ELANE Mutations in Cyclic and Severe Congenital Neutropenia

Genetics and Pathophysiology
Published:November 09, 2012DOI:https://doi.org/10.1016/j.hoc.2012.10.004

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      References

        • Manroe B.L.
        • Weinberg A.G.
        • Rosenfeld C.R.
        • et al.
        The neonatal blood count in health and disease. I. Reference values for neutrophilic cells.
        J Pediatr. 1979; 95: 89-98
        • Haddy T.B.
        • Rana S.R.
        • Castro O.
        Benign ethnic neutropenia: what is a normal absolute neutrophil count?.
        J Lab Clin Med. 1999; 133: 15-22
        • Nieto F.J.
        • Szklo M.
        • Folsom A.R.
        • et al.
        Leukocyte count correlates in middle-aged adults: the Atherosclerosis Risk in Communities (ARIC) study.
        Am J Epidemiol. 1992; 136: 525-537
        • Sennels H.P.
        • Jorgensen H.L.
        • Hansen A.L.
        • et al.
        Diurnal variation of hematology parameters in healthy young males: the Bispebjerg study of diurnal variations.
        Scand J Clin Lab Invest. 2011; 71: 532-541
        • Pilia G.
        • Chen W.M.
        • Scuteri A.
        • et al.
        Heritability of cardiovascular and personality traits in 6,148 Sardinians.
        PLoS Genet. 2006; 2: e132
        • Grann V.R.
        • Ziv E.
        • Joseph C.K.
        • et al.
        Duffy (Fy), DARC, and neutropenia among women from the United States, Europe and the Caribbean.
        Br J Haematol. 2008; 143: 288-293
        • Reich D.
        • Nalls M.A.
        • Kao W.H.
        • et al.
        Reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen receptor for chemokines gene.
        PLoS Genet. 2009; 5: e1000360
        • Grann V.R.
        • Bowman N.
        • Joseph C.
        • et al.
        Neutropenia in 6 ethnic groups from the Caribbean and the U.S.
        Cancer. 2008; 113: 854-860
        • Nalls M.A.
        • Couper D.J.
        • Tanaka T.
        • et al.
        Multiple loci are associated with white blood cell phenotypes.
        PLoS Genet. 2011; 7: e1002113
        • Reiner A.P.
        • Lettre G.
        • Nalls M.A.
        • et al.
        Genome-wide association study of white blood cell count in 16,388 African Americans: the Continental Origins and Genetic Epidemiology Network (COGENT).
        PLoS Genet. 2011; 7: e1002108
        • Crosslin D.R.
        • McDavid A.
        • Weston N.
        • et al.
        Genetic variants associated with the white blood cell count in 13,923 subjects in the eMERGE Network.
        Hum Genet. 2012; 131: 639-652
        • Lange R.D.
        Cyclic hematopoiesis: human cyclic neutropenia.
        Exp Hematol. 1983; 11: 435-451
        • Reimann H.A.
        Periodic disease; a probable syndrome including periodic fever, benign paroxysmal peritonitis, cyclic neutropenia and intermittent arthralgia.
        J Am Med Assoc. 1948; 136: 239-244
        • Borne S.
        Cyclic neutropenia in an infant.
        Pediatrics. 1949; 4: 70-78
        • Krance R.A.
        • Spruce W.E.
        • Forman S.J.
        • et al.
        Human cyclic neutropenia transferred by allogeneic bone marrow grafting.
        Blood. 1982; 60: 1263-1266
        • Horwitz M.S.
        • Duan Z.
        • Korkmaz B.
        • et al.
        Neutrophil elastase in cyclic and severe congenital neutropenia.
        Blood. 2007; 109: 1817-1824
        • Kostmann R.
        Infantile genetic agranulocytosis; agranulocytosis infantilis hereditaria.
        Acta Paediatr Suppl. 1956; 45: 1-78
        • Kostmann R.
        Infantile genetic agranulocytosis: a review with presentation of ten new cases.
        Acta Paediatr Scand. 1975; 64: 362-368
        • Carlsson G.
        • Fasth A.
        Infantile genetic agranulocytosis, morbus Kostmann: presentation of six cases from the original “Kostmann family” and a review.
        Acta Paediatr. 2001; 90: 757-764
        • Horwitz M.
        • Li F.-Q.
        • Albani D.
        • et al.
        Leukemia in severe congenital neutropenia: defective proteolysis suggests new pathways to malignancy and opportunities for therapy.
        Cancer Invest. 2003; 21: 577-585
        • Klein C.
        Genetic defects in severe congenital neutropenia: emerging insights into life and death of human neutrophil granulocytes.
        Annu Rev Immunol. 2011; 29: 399-413
        • Donadieu J.
        • Fenneteau O.
        • Beaupain B.
        • et al.
        Congenital neutropenia: diagnosis, molecular bases and patient management.
        Orphanet J Rare Dis. 2011; 6: 26
        • Carlsson G.
        • van't Hooft I.
        • Melin M.
        • et al.
        Central nervous system involvement in severe congenital neutropenia: neurological and neuropsychological abnormalities associated with specific HAX1 mutations.
        J Intern Med. 2008; 264: 388-400
        • Boztug K.
        • Appaswamy G.
        • Ashikov A.
        • et al.
        A syndrome with congenital neutropenia and mutations in G6PC3.
        N Engl J Med. 2009; 360: 32-43
        • Person R.E.
        • Li F.Q.
        • Duan Z.
        • et al.
        Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2.
        Nat Genet. 2003; 34: 308-312
        • Armistead P.M.
        • Wieder E.
        • Akande O.
        • et al.
        Cyclic neutropenia associated with T cell immunity to granulocyte proteases and a double de novo mutation in GFI1, a transcriptional regulator of ELANE.
        Br J Haematol. 2010; 150: 716-719
        • Takahashi H.
        • Nukiwa T.
        • Basset P.
        • et al.
        Myelomonocytic cell lineage expression of the neutrophil elastase gene.
        J Biol Chem. 1988; 263: 2543-2547
        • Kim Y.M.
        • Haghighat L.
        • Spiekerkoetter E.
        • et al.
        Neutrophil elastase is produced by pulmonary artery smooth muscle cells and is linked to neointimal lesions.
        Am J Pathol. 2011; 179: 1560-1572
        • Donadieu J.
        • Leblanc T.
        • Bader Meunier B.
        • et al.
        Analysis of risk factors for myelodysplasias, leukemias and death from infection among patients with congenital neutropenia. Experience of the French Severe Chronic Neutropenia Study Group.
        Haematologica. 2005; 90: 45-53
        • Rosenberg P.S.
        • Zeidler C.
        • Bolyard A.A.
        • et al.
        Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy.
        Br J Haematol. 2010; 150: 196-199
        • Carlsson G.
        • Fasth A.
        • Berglof E.
        • et al.
        Incidence of severe congenital neutropenia in Sweden and risk of evolution to myelodysplastic syndrome/leukaemia.
        Br J Haematol. 2012; 158: 363-369
        • Freedman M.H.
        • Bonilla M.A.
        • Fier C.
        • et al.
        Myelodysplasia syndrome and acute myeloid leukemia in patients with congenital neutropenia receiving G-CSF therapy.
        Blood. 2000; 96: 429-436
        • Donadieu J.
        • Fenneteau O.
        • Beaupain B.
        • et al.
        Classification and risk factors of hematological complications in a French national cohort of 102 patients with Shwachman-Diamond syndrome.
        Haematologica. 2012; 97: 1312-1319
        • Dong F.
        • Brynes R.K.
        • Tidow N.
        • et al.
        Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia.
        N Engl J Med. 1995; 333: 487-493
        • Sinha S.
        • Zhu Q.S.
        • Romero G.
        • et al.
        Deletional mutation of the external domain of the human granulocyte colony-stimulating factor receptor in a patient with severe chronic neutropenia refractory to granulocyte colony-stimulating factor.
        J Pediatr Hematol Oncol. 2003; 25: 791-796
        • Liu F.
        • Kunter G.
        • Krem M.M.
        • et al.
        Csf3r mutations in mice confer a strong clonal HSC advantage via activation of Stat5.
        J Clin Invest. 2008; 118: 946-955
        • Lightsey A.L.
        • Parmley R.T.
        • Marsh Jr., W.L.
        • et al.
        Severe congenital neutropenia with unique features of dysgranulopoiesis.
        Am J Hematol. 1985; 18: 59-71
        • Putsep K.
        • Carlsson G.
        • Boman H.G.
        • et al.
        Deficiency of antibacterial peptides in patients with morbus Kostmann: an observation study.
        Lancet. 2002; 360: 1144-1149
        • Kawaguchi H.
        • Kobayashi M.
        • Nakamura K.
        • et al.
        Dysregulation of transcriptions in primary granule constituents during myeloid proliferation and differentiation in patients with severe congenital neutropenia.
        J Leukoc Biol. 2003; 73: 225-234
        • Sera Y.
        • Kawaguchi H.
        • Nakamura K.
        • et al.
        A comparison of the defective granulopoiesis in childhood cyclic neutropenia and in severe congenital neutropenia.
        Haematologica. 2005; 90: 1032-1041
        • Donini M.
        • Fontana S.
        • Savoldi G.
        • et al.
        G-CSF treatment of severe congenital neutropenia reverses neutropenia but does not correct the underlying functional deficiency of the neutrophil in defending against microorganisms.
        Blood. 2007; 109: 4716-4723
        • Habscheid W.
        • Bernhardt C.
        • Sold M.
        • et al.
        Dtsch Med Wochenschr. 1991; 116 ([in German]): 1862-1866
        • van Winkelhoff A.J.
        • Schouten-van Meeteren A.Y.
        • Baart J.A.
        • et al.
        Microbiology of destructive periodontal disease in adolescent patients with congenital neutropenia. A report of 3 cases.
        J Clin Periodontol. 2000; 27: 793-798
        • Dick E.P.
        • Prince L.R.
        • Sabroe I.
        Ex vivo-expanded bone marrow CD34+ derived neutrophils have limited bactericidal ability.
        Stem Cells. 2008; 26: 2552-2563
        • Yakisan E.
        • Schirg E.
        • Zeidler C.
        • et al.
        High incidence of significant bone loss in patients with severe congenital neutropenia (Kostmann's syndrome).
        J Pediatr. 1997; 131: 592-597
        • Boechat M.I.
        • Gormley L.S.
        • O'Laughlin B.J.
        Thickened cortical bones in congenital neutropenia.
        Pediatr Radiol. 1987; 17: 124-126
        • Fewtrell M.S.
        • Kinsey S.E.
        • Williams D.M.
        • et al.
        Bone mineralization and turnover in children with congenital neutropenia, and its relationship to treatment with recombinant human granulocyte-colony stimulating factor.
        Br J Haematol. 1997; 97: 734-736
        • Bishop N.J.
        • Williams D.M.
        • Compston J.C.
        • et al.
        Osteoporosis in severe congenital neutropenia treated with granulocyte colony-stimulating factor.
        Br J Haematol. 1995; 89: 927-928
        • Sekhar R.V.
        • Culbert S.
        • Hoots W.K.
        • et al.
        Severe osteopenia in a young boy with Kostmann's congenital neutropenia treated with granulocyte colony-stimulating factor: suggested therapeutic approach.
        Pediatrics. 2001; 108: E54
        • Hirbe A.C.
        • Uluckan O.
        • Morgan E.A.
        • et al.
        Granulocyte colony-stimulating factor enhances bone tumor growth in mice in an osteoclast-dependent manner.
        Blood. 2007; 109: 3424-3431
        • Christopher M.J.
        • Link D.C.
        Granulocyte colony-stimulating factor induces osteoblast apoptosis and inhibits osteoblast differentiation.
        J Bone Miner Res. 2008; 23: 1765-1774
        • Horwitz M.
        • Benson K.F.
        • Person R.E.
        • et al.
        Mutations in ELA2, encoding neutrophil elastase, definea 21-day biological clock in cyclic haematopoiesis.
        Nat Genet. 1999; 23: 433-436
        • Korkmaz B.
        • Horwitz M.S.
        • Jenne D.E.
        • et al.
        Neutrophil elastase, proteinase 3, and cathepsin G as therapeutic targets in human diseases.
        Pharmacol Rev. 2010; 62: 726-759
        • Dale D.C.
        • Person R.E.
        • Bolyard A.A.
        • et al.
        Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia.
        Blood. 2000; 96: 2317-2322
        • Germeshausen M.
        • Zeidler C.
        • Stuhrmann M.
        • et al.
        Digenic mutations in severe congenital neutropenia.
        Haematologica. 2010; 95: 1207-1210
        • Xia J.
        • Bolyard A.A.
        • Rodger E.
        • et al.
        Prevalence of mutations in ELANE, GFI1, HAX1, SBDS, WAS and G6PC3 in patients with severe congenital neutropenia.
        Br J Haematol. 2009; 147: 535-542
        • Lanciotti M.
        • Caridi G.
        • Rosano C.
        • et al.
        Severe congenital neutropenia: a negative synergistic effect of multiple mutations of ELANE (ELA2) gene.
        Br J Haematol. 2009; 146: 578-580
        • Bellanne-Chantelot C.
        • Clauin S.
        • Leblanc T.
        • et al.
        Mutations in the ELA2 gene correlate with more severe expression of neutropenia: a study of 81 patients from the French neutropenia register.
        Blood. 2004; 103: 4119-4125
        • Newburger P.E.
        • Pindyck T.N.
        • Zhu Z.
        • et al.
        Cyclic neutropenia and severe congenital neutropenia in patients with a shared ELANE mutation and paternal haplotype: evidence for phenotype determination by modifying genes.
        Pediatr Blood Cancer. 2010; 55: 314-317
        • Boxer L.A.
        • Stein S.
        • Buckley D.
        • et al.
        Strong evidence for autosomal dominant inheritance of severe congenital neutropenia associated with ELA2 mutations.
        J Pediatr. 2006; 148: 633-636
        • Klein C.
        • Grudzien M.
        • Appaswamy G.
        • et al.
        HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease).
        Nat Genet. 2007; 39: 86-92
        • Carlsson G.
        • Aprikyan A.A.
        • Ericson K.G.
        • et al.
        Neutrophil elastase and granulocyte colony-stimulating factor receptor mutation analyses and leukemia evolution in severe congenital neutropenia patients belonging to the original Kostmann family in northern Sweden.
        Haematologica. 2006; 91: 589-595
        • Salipante S.J.
        • Benson K.F.
        • Luty J.
        • et al.
        Double de novo mutations of ELA2 in cyclic and severe congenital neutropenia.
        Hum Mutat. 2007; 28: 874-881
        • Goriely A.
        • Wilkie A.O.
        Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease.
        Am J Hum Genet. 2012; 90: 175-200
        • Zlotogora J.
        Germ line mosaicism.
        Hum Genet. 1998; 102: 381-386
        • Ancliff P.J.
        • Gale R.E.
        • Hann I.M.
        • et al.
        Paternal mosaicism proves the pathogenic nature of mutations in neutrophil elastase in severe congenital neutropenia.
        Blood. 2001; 98 (Available at:): 1841a
        • Germeshausen M.
        • Schulze H.
        • Ballmaier M.
        • et al.
        Mutations in the gene encoding neutrophil elastase (ELA2) are not sufficient to cause the phenotype of congenital neutropenia.
        Br J Haematol. 2001; 115: 222-224
        • Malcov M.
        • Reches A.
        • Ben-Yosef D.
        • et al.
        Resolving a genetic paradox throughout preimplantation genetic diagnosis for autosomal dominant severe congenital neutropenia.
        Prenat Diagn. 2010; 30: 207-211
        • Benson K.F.
        • Horwitz M.
        Possibility of somatic mosaicism of ELA2 mutation overlooked in an asymptomatic father transmitting severe congenital neutropenia to two offspring.
        Br J Haematol. 2002; 118: 923
        • Ancliff P.J.
        • Gale R.E.
        • Liesner R.
        • et al.
        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 familial form of the disease.
        Blood. 2001; 98: 2645-2650
        • Beekman R.
        • Valkhof M.G.
        • Sanders M.A.
        • et al.
        Sequential gain of mutations in severe congenital neutropenia progressing to acute myeloid leukemia.
        Blood. 2012; 119: 5071-5077
        • Xia J.
        • Link D.C.
        Severe congenital neutropenia and the unfolded protein response.
        Curr Opin Hematol. 2008; 15: 1-7
        • Sherry S.T.
        • Ward M.H.
        • Kholodov M.
        • et al.
        dbSNP: the NCBI database of genetic variation.
        Nucleic Acids Res. 2001; 29: 308-311
        • Nagy E.
        • Maquat L.E.
        A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance.
        Trends Biochem Sci. 1998; 23: 198-199
        • Thusberg J.
        • Vihinen M.
        Bioinformatic analysis of protein structure-function relationships: case study of leukocyte elastase (ELA2) missense mutations.
        Hum Mutat. 2006; 27: 1230-1243
        • Massullo P.
        • Druhan L.J.
        • Bunnell B.A.
        • et al.
        Aberrant subcellular targeting of the G185R neutrophil elastase mutant associated with severe congenital neutropenia induces premature apoptosis of differentiating promyelocytes.
        Blood. 2005; 105: 3397-3404
        • Janoff A.
        • Scherer J.
        Mediators of inflammation in leukocyte lysosomes. IX. Elastinolytic activity in granules of human polymorphonuclear leukocytes.
        J Exp Med. 1968; 128: 1137-1155
        • Weinrauch Y.
        • Drujan D.
        • Shapiro S.D.
        • et al.
        Neutrophil elastase targets virulence factors of enterobacteria.
        Nature. 2002; 417: 91-94
        • Belaaouaj A.
        • Kim K.S.
        • Shapiro S.D.
        Degradation of outer membrane protein A in Escherichia coli killing by neutrophil elastase.
        Science. 2000; 289: 1185-1188
        • Korkmaz B.
        • Hajjar E.
        • Kalupov T.
        • et al.
        Influence of charge distribution at the active site surface on the substrate specificity of human neutrophil protease 3 and elastase. A kinetic and molecular modeling analysis.
        J Biol Chem. 2007; 282: 1989-1997
        • Valenzuela-Fernandez A.
        • Planchenault T.
        • Baleux F.
        • et al.
        Leukocyte elastase negatively regulates Stromal cell-derived factor-1 (patients with SCN-1)/CXCR4 binding and functions by amino-terminal processing of patients with SCN-1 and CXCR4.
        J Biol Chem. 2002; 277: 15677-15689
        • Ma Q.
        • Jones D.
        • Borghesani P.R.
        • et al.
        Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice.
        Proc Natl Acad Sci U S A. 1998; 95: 9448-9453
        • Hernandez P.A.
        • Gorlin R.J.
        • Lukens J.N.
        • et al.
        Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease.
        Nat Genet. 2003; 34: 70-74
        • Carter C.R.
        • Whitmore K.M.
        • Thorpe R.
        The significance of carbohydrates on G-CSF: differential sensitivity of G-CSFs to human neutrophil elastase degradation.
        J Leukoc Biol. 2003; 75: 515-522
        • El Ouriaghli F.
        • Fujiwara H.
        • Melenhorst J.J.
        • et al.
        Neutrophil elastase enzymatically antagonizes the in vitro action of G-CSF: implications for the regulation of granulopoiesis.
        Blood. 2003; 101: 1752-1758
        • Hunter M.G.
        • Druhan L.J.
        • Avalos B.R.
        Proteolytic cleavage of G-CSF and the G-CSFR by neutrophil elastase induces growth inhibition and decreased G-CSFR surface expression: implications for myelopoiesis.
        Blood. 2002; 100 (Available at:): 244a
        • Gullberg U.
        • Bengtsson N.
        • Bulow E.
        • et al.
        Processing and targeting of granule proteins in human neutrophils.
        J Immunol Methods. 1999; 232: 201-210
        • Adkison A.M.
        • Raptis S.Z.
        • Kelley D.G.
        • et al.
        Dipeptidyl peptidase I activates neutrophil-derived serine proteases and regulates the development of acute experimental arthritis.
        J Clin Invest. 2002; 109: 363-371
        • Neurath H.
        Evolution of proteolytic enzymes.
        Science. 1984; 224: 350-357
        • Toomes C.
        • James J.
        • Wood A.J.
        • et al.
        Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis.
        Nat Genet. 1999; 23: 421-424
        • Bode W.
        • Meyer Jr., E.
        • Powers J.C.
        Human leukocyte and porcine pancreatic elastase: X-ray crystal structures, mechanism, substrate specificity, and mechanism-based inhibitors.
        Biochemistry. 1989; 28: 1951-1963
        • Ortiz P.G.
        • Skov B.G.
        • Benfeldt E.
        Alpha1-antitrypsin deficiency-associated panniculitis: case report and review of treatment options.
        J Eur Acad Dermatol Venereol. 2005; 19: 487-490
        • Bottomley S.P.
        The structural diversity in alpha1-antitrypsin misfolding.
        EMBO Rep. 2011; 12: 983-984
        • Zeng W.
        • Silverman G.A.
        • Remold-O'Donnell E.
        Structure and sequence of human M/NEI (monocyte/neutrophil elastase inhibitor), an Ov-serpin family gene.
        Gene. 1998; 213: 179-187
        • Ye S.
        • Goldsmith E.J.
        Serpins and other covalent protease inhibitors.
        Curr Opin Struct Biol. 2001; 11: 740-745
        • Moreau T.
        • Baranger K.
        • Dade S.
        • et al.
        Multifaceted roles of human elafin and secretory leukocyte proteinase inhibitor (SLPI), two serine protease inhibitors of the chelonianin family.
        Biochimie. 2008; 90: 284-295
        • Doumas S.
        • Kolokotronis A.
        • Stefanopoulos P.
        Anti-inflammatory and antimicrobial roles of secretory leukocyte protease inhibitor.
        Infect Immun. 2005; 73: 1271-1274
        • Grenda D.S.
        • Johnson S.E.
        • Mayer J.R.
        • et al.
        Mice expressing a neutrophil elastase mutation derived from patients with severe congenital neutropenia have normal granulopoiesis.
        Blood. 2002; 100: 3221-3228
        • Chao J.R.
        • Parganas E.
        • Boyd K.
        • et al.
        Hax1-mediated processing of HtrA2 by Parl allows survival of lymphocytes and neurons.
        Nature. 2008; 452: 98-102
        • Karsunky H.
        • Zeng H.
        • Schmidt T.
        • et al.
        Inflammatory reactions and severe neutropenia in mice lacking the transcriptional repressor Gfi1.
        Nat Genet. 2002; 30: 295-300
        • Hock H.
        • Hamblen M.J.
        • Rooke H.M.
        • et al.
        Intrinsic requirement for zinc finger transcription factor Gfi-1 in neutrophil differentiation.
        Immunity. 2003; 18: 109-120
        • Zarebski A.
        • Velu C.S.
        • Baktula A.M.
        • et al.
        The human severe congenital neutropenia-associated Gfi1 N382S mutant blocks murine granulopoiesis through CSF1.
        Immunity. 2008; (Available at:)
        • Cheung Y.Y.
        • Kim S.Y.
        • Yiu W.H.
        • et al.
        Impaired neutrophil activity and increased susceptibility to bacterial infection in mice lacking glucose-6-phosphatase-beta.
        J Clin Invest. 2007; 117: 784-793
        • Smirnova O.A.
        Kosm Biol Aviakosm Med. 1985; 19 ([in Russian]): 77-80
        • Pacheco J.M.
        • Traulsen A.
        • Antal T.
        • et al.
        Cyclic neutropenia in mammals.
        Am J Hematol. 2008; 83: 920-921
        • Morley A.
        Cyclic hemopoiesis and feedback control.
        Blood Cells. 1979; 5: 283-296
        • Haurie C.
        • Dale D.C.
        • Mackey M.C.
        Cyclical neutropenia and other periodic hematological disorders: a review of mechanisms and mathematical models.
        Blood. 1998; 92: 2629-2640
        • Horwitz M.
        • Benson K.F.
        • Duan Z.
        • et al.
        Role of neutrophil elastase in bone marrow failure syndromes: molecular genetic revival of the chalone hypothesis.
        Curr Opin Hematol. 2003; 10: 49-54
        • Rytomaa T.
        Role of chalone in granulopoiesis.
        Br J Haematol. 1973; 24: 141-146
        • Leitch H.A.
        • Levy J.G.
        Reversal of camal-mediated alterations of normal and leukemic in-vitro myelopoiesis using inhibitors of proteolytic activity.
        Leukemia. 1994; 8: 605-611
        • Li F.Q.
        • Horwitz M.
        Characterization of mutant neutrophil elastase in severe congenital neutropenia.
        J Biol Chem. 2001; 276: 14230-14241
        • Kollner I.
        • Sodeik B.
        • Schreek S.
        • et al.
        Mutations in neutrophil elastase causing congenital neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein response.
        Blood. 2006; 108: 493-500
        • Aoki Y.
        Crystallization and characterization of a new protease in mitochondria of bone marrow cells.
        J Biol Chem. 1978; 253: 2026-2032
        • Clark J.M.
        • Vaughan D.W.
        • Aiken B.M.
        • et al.
        Elastase-like enzymes in human neutrophils localized by ultrastructural cytochemistry.
        J Cell Biol. 1980; 84: 102-119
        • Kolkenbrock H.
        • Zimmermann J.
        • Burmester G.R.
        • et al.
        Activation of progelatinase B by membranes of human polymorphonuclear granulocytes.
        Biol Chem. 2000; 381: 49-55
        • Owen C.A.
        • Campbell M.A.
        • Sannes P.L.
        • et al.
        Cell surface-bound elastase and cathepsin G on human neutrophils: a novel, non-oxidative mechanism by which neutrophils focus and preserve catalytic activity of serine proteinases.
        J Cell Biol. 1995; 131: 775-789
        • Lane A.A.
        • Ley T.J.
        Neutrophil elastase is important for PML-retinoic acid receptor alpha activities in early myeloid cells.
        Mol Cell Biol. 2005; 25: 23-33
        • Belmokhtar C.A.
        • Torriglia A.
        • Counis M.F.
        • et al.
        Nuclear translocation of a leukocyte elastase inhibitor/elastase complex during staurosporine-induced apoptosis: role in the generation of nuclear L-DNase II activity.
        Exp Cell Res. 2000; 254: 99-109
        • Nakagami Y.
        • Ito M.
        • Hara T.
        • et al.
        Loss of TRF2 by radiation-induced apoptosis in HL60 cells.
        Radiat Med. 2002; 20: 121-129
        • Torriglia A.
        • Perani P.
        • Brossas J.Y.
        • et al.
        L-DNase II, a molecule that links proteases and endonucleases in apoptosis, derives from the ubiquitous serpin leukocyte elastase inhibitor.
        Mol Cell Biol. 1998; 18: 3612-3619
        • Papayannopoulos V.
        • Metzler K.D.
        • Hakkim A.
        • et al.
        Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps.
        J Cell Biol. 2010; 191: 677-691
        • Salipante S.J.
        • Rojas M.E.
        • Korkmaz B.
        • et al.
        Contributions to neutropenia from PFAAP5 (N4BP2L2), a novel protein mediating transcriptional repressor cooperation between Gfi1 and neutrophil elastase.
        Mol Cell Biol. 2009; 29: 4394-4405
        • Benson K.F.
        • Li F.Q.
        • Person R.E.
        • et al.
        Mutations associated with neutropenia in dogs and humans disrupt intracellular transport of neutrophil elastase.
        Nat Genet. 2003; 35: 90-96
        • Campbell E.J.
        • Owen C.A.
        The sulfate groups of chondroitin sulfate- and heparan sulfate-containing proteoglycans in neutrophil plasma membranes are novel binding sites for human leukocyte elastase and cathepsin G.
        J Biol Chem. 2007; 282: 14645-14654
        • Lothrop Jr., C.D.
        • Coulson P.A.
        • Nolan H.L.
        • et al.
        Cyclic hormonogenesis in gray collie dogs: interactions of hematopoietic and endocrine systems.
        Endocrinology. 1987; 120: 1027-1032
      1. Horwitz M, Benson KF, Duan Z, et al. Hereditary neutropenia: dogs explain human neutrophil elastase mutations. Trends Mol Med, in press. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15059607.

        • Chiang P.W.
        • Spector E.
        • Thomas M.
        • et al.
        Novel mutation causing Hermansky-Pudlak syndrome type 2.
        Pediatr Blood Cancer. 2010; 55: 1438
        • Li W.
        • Feng Y.
        • Hao C.
        • et al.
        The BLOC interactomes form a network in endosomal transport.
        J Genet Genomics. 2007; 34: 669-682
        • Richmond B.
        • Huizing M.
        • Knapp J.
        • et al.
        Melanocytes derived from patients with Hermansky-Pudlak syndrome types 1, 2, and 3 have distinct defects in cargo trafficking.
        J Invest Dermatol. 2005; 124: 420-427
        • Meng R.
        • Bridgman R.
        • Toivio-Kinnucan M.
        • et al.
        Neutrophil elastase-processing defect in cyclic hematopoietic dogs.
        Exp Hematol. 2010; 38: 104-115
        • Introne W.
        • Boissy R.E.
        • Gahl W.A.
        Clinical, molecular, and cell biological aspects of Chediak-Higashi syndrome.
        Mol Genet Metab. 1999; 68: 283-303
        • Barbosa M.D.
        • Nguyen Q.A.
        • Tchernev V.T.
        • et al.
        Identification of the homologous beige and Chediak-Higashi syndrome genes.
        Nature. 1996; 382: 262-265
        • Cavarra E.
        • Martorana P.A.
        • Cortese S.
        • et al.
        Neutrophils in beige mice secrete normal amounts of cathepsin G and a 46 kDa latent form of elastase that can be activated extracellularly by proteolytic activity.
        Biol Chem. 1997; 378: 417-423
        • Gallin J.I.
        • Bujak J.S.
        • Patten E.
        • et al.
        Granulocyte function in the Chediak-Higashi syndrome of mice.
        Blood. 1974; 43: 201-206
        • Kramer J.W.
        • Davis W.C.
        • Prieur D.J.
        The Chediak-Higashi syndrome of cats.
        Lab Invest. 1977; 36: 554-562
        • Prieur D.J.
        • Collier L.L.
        Neutropenia in cats with the Chediak-Higashi syndrome.
        Can J Vet Res. 1987; 51: 407-408
        • Duan Z.
        • Horwitz M.
        Gfi-1 takes center stage in hematopoietic stem cells.
        Trends Mol Med. 2005; 11: 49-52
        • Duan Z.
        • Horwitz M.
        Targets of the transcriptional repressor oncoprotein Gfi-1.
        Proc Natl Acad Sci U S A. 2003; 100: 5932-5937
        • Grenda D.S.
        • Murakami M.
        • Ghatak J.
        • et al.
        Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis.
        Blood. 2007; 110: 4179-4187
        • Nanua S.
        • Murakami M.
        • Xia J.
        • et al.
        Activation of the unfolded protein response is associated with impaired granulopoiesis in transgenic mice expressing mutant Elane.
        Blood. 2011; 117: 3539-3547
        • Delepine M.
        • Nicolino M.
        • Barrett T.
        • et al.
        EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome.
        Nat Genet. 2000; 25: 406-409
        • Senee V.
        • Vattem K.M.
        • Delepine M.
        • et al.
        Wolcott-Rallison syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity.
        Diabetes. 2004; 53: 1876-1883
        • Demo S.D.
        • Kirk C.J.
        • Aujay M.A.
        • et al.
        Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome.
        Cancer Res. 2007; 67: 6383-6391
        • Parmley R.T.
        • Presbury G.J.
        • Wang W.C.
        • et al.
        Cyclic ultrastructural abnormalities in human cyclic neutropenia.
        Am J Pathol. 1984; 116: 279-288