Clinical implications of ELA2-, HAX1-, and G-CSF-receptor (CSF3R) mutations in severe congenital neutropenia

British Journal of Haematology

Volumn 144, Issue 4, 2009, Pages 459-467

  Zeidler, Cornelia ^a   Germeshausen, Manuela ^a   Klein, Christoph ^a   Welte, Karl ^a  

^a HANNOVER MEDICAL SCHOOL   (Germany)

Author keywords

Acute myeloid leukemia; ELA2; G CSFR (CSF3R) mutations; HAX1; Severe congenital neutropenia

Indexed keywords

ELASTASE II; GRANULOCYTE COLONY STIMULATING FACTOR RECEPTOR; PROTEIN HAX1; PROTEIN X; RECOMBINANT GRANULOCYTE COLONY STIMULATING FACTOR; SERINE PROTEINASE; UNCLASSIFIED DRUG;

ACUTE GRANULOCYTIC LEUKEMIA; AUTOSOMAL DOMINANT INHERITANCE; CANCER INCIDENCE; DISEASE SEVERITY; GENE EXPRESSION; GENE MUTATION; GENETIC DISORDER; GENETIC RISK; GENOTYPE; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HUMAN; LEUKEMIA; LEUKEMOGENESIS; NEUTROPENIA; PATHOPHYSIOLOGY; PHENOTYPE; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; REVIEW;

CHILD; GRANULOCYTE COLONY STIMULATING FACTOR, RECOMBINANT; HUMANS; LEUKEMIA; MUTATION; NEUTROPENIA; PROTEINS; RECEPTORS, GRANULOCYTE COLONY-STIMULATING FACTOR; SERINE ENDOPEPTIDASES;

EID: 58549087140     PISSN: 00071048     EISSN: 13652141     Source Type: Journal    
DOI: 10.1111/j.1365-2141.2008.07425.x     Document Type: Review

References (65)

1. Ancliff, P.J., Gale, R.E., Watts, M.J., Liesner, R., Hann, I.M., Strobel, S. Linch, D.C. (2002) Paternal mosaicism proves the pathogenic nature of mutations in neutrophil elastase in severe congenital neutropenia. Blood, 100, 707 709.
2. Ancliff, P.J., Gale, R.E., Liesner, R., Hann, I. Linch, D.C. (2003) Long-term follow-up of granulocyte colony-stimulating factor receptor mutations in patients with severe congenital neutropenia: implications for leukaemogenesis and therapy. British Journal of Haematology, 120, 685 690.
3. Bagby, G.C. (2008) Discovering early molecular determinants of leukemogenesis. Journal of Clinical Investigation, 118, 847 850.
4. Belaaouaj, A., McCarthy, R., Baumann, M., Gao, Z., Ley, T.J., Abraham, S.N. Shapiro, S.D. (1998) Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis. Nature Medicine, 4, 615 618.
5. Bellanné-Chantelot, C., Clauin, S., Leblanc, T., Cassinat, B., Rodrigues-Lima, F., Beaufils, S., Vaury, C., Barkaoui, M., Fenneteau, O., Maier-Redelsperger, M., Chomienne, C. Donadieu, J. (2004) Mutations in the ELA2 gene correlate with more severe expression of neutropenia: a study of 81 patients from the French Neutropenia Register. Blood, 103, 4119 4125.
6. Bernard, T., Gale, R.E., Evans, J.P. Linch, D.C. (1998) Mutations of the granulocyte-colony stimulating factor receptor in patients with severe CN are not required for transformation to acute myeloid leukaemia and may be a bystander phenomenon. British Journal of Haematology, 101, 141 149.
7. Bonilla, M.A., Gillio, A.P., Ruggeiro, M., Kernan, N.A., Brochstein, J.A., Abboud, M., Fumagalli, L., Vincent, M., Gabrilove, J.L., Welte, K., Souza, L. O'Reilly, R.J. (1989) Effects of recombinant human granulocyte colony-stimulating factor on neutropenia in patients with congenital agranulocytosis. New England Journal of Medicine, 320, 1574 1580.
8. Boxer, L.A., Stein, S., Buckley, D., Bolyard, A.A. Dale, D.C. (2006) Strong evidence for autosomal dominant inheritance of severe congenital neutropenia associated with ELA2 mutations. Journal of Pediatrics, 148, 633 636.
9. Bux, J., Behrens, G., Jaeger, G. Welte, K. (1998) Diagnosis and clinical course of autoimmune neutropenia in infancy: analysis of 240 cases. Blood, 91, 181 186.
10. Carlsson, G. Fasth, A. (2001) Infantile genetic agranulocytosis, morbus Kostmann: presentation of six cases from the original "Kostmann family" and a review. Acta Paediatrica, 90, 757 764.
11. Carlsson, G., Aprikyan, A.A., Tehranchi, R., Dale, D.C., Porwit, A., Hellström-Lindberg, E., Palmblad, J., Henter, J.I. Fadeel, B. (2004) Kostmann syndrome: severe congenital neutropenia associated with defective expression of Bcl-2, constitutive mitochondrial release of cytochrome c, and excessive apoptosis of myeloid progenitor cells. Blood, 103, 3355 3361.
12. Carlsson, G., Wahlin, Y.B., Johansson, A., Olsson, A., Eriksson, T., Claesson, R., Hänström, L. Henter, J.I. (2006a) Periodontal disease in patients from the original Kostmann family with severe congenital neutropenia. Journal of Periodontology, 77, 744 751.
13. Carlsson, G., Aprikyan, A.A., Ericson, K.G., Stein, S., Makaryan, V., Dale, D.C., Nordenskjöld, M., Fadeel, B., Palmblad, J. Henter, J.I. (2006b) 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. Hematologica, 91, 589 595.
14. Carlsson, G., Van't Hooft, I., Melin, M., Entesarian, M., Laurencikas, E., Nennesmo, I., Trȩbińska, A., Grzybowska, E., Palmblad, J., Dahl, N., Nordenskjöld, M., Fadeel, B. Henter, J.I. (2008) Central nervous system involvement in severe congenital neutropenia: neurological and neuropsychological abnormalities associated with specific HAX1 mutations. Journal of Internal Medicine, doi :.
15. Chao, J.R., Parganas, E., Boyd, K., Hong, C.Y., Opferman, J.T. Ihle, J.N. (2008) Hax1-mediated processing of HtrA2 by Parl allows survival of lymphocytes and neurons. Nature, 452, 98 102.
16. Dale, D.C., Bonilla, M.A., Davis, M.W., Nakanishi, A.M., Hammond, W.P., Kurtzberg, J., Wang, W., Jakubowski, A., Winton, E., Lalezari, P., Robinson, W., Glaspy, J.A., Emerson, S., Gabrilove, J., Vincent, M. Boxer, L.A. (1993) A randomized controlled phase III trial of recombinant human granulocyte colony-stimulating factor (Filgrastim) for treatment of severe chronic neutropenia. Blood, 81, 2496 2502.
17. Dale, D.C., Person, D.E., Bolyard, A.A., Aprikyan, A.G., Bos, C., Bonilla, M.A., Boxer, L.A., Kannourakis, G., Zeidler, C., Welte, K., Benson, K.F. Horwitz, M. (2000) Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood, 96, 2317 2322.
18. Donadieu, J., Leblanc, T., Bader Meunier, B., Barkaoui, M., Fenneteau, O., Bertrand, Y., Maier-Redelsperger, M., Micheau, M., Stephan, J.L., Phillipe, N., Bordigoni, P., Babin-Boilletot, A., Bensaid, P., Manel, A.M., Vilmer, E., Thuret, I., Blanche, S., Gluckman, E., Fischer, A., Mechinaud, F., Joly, B., Lamy, T., Hermine, O., Cassinat, B., Bellanné-Chantelot, C. Chomienne, C., French Severe Chronic Neutropenia Study Group (2005) Analysis of risk factors for myelodysplasia/leukemia and infectious death among patients with CN: experience of the French Severe Chronic Neutropenia Study Group. Haematologica, 90, 45 53.
19. Dong, F., Brynes, R.K., Tidow, N., Welte, K., Löwenberg, B. Touw, I.P. (1995) Mutations in the gene for the granulocyte-colony stimulating factor receptor in patients with acute myeloid leukemia preceded by severe CN. New England Journal of Medicine, 333, 487 493.
20. Freedman, M.H. (1997) Safety of long-term administration of granulocyte colony-stimulating factor for severe chronic neutropenia. Current Opinion in Hematology, 4, 217 224.
21. Germeshausen, M., Ballmaier, M., Schulze, H., Welte, K., Flohr, T., Beiske, K., Storm-Mathisen, I. Abrahamsen, T.G. (2001) Granulocyte colony-stimulating factor receptor mutations in a patient with acute lymphoblastic leukemia secondary to severe CN. Blood, 97, 829 830.
22. Germeshausen, M., Schulze, H., Kratz, C., Wilkens, L., Repp, R., Shannon, K., Welte, K. Ballmaier, M. (2005) An acquired G-CSF receptor mutation results in increased proliferation of CMML cells from a patient with severe CN. Leukemia, 19, 611 617.
23. Germeshausen, M., Ballmaier, M. Welte, K. (2007) Incidence of CSF3R mutations in severe CN and relevance for leukemogenesis: results of a long-term survey. Blood, 109, 93 99.
24. Germeshausen, M., Grudzien, M., Zeidler, C., Abdollahpour, H., Yetgin, S., Rezaei, N., Ballmaier, M., Grimbacher, B., Welte, K. Klein, C. (2008a) Novel HAX1 mutations in patients with severe congenital neutropenia reveal isoform-dependent genotype-phenotype associations. Blood, 111, 4954 4957.
25. Germeshausen, M., Skokowa, J., Ballmaier, M., Zeidler, C. Welte, K. (2008b) G-CSF receptor mutations in patients with congenital neutropenia. Current Opinion in Hematology, (in press).
26. Göhring, G., Karow, A., Steinemann, D., Wilkens, L., Lichter, P., Zeidler, C., Welte, K. Schlegelberger, B. (2007) Chromosomal aberrations in congenital bone marrow failure disorders - an early indicator for leukemogenesis? Annals of Hematology, 86, 733 739.
27. Grenda, D.S., Johnson, S.E., Mayer, J.R., McLemore, M.L., Benson, K.F., Horwitz, M. Link, D.C. (2002) Mice expressing a neutrophil elastase mutation derived from patients with severe congenital neutropenia have normal granulopoiesis. Blood, 100, 3221 3228.
28. Grenda, D.S., Murakami, M., Ghatak, J., Xia, J., Boxer, L.A., Dale, D., Dinauer, M.C. Link, D.C. (2007) Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis. Blood, 110, 4179 4187.
29. Hermans, M.H., Antonissen, C., Ward, A.C., Mayen, A.E., Ploemacher, R.E. Touw, I.P. (1999) Sustained receptor activation and hyperproliferation in response to granulocyte colony-stimulating factor (G-CSF) in mice with a severe congenital neutropenia/acute myeloid leukemia-derived mutation in the G-CSF receptor gene. Journal of Experimental Medicine, 189, 683 692.
30. Hermans, M.H., van de Geijn, G.J., Antonissen, C., Gits, J., van Leeuwen, D., Ward, A.C. Touw, I.P. (2003) Signaling mechanisms coupled to tyrosines in the granulocyte colony-stimulating factor receptor orchestrate G-CSF-induced expansion of myeloid progenitor cells. Blood, 101, 2584 2590.
31. Horwitz, M.S., Duan, Z., Korkmaz, B., Lee, H.H., Mealiffe, M.E. Salipante, S.J. (2007) Neutrophil elastase in cyclic and severe congenital neutropenia. Blood, 109, 1817 1824.
32. Hunter, M.G. Avalos, B.R. (2000) Granulocyte colony-stimulating factor receptor mutations in severe congenital neutropenia transforming to acute myelogenous leukemia confer resistance to apoptosis and enhance cell survival. Blood, 95, 2132 2137.
33. Irandoust, M.I., Aarts, L.H., Roovers, O., Gits, J., Erkeland, S.J. Touw, I.P. (2007) Suppressor of cytokine signaling 3 controls lysosomal routing of G-CSF receptor. EMBO Journal, 26, 1782 1793.
34. Ishikawa, N., Okada, S., Miki, M., Shirao, K., Kihara, H., Tsumura, M., Nakamura, K., Kawaguchi, H., Ohtsubo, M., Yasunaga, S., Matsubara, K., Sako, M., Hara, J., Shiohara, M., Kojima, S., Takihara, Y. Kobayashi, M. (2008) Neurodevelopmental abnormalities associated with severe congenital neutropenia due to the R86X mutation in the HAX1 gene. Journal of Medical Genetics, doi:.
35. Kawaguchi, H., Kobayashi, M., Nakamura, K., Konishi, N., Miyagawa, S., Sato, T., Toyoda, H., Komada, Y., Kojima, S., Todoroki, Y., Ueda, K. Katoh, O. (2003) Dysregulation of transcriptions in primary granule constituents during myeloid proliferation and differentiation in patients with severe congenital neutropenia. Journal of Leukocyte Biology, 73, 225 234.
36. Klein, C., Grudzien, M., Appaswamy, G., Germeshausen, M., Sandrock, I., Schäffer, A.A., Rathinam, C., Boztug, K., Schwinzer, B., Rezaei, N., Bohn, G., Melin, M., Carlsson, G., Fadeel, B., Dahl, N., Palmblad, J., Henter, J.I., Zeidler, C., Grimbacher, B. Welte, K. (2007) HAX1 deficiency causes autosomal recessive severe CN (Kostmann disease). Nature Genetics, 39, 86 92.
37. Köllner, I., Sodeik, B., Schreek, S., Heyn, H., von Neuhoff, N., Germeshausen, M., Zeidler, C., Krüger, M., Schlegelberger, B., Welte, K. Beger, C. (2006) Mutations in neutrophil elastase causing congenital neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein response. Blood, 108, 493 500.
38. Kostmann, R. (1956) Infantile genetic agranulocytosis. Acta Paediatrica Scandinavica, 45, 1 78.
39. Kostmann, R. (1975) Infantile genetic agranulocytosis: a review with presentation of ten new cases. Acta Paediatrica Scandinavica, 64, 362 368.
40. Link, D.C., Kunter, G., Kasai, Y., Zhao, Y., Miner, T., McLellan, M.D., Ries, R.E., Kapur, D., Nagarajan, R., Dale, D.C., Bolyard, A.A., Boxer, L.A., Welte, K., Zeidler, C., Donadieu, J., Bellanné-Chantelot, C., Vardiman, J.W., Caligiuri, M.A., Bloomfield, C.D., DiPersio, J.F., Tomasson, M.H., Graubert, T.A., Westervelt, P., Watson, M., Shannon, W., Baty, J., Mardis, E.R., Wilson, R.K. Ley, T.J. (2007) Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe CN. Blood, 110, 1648 1655.
41. Liu, F., Kunter, G., Krem, M.M., Eades, W.C., Cain, J.A., Tomasson, M.H., Hennighausen, L. Link, D.C. (2008) Csf3r mutations in mice confers a strong clonal HSC advantage via activation of Stat5. Journal of Clinical Investigation, 118, 946 955.
42. Matsubara, K., Imai, K., Okada, S., Miki, M., Ishikawa, N., Tsumura, M., Kato, T., Ohara, O., Nonoyama, S. Kobayashi, M. (2007) Severe developmental delay and epilepsy in a Japanese patient with severe congenital neutropenia due to HAX1 deficiency. Haematologica, 92, e123 e125.
43. McLemore, M.L., Poursine-Laurent, J. Link, D.C. (1998) Increased granulocyte colony-stimulating factor responsiveness but normal resting granulopoiesis in mice carrying a targeted granulocyte colony-stimulating factor receptor mutation derived from a patient with severe congenital neutropenia. Journal of Clinical Investigation, 102, 483 492.
44. Moore, M.A., Dorn, D.C., Schuringa, J.J., Chung, K.Y. Morrone, G. (2007) Constitutive activation of Flt3 and STAT5A enhances self-renewal and alters differentiation of hematopoietic stem cells. Experimental Hematology, 35 (Suppl. 1 105 116.
45. Rezaei, N., Chavoshzadeh, Z., Alaei, O.R., Sandrock, I. Klein, C. (2008) Association of HAX1-deficiency with neurological disorder. Neuropediatrics, (in press).
46. Rosenberg, P.S., Alter, B.P., Bolyard, A.A., Bonilla, M.A., Boxer, L.A., Cham, B., Fier, C., Freedman, M., Kannourakis, G., Kinsey, S., Schwinzer, B., Zeidler, C., Welte, K. Dale, D.C. (2006) Severe Chronic Neutropenia International Registry. The incidence of leukemia and mortality from sepsis in patients with severe CN receiving long-term G-CSF therapy. Blood, 107, 4628 4635.
47. Rosenberg, P.S., Alter, B.P., Link, D.C., Stein, S., Rodger, E., Bolyard, A.A., Aprikyan, A.A., Bonilla, M.A., Dror, Y., Kannourakis, G., Newburger, P.E., Boxer, L.A. Dale, D.C. (2008) Neutrophil elastase mutations and risk of leukaemia in severe congenital neutropenia. British Journal of Haematology, 140, 210 213.
48. Schaffer, A.A. Klein, C. (2007) Genetic heterogeneity in severe congenital neutropenia: how many aberrant pathways can kill a neutrophil? Current Opinion in Allergy and Clinical Immunology, 7, 481 494.
49. Schilke, R., Stanulla, M., Finke, C.H., Felgenhauer, F.B., Strauss, G., Welte, K. Zeidler, C. (2006) Influence of periodontitis co-factors in patients with severe chronic neutropenia. Journal of Dental Research, 85 (Spec Iss A Nr.1138.
50. Skokowa, J., Cario, G., Uenalan, M., Schambach, A., Germeshausen, M., Battmer, K., Zeidler, C., Lehmann, U., Eder, M., Baum, C., Grosschedl, R., Stanulla, M., Scherr, M. Welte, K. (2006) LEF-1 is crucial for neutrophil granulocytopoiesis and its expression is severely reduced in CN. Nature Medicine, 12, 1191 1197.
51. Skokowa, J., Germeshausen, M., Zeidler, C. Welte, K. (2007) Severe congenital neutropenia: inheritance and pathophysiology. Current Opinion in Hematology, 14, 22 28.
52. Sloand, E.M., Yong, A.S., Ramkissoon, S., Solomou, E., Bruno, T.C., Kim, S., Fuhrer, M., Kajigaya, S., Barrett, A.J. Young, N.S. (2006) Granulocyte colony-stimulating factor preferentially stimulates proliferation of monosomy 7 cells bearing the isoform IV receptor. Proceedings of the National Academy of Sciences of the United States of America, 103, 14483 14488.
53. Tidow, N., Pilz, C., Teichmann, B., Müller-Brechlin, A., Germeshausen, M., Kasper, B., Rauprich, P., Sykora, K.W. Welte, K. (1997) Clinical relevance of point mutations in the cytoplasmatic domain of the granulocyte-colony stimulating factor gene in patients with severe CN. Blood, 88, 2369 2375.
54. Touw, I.P. van de Geijn, G.J. (2007) Granulocyte colony-stimulating factor and its receptor in normal myeloid cell development, leukemia and related blood cell disorders. Frontiers in Bioscience, 12, 800 815.
55. Tschan, C.A., Pilz, C., Zeidler, C., Welte, K. Germeshausen, M. (2001) Time course of increasing numbers of mutations in the granulocyte colony-stimulating factor receptor gene in a patient with CN who developed leukemia. Blood, 97, 1882 1884.
56. van de Geijn, G.J., Gits, J., Aarts, L.H., Heijmans-Antonissen, C. Touw, I.P. (2004) G-CSF receptor truncations found in SCN/AML relieve SOCS3-controlled inhibition of STAT5 but leave suppression of STAT3 intact. Blood, 104, 667 674.
57. Welte, K. Dale, D. (1996) Pathophysiology and treatment of severe chronic neutropenia. Annals of Hematology, 72, 158 165. Review.
58. Welte, K. Boxer, L. (1997) Severe chronic neutropenia: Pathophysiology and therapy. Seminars in Hematology, 34, 267 278.
59. Welte, K., Zeidler, C., Reiter, A., Müller, W., Odenwald, E., Souza, L. Riehm, H. (1990) Differential effects of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor in children with severe congenital neutropenia. Blood, 75, 1056 1063.
60. Welte, K., Zeidler, C. Dale, D.C. (2006) Severe congenital neutropenia. Seminars in Hematology, 43, 189 195.
61. Wierenga, A.T., Schepers, H., Moore, M.A., Vellenga, E. Schuringa, J.J. (2006) STAT5-induced self-renewal and impaired myelopoiesis of human hematopoietic stem/progenitor cells involves down-modulation of C/EBPalpha. Blood, 107, 4326 4333.
62. Xia, J. Link, D.C. (2008) Severe congenital neutropenia and the unfolded protein response. Current Opinion in Hematology, 15, 1 7. Review.
63. Yakisan, E., Schirg, E., Zeidler, C., Bishop, N.J., Reiter, A., Hirt, A., Riehm, H. Welte, K. (1997) High incidence of significant bone loss in patients with severe congenital neutropenia (Kostmann's syndrome). Journal of Pediatrics, 131, 592 597.
64. Zeidler, C., Welte, K., Barak, Y., Barriga, F., Bolyard, A.A., Boxer, L., Cornu, G., Cowan, M.J., Dale, D.C., Flood, T., Freedman, M., Gadner, H., Mandel, H., O'Reilly, R.J., Ramenghi, U., Reiter, A., Skinner, R., Vermylen, C. Levine, J.E. (2000a) Stem cell transplantation in patients with severe CN without evidence of leukemic transformation. Blood, 95, 1195 1198.
65. Zeidler, C., Boxer, L., Dale, D.C., Freedman, M.H., Kinsey, S. Welte, K. (2000b) Management of Kostmann syndrome in the G-CSF era. British Journal of Haematology, 109, 490 495.