Mutations in neutrophil elastase causing congenital neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein response

Wnt3a stimulates maturation of impaired neutrophils developed from severe congenital neutropenia patient-derived pluripotent stem cells

“…It has been reported that induction of the endoplasmic reticulum stress (ER) response and the unfolded protein response (UPR) has been advanced as a potential explanation for the molecular pathogenesis of SCN (18,19). Thus, we examined activation of the UPR by X-box binding protein 1 (XBP-1) mRNA splicing on day 7.…”

Granulopoïèse et leucémogenèse

“…De même, il n'a pas été retrouvé de corrélation entre les mutations et l'activité enzymatique de la protéine. En revanche, des anomalies de conformation de la protéine et son accumulation au niveau intracytoplasmique [8,9] ont été décrites. Un taux excessif de la protéine entraînerait une mort cellulaire par apoptose.…”

Observations on the Pathophysiology and Mechanisms for Cyclic Neutropenia

“…These mutations are now hypothesized to cause a less severe degree of accelerated apoptosis than those associated with severe congenital neutropenia. Current evidence indicates that the accelerated apoptosis of neutrophils in cyclic neutropenia is a caspase independent process [21]. Cyclic neutropenia and severe congenital neutropenia are recognized as different diseases, but the finding that mutations in the ELA-2 gene can cause both diseases prompted genotype-phenotype studies.…”

“…The patterns of mutation in the two diseases shown in Figure 2. Modeling studies suggest that the mutations causing cyclic neutropenia affect the binding of neutrophil elastase to its substrates and natural inhibitors, whereas those causing congenital neutropenia may predominantly affect molecular association and folding for storage in the primary granules [21]. It is not yet clear whether specific ELA2 mutations, particularly those associated with congenital neutropenia, are associated with evolution to leukemia or if the risk of leukemia is an intrinsic risk due to more rapid turnover of progenitor cells as a response to ineffective formation of neutrophils.…”

“…It is significant that the break in cell development is at the pro-myelocyte to myelocyte transition, the stage at which the enzyme neutrophil elastase is normally synthesized and packaged in the primary granules. At the cellular and molecular level, mutant neutrophil elastase triggers accelerated apoptosis, either as a direct effect of the mutant protein or secondary to the unfolded protein response with induction of caspase-independent apoptosis [18,21].…”