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Blood, 1 June 2004, Vol. 103, No. 11, pp. 3993-3994. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Dale, D. C. Search for Related Content PubMed Articles by Dale, D. C. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS Neutrophil elastase and neutropenia 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 x 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. David C. Dale University of Washington References Gullberg U, Andersson E, Garwicz D, Lindmark A, Olsson I. Biosynthesis, processing and sorting of neutrophil proteins: insight into neutrophil granule development. Eur J Haematol. 1997;58: 137-153.[Medline] [Order article via Infotrieve] Horwitz M, Benson KF, Person RE, Aprikyan AG, Dale DC. Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic hematopoiesis. Nat Genet. 1999;23: 433-436.[CrossRef][Medline] [Order article via Infotrieve] Dale DC, Person RE, Bolyard AA, et al. Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood. 2000;96: 2317-2322.[Abstract/Free Full Text] Ancliff PJ, Gale RE, Leisner R, Hann IM, Linch DC. Mutations in the ELA2 gene encoding neutrophil elastase are present in most patients with sporadic severe congenital neutropenia but only in some patients with the familiar form of the disease. Blood. 2001;98: 2645-2650.[Abstract/Free Full Text] Dale DC, Cottle TE, Fier CJ, et al. Severe Chronic Neutropenia: treatment and follow-up of patients in the severe chronic neutropenia international registry. Am J Hematol. 2003;72: 82-93.[CrossRef][Medline] [Order article via Infotrieve] Freedman MH, Alter BP. Risk of myelodysplastic syndrome and acute myeloid leukemia in congenital neutropenias. Semin Hematol. 2002;39: 128-133.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Mutations in the ELA2 gene correlate with more severe expression of neutropenia: a study of 81 patients from the French Neutropenia Register Christine Bellanné-Chantelot, Séverine Clauin, Thierry Leblanc, Bruno Cassinat, Fernando Rodrigues-Lima, Sandrine Beaufils, Christelle Vaury, Mohamed Barkaoui, Odile Fenneteau, Micheline Maier-Redelsperger, Christine Chomienne, and Jean Donadieu Blood 2004 103: 4119-4125. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Dale, D. C. Search for Related Content PubMed Articles by Dale, D. C. 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