Disease relevance of CSF3R

• Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis: results of a long-term survey [1].
• Polymerase chain reaction analysis of the 31 phage clones established that 29 were derived from class I hGCSFR mRNA, one was derived from class III mRNA, and one was derived from class IV mRNA [2].
• In bone marrow CD34 cells of patients with myelodysplastic syndrome and monosomy 7, GCSF receptor (GCSFR) protein was increased [3].
• In this communication acute myelogenous leukemia (AML) associated with a mutation of the G-CSF receptor (G-CSF-R) developed in a patient with SCN maintained on long-term G-CSF therapy [4].
• Mutations in the granulocyte colony-stimulating factor receptor (G-CSF-R) gene leading to a truncated protein have been identified in a cohort of neutropenia patients highly predisposed to acute myeloid leukemia [5].

High impact information on CSF3R

• Here we describe the identification of a novel point mutation in the extracellular domain of the G-CSF receptor (G-CSF-R) in an SCN patient who failed to respond to G-CSF treatment [6].
• When this mutant G-CSF-R was expressed in myeloid cells, it was defective in both proliferation and survival signaling [6].
• GCSFR signal transduction via the Jak/Stat system was abnormal in monosomy 7 CD34 cells, with increased phosphorylated signal transducer and activation of transcription protein, STAT1-P, and increased STAT5-P relative to STAT3-P [3].
• Introduction of the fatty mutation into a OB-R/G-CSF-R chimera generates a receptor with constitutive character that is similar but distinct from that of OB-R(fa) [7].
• We detected CSF3R nonsense mutations at 17 different nucleotide positions (thereof 10 new mutations) which lead to a loss of 1 to all 4 tyrosine residues in the intracellular domain of the receptor [1].

Biological context of CSF3R

• Point mutations in the gene for the granulocyte colony-stimulating factor (G-CSF) receptor CSF3R have been implicated in the progression of severe congenital neutropenia (CN) to leukemia [1].
• Localization of the CSF3R on chromosome 1 was further confirmed by the spot-blot hybridization of sorted human chromosomes [8].
• Assignment of the human granulocyte colony-stimulating factor receptor gene (CSF3R) to chromosome 1 at region p35-p34.3 [8].
• In contrast, maximal Stat3 tyrosine phosphorylation required amino acids 96 to 183 of the G-CSF-R cytoplasmic domain, Stat3 DNA binding could occur with a receptor truncated 96 amino acids from the transmembrane domain and containing a single tyrosine residue, but was reduced in comparison with the full-length receptor [9].
• The abnormal response of monosomy 7 cells to GCSF would be explained by the expansion of undifferentiated monosomy 7 clones expressing the class IV GCSFR, which is defective in signaling cell maturation [3].

Anatomical context of CSF3R

• While information exists about the distribution of these isoforms in hematopoietic cells and placenta, G-CSF-R isoforms on non-hematopoietic fetal tissues have not been described [10].
• These findings indicate that Y764 of G-CSF-R is crucial for maintaining the proliferation/differentiation balance during G-CSF-driven neutrophil development and suggest a role for multiple signaling mechanisms in maintaining this balance [11].
• Both chimeric receptors and the full-length GCSFR in expressed in M1 myeloid leukemic cells to measure differentiation induction, in embryonic stem cells to measure differentiation inhibition, and in Ba/F3 cells to measure cell proliferation [12].
• A defined region of the cytoplasmic domain of the granulocyte colony-stimulating factor receptor (G-CSF-R) transmits signals for maturation or differentiation of myeloid progenitor cells [13].
• It acts by binding to specific cell-surface receptors (G-CSF-R), which are expressed on cells of granulocytic lineage, human endothelial cells, and placenta [14].

Associations of CSF3R with chemical compounds

• When all four intracellular tyrosines of the GCSF-R were replaced with phenylalanine (FFFF GCSF-R), cell proliferation and survival were compromised [15].

Physical interactions of CSF3R

• Our cell-level model suggests that ligand depletion may be reduced in vitro by decreasing the endosomal affinity of endocytosed GCSF/GCSFR complexes, matching experimental findings [16].

Regulatory relationships of CSF3R

• Granulocyte colony-stimulating factor (G-CSF) downregulates its receptor (CD114) on neutrophils and induces gelatinase B release in humans [17].
• In addition, we investigated the expression of p53 and granulocyte colony-stimulating factor receptor (GCSF-R) to examine the prognostic significance of them in the same samples [18].

Other interactions of CSF3R

• Together these data add to our understanding of the mechanisms of cytokine receptor signaling, emphasize the role of GCSFR mutations in the etiology of SCN, and implicate such mutations in G-CSF hyporesponsiveness [6].
• Polymerase chain reaction using oligonucleotides specific for the human CSF3R produced a specifically amplified DNA fragment with DNA from mouse A9 cells that contained human chromosome 1 but not other human chromosomes [8].
• Thus, distinct cytoplasmic domains within the LIFRalpha, gp130, and GCSF-R transduce proliferative and differentiation suppressing signals [19].
• Our results suggest that direct binding of Shc by the GCSF-R is not essential for JNK activation [15].
• A proportion of LCAM expressed GCSF receptor on the cell surface, but IL-6 receptor could not be detected [20].

Analytical, diagnostic and therapeutic context of CSF3R

• The gene for the granulocyte colony-stimulating factor (G-CSF) receptor (CSF3R) was localized on the p35-p34.3 region of human chromosome 1 by in situ hybridization using human G-CSF receptor cDNA as the probe [8].
• In addition, the hGCSFR gene was chromosomally localized by Southern blot analysis of its segregation pattern in a panel of rodent-human hybrid DNAs using the radiolabeled cDNA probe [2].
• The blast count in the blood and bone marrow fell to undetectable levels twice on withholding G-CSF and without chemotherapy administration, but the mutant G-CSF-R was detectable during this period [4].
• To determine if mutations of the G-CSF-R are more widespread in hematological malignancies, we have investigated a total of 47 patients, including 29 patients with blast crisis of chronic myeloid leukemia (CML-BC) and 18 patients with de novo acute leukemia as well as 19 normal controls, by RT-PCR and SSCP analysis [13].
• G-CSF-R protein, and specific intracellular signaling proteins (Janus tyrosine kinase-1, Janus tyrosine kinase-2, and tyrosine kinase-2), were sought by immunohistochemistry [21].

References