Granulocyte Colony-Stimulating Factor Receptor Mutations in Myeloid Malignancy

Abstract

Granulocyte colony-stimulating factor is a cytokine able to stimulate both myelopoiesis and hematopoietic stem cell mobilization, which has seen it used extensively in the clinic to aid hematopoietic recovery. It acts specifically via the homodimeric granulocyte colony-stimulating factor receptor (G-CSFR), which is principally expressed on the surface of myeloid and hematopoietic progenitor cells. A number of pathogenic mutations have now been identified in CSF3R, the gene encoding G-CSFR. These fall into distinct classes, each of which is associated with a particular spectrum of myeloid disorders, including malignancy. This review details the various CSF3R mutations, their mechanisms of action, and contribution to disease, as well as discussing the clinical implications of such mutations.

Granulocyte colony-stimulating factor receptor signaling in severe congenital neutropenia, chronic neutrophilic leukemia, and related malignancies

“…This class of mutations in the CSF3R gene affects the extracellular domain of the G-CSFR and are commonly associated with SCN and chronic idiopathic neutropenic (CIN) patient groups (figure 2 B) (30, 31). These mutants also act in a dominant negative manner to deteriorate co-expressed wild-type receptors leading to a degenerate state of neutrophil production (30).…”

“…These mutants also act in a dominant negative manner to deteriorate co-expressed wild-type receptors leading to a degenerate state of neutrophil production (30). An extracellular mutant P229H was the first reported extracellular CSF3R mutation (30, 31). It changes the conserved di-proline hinge motif on the receptor thus disrupting the ligand binding cytokine receptor homology (CRH) domain and overall architecture of the ligand/receptor complex (31).…”

“…An extracellular mutant P229H was the first reported extracellular CSF3R mutation (30, 31). It changes the conserved di-proline hinge motif on the receptor thus disrupting the ligand binding cytokine receptor homology (CRH) domain and overall architecture of the ligand/receptor complex (31). The change in the receptor architecture limits G-CSF binding and dimerization which leads to an abnormal G-CSF mediated downstream signaling of G-CSFR.…”

Pangolin genomes and the evolution of mammalian scales and immunity

“…4A). CSF3R proteins are present on precursor cells in the bone marrow, playing important roles in the proliferation and differentiation into mature neutrophilic granulocytes and macrophages which are essential for combating infection (Liongue and Ward 2014). As predicted by Protein Variation Effect Analyzer (PROVEAN), CSF3R protein contains a critical pangolin-specific mutation at position 247(G→H) in the functionally relevant Fibronection Type III domain that likely affects its protein function in pangolins (Fig.…”

Analysis of Efficacy and Prognostic Factors of CLAG Treatment in Chinese Patients with Refractory or Relapsed Acute Myeloid Leukemia

“…Other than the synergistic effects between cladribine and Ara-C, cladribine is able to increase cell death by breaking single-strand DNA or suppressing DNA synthesis [13]. Thirdly, G-CSF, a cytokine with widespread application in hematopoietic recovery, contributes to the mobilization of hematopoietic precursor cells as well as the proliferation and differentiation of myeloid cells, and G-CSF stimulates a variety of functions of mature neutrophils [14, 15]. Furthermore, G-CSF potentiates the accumulation of Ara-CTP, thereby enhancing the Ara-C effect without increasing neurotoxicity [16].…”