Neutrophil elastase and neutropenia

HEMATOPOIESIS

Neutrophil elastase ([NE] also called elastase-2 [ELA-2]) is a powerful serine protease stored in the primary granule of neutrophils.¹  This enzyme is synthesized primarily at the promyelocyte stage of neutrophil development in the bone marrow. The human gene for NE is located at 19 p 13.3, and mutations in NE are regarded as the primary cause of cyclic neutropenia and some, but not all, cases of severe congenital neutropenia.^2-4 

In this issue of Blood, Bellanné-Chantelot and colleagues (page 4119) report on studies of the clinical, hematologic, and genetic characteristics for 81 patients with cyclic or congenital neutropenia followed in the French Neutropenia Registry. The French registry is a national cooperative organization providing data for a geographically defined population with severe chronic neutropenia (ie, patients with blood neutrophil levels regularly or cyclically less than 0.5 × 10⁹/L for longer than 3 months). This paper presents several important observations. (1) In a population study, the patients with NE mutations have more severe neutropenia and more severe bacterial infections. These patients are also at greater risk for evolving to myelodysplasia or acute myeloid leukemia (AML). Thus, sequencing of the NE gene may provide important prognostic information for management of individual patients. (2) All NE mutations associated with neutropenia are heterozygous. Relatives of affected individuals are relatively likely to also have NE mutations, although their neutropenia may not be as severe as in the index case. (3) Cyclic neutropenia and severe congenital neutropenia are predominantly autosomal dominant disorders. Thus, finding a patient with severe neutropenia should prompt a review of the history and blood counts in the patient's relatives and appropriate genetic counseling. (4) The severity of neutropenia and the risk of AML cannot yet be predicted from the location or nature of the NE mutations.

It is now well known that most patients with cyclic and congenital neutropenia respond readily to treatment with granulocyte colony-stimulating factor (G-CSF).⁵  Based on 15 years of observations, this treatment has not been associated with evolution to acute myeloid leukemia in patients with cyclic neutropenia. On the other hand, patients whose clinical phenotype and mutational analysis are consistent with the diagnosis of severe congenital neutropenia are at risk for evolution to leukemia.⁶  In this report, 4 of 54 patients with congenital neutropenia developed AML. All of the patients who developed AML had mutations of the NE gene. This report suggests that some, but not all, mutations in the NE gene may lead to AML. A number of laboratories are now deeply engaged in verifying and trying to understand this important observation.

This excellent report clearly shows the steady progress being made in understanding the causes and consequences of disease causing severe chronic neutropenia.