CSF-R). These mutations introduce premature stop codons, which result in truncation of 82-98 COOH-terminal amino acids of the receptor. SCN patients who develop secondary myelodysplastic syndrome and acute myeloid leukemia almost invariably acquired a GCSFR mutation, suggesting that this genetic alteration represents a key step in leukemogenesis. Here we show that an equivalent mutation targeted in mice (gcsfr-∆715) results in the selective expansion of the G-CSF- responsive progenitor (G-CFC) compartment in the bone marrow. In addition, in vivo treatment of gcsfr-∆715 mice with G-CSF results in increased production of neutrophils leading to a sustained neutrophilia. This hyperproliferative response to G-CSF is accompanied by prolonged activation of signal transducer and activator of transcription (STAT) complexes and extended cell surface expression of mutant receptors due to defective internalization. In view of the continuous G-CSF treatment of SCN patients, these data provide insight into why progenitor cells expressing truncated receptors clonally expand in vivo, and why these cells may be targets for additional genetic events leading to leukemia.
JournalJournal of Experimental Medicine
Pagination683 - 692
PublisherRockefeller University Press
LocationNew York, N.Y.
Link to full text
Publication classificationC1.1 Refereed article in a scholarly journal
Copyright notice1999, Rockefeller University Press
Acute DiseaseAnimalsBone MarrowCell DifferentiationCell DivisionCell Transformation, NeoplasticColony-Forming Units AssayDNA-Binding ProteinsEndocytosisGranulocyte Colony-Stimulating FactorHematopoietic Stem CellsHumansImmunologic Deficiency SyndromesKineticsLeukemia, MyeloidLymphocyte ActivationMiceMice, TransgenicMilk ProteinsNeutropeniaReceptors, Granulocyte Colony-Stimulating FactorSTAT1 Transcription FactorSTAT5 Transcription FactorSequence DeletionSpecific Pathogen-Free OrganismsTrans-Activatorssevere congenital neutropeniagranulocyte colony-stimulating factor receptormutationsacute myeloid leukemiaScience & TechnologyLife Sciences & BiomedicineImmunologyMedicine, Research & ExperimentalResearch & Experimental Medicinegranulocyte colony-stimulating factor receptor mutationsHEMATOPOIETIC STEM-CELLSINDUCED-DIFFERENTIATIONTYROSINE KINASEBONE-MARROWSTAT3GROWTHPROLIFERATIONREGIONSSRCPHOSPHORYLATION