title: Alternatively spliced, truncated GCSF receptor promotes leukemogenic properties and sensitivity to JAK inhibition.
abstract: Granulocyte colony-stimulating factor (GCSF) drives the production of myeloid progenitor and precursor cells toward neutrophils via the GCSF receptor (GCSFR, gene name CSF3R). Children with severe congenital neutropenia chronically receive pharmacologic doses of GCSF, and ∼30% will develop myelodysplasia/acute myeloid leukemia (AML) associated with GCSFR truncation mutations. In addition to mutations, multiple isoforms of CSF3R have also been reported. We found elevated expression of the alternatively spliced isoform, class IV CSF3R in adult myelodysplastic syndrome/AML patients. Aside from its association with monosomy 7 and higher rates of relapse in pediatric AML patients, little is known about the biology of the class IV isoform. We found developmental regulation of CSF3R isoforms with the class IV expression more representative of a progenitor cell stage. Striking differences were found in phosphoprotein signaling involving Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and cell cycle gene expression. Enhanced proliferation by class IV GCSFR was associated with diminished STAT3 and STAT5 activation, yet showed sensitivity to JAK2 inhibitors. Alterations in the C-terminal domain of the GCSFR result in leukemic properties of enhanced growth, impaired differentiation and resistance to apoptosis, suggesting that they can behave as oncogenic drivers, sensitive to JAK2 inhibition.
authors.affiliation: Department of Pediatrics (Hematology-Oncology) and Cell and Molecular Biology, Lurie Children's Hospital of Chicago, Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: H M
authors.initials: HM
authors.lastname: Mehta
authors.affiliation: 1] Department of Pediatrics (Hematology-Oncology) and Cell and Molecular Biology, Lurie Children's Hospital of Chicago, Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA [2] Division of Molecular Therapy, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Futami
authors.affiliation: Department of Pediatrics (Hematology-Oncology) and Cell and Molecular Biology, Lurie Children's Hospital of Chicago, Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: T
authors.initials: T
authors.lastname: Glaubach
authors.affiliation: Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
authors.forename: D W
authors.initials: DW
authors.lastname: Lee
authors.affiliation: 1] Department of Pediatrics (Hematology-Oncology) and Cell and Molecular Biology, Lurie Children's Hospital of Chicago, Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA [2] Department of Pediatrics (Hematology-Oncology), University of Rochester School of Medicine, Rochester, NY, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Andolina
authors.affiliation: Department of Pediatrics (Hematology-Oncology) and Cell and Molecular Biology, Lurie Children's Hospital of Chicago, Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Pediatrics (Hematology-Oncology) and Cell and Molecular Biology, Lurie Children's Hospital of Chicago, Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Whichard
authors.affiliation: Department of Pediatrics (Hematology-Oncology) and Cell and Molecular Biology, Lurie Children's Hospital of Chicago, Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: M
authors.initials: M
authors.lastname: Quinn
authors.affiliation: Department of Pediatrics (Hematology-Oncology) and Cell and Molecular Biology, Lurie Children's Hospital of Chicago, Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: H F
authors.initials: HF
authors.lastname: Lu
authors.affiliation: Cleveland Clinic, Taussig Cancer Institute, Translational Hematology and Oncology Research, Cleveland, OH, USA.
authors.forename: W M
authors.initials: WM
authors.lastname: Kao
authors.affiliation: Cleveland Clinic, Taussig Cancer Institute, Translational Hematology and Oncology Research, Cleveland, OH, USA.
authors.forename: B
authors.initials: B
authors.lastname: Przychodzen
authors.affiliation: Department of Biomedical Engineering, University of Minnesota, MN, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Sarkar
authors.affiliation: Department of Medicine, Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: A
authors.identifier: 0000000166933362
authors.initials: A
authors.lastname: Minella
authors.affiliation: Cleveland Clinic, Taussig Cancer Institute, Translational Hematology and Oncology Research, Cleveland, OH, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Maciejewski
authors.affiliation: Department of Pediatrics (Hematology-Oncology) and Cell and Molecular Biology, Lurie Children's Hospital of Chicago, Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Corey
mesh_terms: D000328:Adult; D017398:Alternative Splicing; D000818:Animals; D002460:Cell Line; D002648:Child; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016188:Receptors, Granulocyte Colony-Stimulating Factor; D053612:Janus Kinases