Neutrophil Elastase Defects in Congenital Neutropenia

Abstract

Severe congenital neutropenia (SCN) is a rare hematological condition with heterogenous genetic background. Neutrophil elastase (NE) encoded by ELANE gene is mutated in over half of the SCN cases. The role of NE defects in myelocytes maturation arrest in bone marrow is widely investigated; however, the mechanism underlying this phenomenon has still remained unclear. In this review, we sum up the studies exploring mechanisms of neutrophil deficiency, biological role of NE in neutrophil and the effects of ELANE mutation and neutropenia pathogenesis. We also explain the hypotheses presented so far and summarize options of neutropenia therapy.

Keywords: ELANE mutations; cyclic neutropenia; mislocalization; mistrafficking; neutrophil elastase; severe congenital neutropenia; unfolded protein response.

Figure 1

(A) Mutational spectrum of the neutrophil elastase (ClinVar database; RefSeq NM_001972.4) (34). The lolliplot reports mutations projected on the schematic Trypsin domain of the human NE protein. The lolliplot was produced using the MutationMapper software, freely available through the Cbioportal (https://www.cbioportal.org/mutation_mapper) (35, 36). In the scheme, mutations are reported as circles (green for missense mutations; black for duplication; brown for inframe deletions and insertions; violet for all the other types. (B) 267-residue preproprotein scheme and post-translational modification at both ends. (C) 3D structure of human neutrophil elastase 3Q76 (uncomplexed). Image created using Mol* from RCSB PDB (37, 38).

Figure 2

(A) Neutrophil elastase is trafficked from Golgi to the granules. (B) Mistrafficking. Mutation in ELANE results in intact C-terminal of NE disrupting an interaction between AP3 which mislocates it to the cytoplasm, plasma and nuclear membrane. (C) Overexpressed ELANE due to mutation in GFI1 results in the transporter system overwhelmed by NE. (D) Unfolded protein response. Misfolded NE accumulation in ER leads to the ER stress and molecular chaperones upregulation and a subsequent induction of the UPR. (E) PML-mediated feed-forward loop. PML binds to ELANE promoter inducing misfolded NE expression thus increases ROS production and PML-NBs formation. (F) Either Lef-1 downregulates ELANE downstream or the Wnt pathway is downregulated through a negative feedback loop from mutated ELANE. Created with BioRender.com.

Figure 3

At the stage of promyelocyte the increased ROS level triggered by misfolded elastase leads to oxidative damage, which may be responsible for 2^nd hits and initiate malignant transformation. PML-NBs via MYC and mTOR signaling promotes malignant cell proliferation. Created with BioRender.com.