title: Leukemia in severe congenital neutropenia: defective proteolysis suggests new pathways to malignancy and opportunities for therapy.
abstract: Severe congenital neutropenia (SCN), a heterogeneous disorder that includes Kostmann syndrome, predisposes to myelodysplasia and acute myelogenous leukemia. Recently identified heterozygous mutations in the gene ELA2, encoding neutrophil elastase on human chromosome 19pter, account for the majority of autosomal dominant cases of SCN, including those demonstrating neoplastic progression. The involvement of the serine protease neutrophil elastase, localized to the granules of neutrophils and monocytes, implies an unexpected role for proteolytic regulation of hematopoiesis. Continued elucidation of the clinical features, molecular genetics, and biochemistry is likely to provide insight into novel pathways of leukemia induction with attendant prospects for new avenues of therapy.
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, 1705 NE Pacific Street, HSB-K236B, Seattle, WA 98195-7720, USA. horwitz@u.washington.edu
authors.forename: Marshall
authors.initials: M
authors.lastname: Horwitz
authors.forename: Feng-Qian
authors.initials: FQ
authors.lastname: Li
authors.forename: Dalila
authors.initials: D
authors.lastname: Albani
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Duan
authors.forename: Richard E
authors.initials: RE
authors.lastname: Person
authors.forename: Kimberly
authors.initials: K
authors.lastname: Meade-White
authors.forename: Kathleen F
authors.initials: KF
authors.lastname: Benson
mesh_terms: D003937:Diagnosis, Differential; D006410:Hematopoiesis; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D019272:Leukocyte Elastase / Q000235:genetics* / Q000494:pharmacology; D009436:Neural Tube Defects / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D009503:Neutropenia / Q000151:congenital* / Q000503:physiopathology*; D011506:Proteins / Q000378:metabolism; D012307:Risk Factors
chemical_list: D011506:Proteins; D019272:Leukocyte Elastase