Neutrophil elastase in cyclic and severe congenital neutropenia

Abstract

Mutations in ELA2 encoding the neutrophil granule protease, neutrophil elastase (NE), are the major cause of the 2 main forms of hereditary neutropenia, cyclic neutropenia and severe congenital neutropenia (SCN). Genetic evaluation of other forms of neutropenia in humans and model organisms has helped to illuminate the role of NE. A canine form of cyclic neutropenia corresponds to human Hermansky-Pudlak syndrome type 2 (HPS2) and results from mutations in AP3B1 encoding a subunit of a complex involved in the subcellular trafficking of vesicular cargo proteins (among which NE appears to be one). Rare cases of SCN are attributable to mutations in the transcriptional repressor Gfi1 (among whose regulatory targets also include ELA2). The ultimate biochemical consequences of the mutations are not yet known, however. Gene targeting of ELA2 has thus far failed to recapitulate neutropenia in mice. The cycling phenomenon and origins of leukemic transformation in SCN remain puzzling. Nevertheless, mutations in all 3 genes are capable of causing the mislocalization of NE and may also induce the unfolded protein response, suggesting that there might a convergent pathogenic mechanism focusing on NE.

Figure 1

Cyclic neutropenia transferred from an affected sibling to her unaffected sister by bone marrow transplantation. The donor and recipient cycle nearly synchronously. The family is pedigree number 601 from Horwitz et al, which segregates the ELA2 +5 G>A mutation in intron 4. The unaffected sister (who lacked the family's ELA2 mutation) underwent bone marrow transplantation for the treatment of acute lymphoblastic leukemia; her affected sister (later found to have an ELA2 mutation) was HLA matched and served as the donor. Adapted from Krance et al with permission.

Figure 2

Correlation of mutations in ELA2, encoding NE, with cyclic neutropenia or SCN. There are 2 categories of mutations: those reported exclusively in SCN (blue, below the gene structure) or those reported predominantly in cyclic neutropenia (but that also may have been described in SCN; pink, above the line). *, amino acid substitutions; ▾, deletions (or nonsense mutations); ▴, an insertion. Exon 4 deletions are in frame, and the cluster of exon 5 deletions are all frame-shift, chain-terminating events.

Figure 3

Feedback loop hypothesis to explain hematopoietic cycling. NE is postulated to inhibit further differentiation by a myeloblast (red line). Blue sine wave denotes neutrophil count oscillations. In this model, NE is produced by the terminally differentiating cohort of neutrophils and ultimately feeds back to inhibit further production of neutrophils, which results in loss of the inhibitory cycle—at least for a while, until production of neutrophils resume, followed again by the inhibitory action of NE in a cyclic manner.