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.

Keywords: AML; CNL; CSF3R; G-CSF; G-CSFR; MDS; SCN.

Figure 1

Granulocyte colony-stimulating factor receptor perturbations in disease. Schematic representation of the mature G-CSFR (RefSeq NP_000751.3), showing important subdomains and residues conserved among members of the hematopoietin receptor superfamily, including the N-terminal Ig domain, four conserved cysteines (thin line), and WSXWS motif (thick line) within the CRH domain, fibronectin, and transmembrane domains as well as Box 1–3 (gray rectangles) and important tyrosine residues within the cytoplasmic region. The relative positions of various classes of mutation are indicated on the right along with the respective clinical manifestations of these and other G-CSFR perturbations. Abbreviations: Ig, immunoglobulin-like; CRH, cytokine receptor homology; SCN, severe congenital neutropenia; CNL, chronic neutrophilic leukemia; MDS, myelodysplastic syndrome; AML, acute myeloid leukemia.

Figure 2

Inhibitors of signaling pathways downstream of G-CSFR. Schematic representation of the intracellular domain of G-CSFR, showing the important Box 1–3 sequences (gray rectangles), as well as the tyrosine residues that serve important docking sites for the downstream signaling proteins indicated. Known inhibitors of these are shown.