sign in sign up
<<
Home , Agranulocytosis

Congenital

Kaan BOZTUĞ

Hannover Medical School, Department of Pediatric /Oncology, Almanya

ongenital neutropenia syndromes represent also carry heterozygous mutations in ELA2 (Dale C a heterogenous group of disorders affecting et al., 2000). To date, more than 50 distinct ELA2 both homeostasis and neutrophil mutations have been described in SCN (Horwitz function (Boztug et al., 2008b; Welte et al., 2006). et al., 2007), accounting for approximately 40% The neutropenia is called „severe“ when absolute of patients with SCN (SCN international registry, neutrophil counts (ANC) are below 0.5x109/L. unpublished results, 2008). We have recently been Patients with severe congenital neutropenia (SCN) able to identify mutations in the gene encoding the suffer from recurrent bacterial and fungal infec- mitochondrial protein HAX1 as a cause of autosom- tions, and without treatment with recombinant al recessive SCN (Klein et al., 2007). HAX1 muta- human G-CSF (rh-GCSF) children usually die with- tions were also identified as the cause of SCN in in their first years of life (Bonilla et al., 1989; Welte the original Kostmann pedigee (Klein et al., 2007). et al., 1990), while treatment with rh-G-CSF can HAX1 mutations may account for approximately lead to increased ANCs and decreased infectious 15% of patients with SCN (SCNIR, unpublished complications. However, the prognosis of patients results). Very rare genetic causes of SCN comprise with SCN is limited by a persistent susceptibility to mutations in GFI (Person et al., 2003), which is a even with normalized neutrophil counts zink-finger transcription factor critical for myeloid and the evolution of myelodysplastic syndromes differentiation, or activating mutations in the WAS or acute myeloid (AML). At present, the gene which disrupt the autoinhibitory state of the only curative therapy consists of allogeneic bone protein (Ancliff et al., 2006; Devriendt et al., 2001). marrow transplantation, which is associated with Recently, we were able to discover a novel subtype a favorable prognosis only when an HLA-matched of SCN associating neutropenia and complex devel- donor is available (Choi et al., 2005; Ferry et al., opmental aberrations, caused by mutations in the 2005; Zeidler et al., 2000). glucose-regulating gene G6PC3, the gene product of which is located in the endoplasmic reticulum Genetics of congenital neutropenia syndromes (Boztug et al., 2008a). Remarkable progress has been made with regards to the identification of the genetic defects In addition to the „classical Kostmann“-phe- causing SCN. The disease was initially described notype of SCN, several disorders combining con- by the Swedish pediatrician Rolf Kostmann in genital neutropenia and hypopigmentation have 1956 (Kostmann, 1956). Horwitz et al. discovered been described and have enabled an understand- heterozygous mutations in the gene encoding neu- ing of the complex interplay between the biol- trophil elastase (ELA2) in patients with autosomal ogy of lysosomes in pigmentation and immune dominant (CyN), a condition regulation (reviewed in (Stinchcombe et al., 2004)). with oscillating neutrophil counts but less severe Four distinct albinism-neutropenia disorders have clinical symptoms) (Horwitz et al., 1999). Subse- been described to date: Chédiak-Higashi syndrome quently, it was recognized that many patients suf- (CHS), Griscelli syndrome type 2, Hermansky-Pud- fering from autosomal dominant or sporadic SCN lak syndrome type 2 (HPS2) and p14 deficiency.

7-10 Ekim 2009, Antalya 187 BOZTUĞ K. Congenital Neutropenia

In contrast to SCN, mature are found 2006), a transcription factor with multiple target in bone marrow smears from these patients, while genes including C/EBPa. LEF-1 has a recognized, a paucity of neutrophils is present in peripheral critical role in myelopoiesis (Mueller and Pabst, blood. Chédiak-Higashi syndrome (Chediak, 1952; 2006), and ectopic expression of LEF-1 was able to Higashi, 1954) is characterized by hypopigmen- overcome the observed maturation arrest in SCN tation, bleeding diathesis and a complex immu- patient cells in vitro (Skokowa et al., 2006). An nodeficiency caused by defective NK cell function alternative hypothesis suggests that the observed and neutropenia (Grenda and Link, 2006). On a maturation „arrest“ may rather reflect increased molecular level, CHS is caused by mutations in lys- premature cell death at the level of osomal trafficking regulator (LYST/CHS) gene (Bar- stage of differentiation (Carlsson et al., 2006). bosa et al., 1996); however, some patients with a Intriguingly, several studies have shown that neu- CHS-like clinical phenotype do not show mutations trophils or bone marrow precursor cells from SCN in LYST/CHS, suggesting that there may be more patients show a phenotype of enhanced apoptosis genetic defects leading to a CHS phenotype. HPS2 as compared to cells from healthy individuals, is a rare disorder characterized by oculocutane- indepent of the underlying genetic etiology (Boztug ous albinism, defective thrombocyte granules, and et al., 2009; Carlsson et al., 2004; Grenda et al., bleeding diathesis in association with congenital 2007; Klein et al., 2007). neutropenia. The molecular defects are mutations in the AP3B1 gene, encoding a protein of the het- erotrimeric adaptor protein 3 (AP3) complex which A recent concept is that conditions which lead is crucial for the control of intracellular, vesicular to disturbance of the endoplasmic reticulum home- cargo transport (Dell‘Angelica et al., 1999). Finally, ostasis such as accumulation of misfolded proteins p14 deficiency has been described very recently can induce activation of an intracellular signaling as a syndrome of short stature, hypogammaglob- cascade called „unfolded protein response“, which ulinemia, reduced numbers of class-switched B may ultimately result in apoptosis. This mecha- lymphocytes and defective cytotoxic function, nism needs to be tightly controlled so that cells caused by mutations in the p14 (MAPBPIP) gene. can ensure the quality and abundance of poten- P14 is required for proper assembly of late endo- tially dangerous proteins. To prevent misfolding somes, as p14 deficient cells show an abnormally and overabundance of mutated molecules or in scattered distribution of late endosomes and con- response to alterations in the cellular status, sen- secutively altered mitogen-activated protein kinase sors facing the ER lumen and effectors which con- signal transduction (Bohn et al., 2006; Teis et al., vey the signal to other compartments of the cell. 2006). Three canonical pathways of ER stress transduc- ers have been identified, namely inositol-requiring Molecular pathophysiology of severe protein 1a (IRE1a), activating transcription fac- congenital neutropenia tor-6 (ATF6), and protein kinase RNA (PKR)-like The molecular pathophysiology underlying dif- ER kinase (PERK), respectively (reviewed in (Ron ferent genetic subforms of SCN has remained and Walter, 2007)). There is increasing evidence largely unclear. The most strking phenotype of that ER stress plays a cricitcal pathophysiological SCN is the observed, so-called „maturation arrest“ role in a variety of dieseases including diabetes of myeloid cells in the bone marrow. Initially, this mellitus, cancer or neurodegenerative disorders maturation arrest was thought to be the result of (reviewed in (Lin et al., 2008; Todd et al., 2008)). In defective cytokine signaling. However, the serum of case of ELA2 deficient SCN, activation of the UPR SCN patients contains normals or increased levels has been documented in by independent groups of of G-CSF and G-CSF receptors on neutrophils, investigators (Grenda et al., 2007; Köllner et al., with no impaired biological activity of G-CSF 2006). However, it is at present unclear whether (Kyas et al., 1992). More recently, the concept that this concept applies to other genetic forms of SCN an intrinsic defect of differentiation as well. Of note, as part of our very recent discov- underlies the neutropenia phenotype has gained ery of human G6PC3 deficiency as a novel SCN support, and Skokowa et al. were able to dem- syndrome, we could document the importance of onstrate that myeloid progenitor cells from SCN an adequate control of glucose homeostasis for the patients have markedly decreased levels of lym- endoplasmic reticulum in neutrophils (Boztug et phoid enhancer factor-1 (LEF-1) (Skokowa et al., al., 2008a).

188 35. Ulusal Hematoloji Kongresi Congenital Neutropenia BOZTUĞ K.

Taken together, the molecular mechanisms of 8. Carlsson, G., Andersson, M., Putsep, K., Garwicz, neutrophil apoptosis in various genetic subforms D., Nordenskjold, M., Henter, J. I., Palmblad, are thus far incompletely understood. Nonetheless, J., and Fadeel, B. (2006). Kostmann syndrome recent studies have provided evidence of activation or infantile genetic agranulocytosis, part one: celebrating 50 years of clinical and basic research of the unfolded protein response in SCN, and it is on severe congenital neutropenia. Acta Paediatr 95, an interesting concept that this may provide a uni- 1526-1532. fying explanation of the neutropenia seen in SCN 9. Carlsson, G., Aprikyan, A. A., Tehranchi, R., Dale, of different genetic etiology. Our findings may also D. C., Porwit, A., Hellstrom-Lindberg, E., Palmblad, help to understand general pathophysiologic path- J., Henter, J. I., and Fadeel, B. (2004). Kostmann ways which may be applicable to other pathologies syndrome: severe congenital neutropenia associated with defective expression of Bcl-2, such as neurodegenerative diseases or cancer. constitutive mitochondrial release of cytochrome c, and excessive apoptosis of myeloid progenitor cells. Blood 103, 3355-3361. References 10. Chediak, M. (1952). Nouvelle anomalie leucocytaire de caractère constitutionnel et familial. Rev Hèmat 1. Ancliff, P. J., Blundell, M. P., Cory, G. O., Calle, 7, 362-367. Y., Worth, A., Kempski, H., Burns, S., Jones, 11. Choi, S. W., Boxer, L. A., Pulsipher, M. A., G. E., Sinclair, J., Kinnon, C., et al. (2006). Two Roulston, D., Hutchinson, R. J., Yanik, G. A., novel activating mutations in the Wiskott-Aldrich Cooke, K. R., Ferrara, J. L., and Levine, J. E. syndrome protein result in congenital neutropenia. (2005). Stem cell transplantation in patients with Blood 108, 2182-2189. severe congenital neutropenia with evidence of leukemic transformation. Bone Marrow Transplant 2. Barbosa, M. D., Nguyen, Q. A., Tchernev, V. T., 35, 473-477. Ashley, J. A., Detter, J. C., Blaydes, S. M., Brandt, S. J., Chotai, D., Hodgman, C., Solari, R. C., et 12. Dale, D. C., Person, R. E., Bolyard, A. A., al. (1996). Identification of the homologous beige Aprikyan, A. G., Bos, C., Bonilla, M. A., Boxer, L. and Chediak-Higashi syndrome genes. Nature 382, A., Kannourakis, G., Zeidler, C., Welte, K., et al. 262-265. (2000). Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. 3. Bohn, G., Allroth, A., Brandes, G., Thiel, J., Blood 96, 2317-2322. Glocker, E., Schäffer, A. A., Rathinam, C., Taub, 13. Dell‘Angelica, E. C., Shotelersuk, V., Aguilar, R. C., N., Teis, D., Zeidler, C., et al. (2006). A novel Gahl, W. A., and Bonifacino, J. S. (1999). Altered human primary syndrome trafficking of lysosomal proteins in Hermansky- caused by deficiency of the endosomal adaptor Pudlak syndrome due to mutations in the beta 3A protein p14. Nat Med 13, 38-45. subunit of the AP-3 adaptor. Mol Cell 3, 11-21. 14. Devriendt, K., Kim, A. S., Mathijs, G., Frints, S. 4. Bonilla, M. A., Gillio, A. P., Ruggeiro, M., Kernan, G., Schwartz, M., Van Den Oord, J. J., Verhoef, G. N. A., Brochstein, J. A., Abboud, M., Fumagalli, L., E., Boogaerts, M. A., Fryns, J. P., You, D., et al. Vincent, M., Gabrilove, J. L., and Welte, K. (1989). (2001). Constitutively activating mutation in WASP Effects of recombinant human granulocyte colony- causes X-linked severe congenital neutropenia. Nat stimulating factor on neutropenia in patients with Genet 27, 313-317. congenital agranulocytosis. N Engl J Med 320, 1574-1580. 15. Di Sano, F., Ferraro, E., Tufi, R., Achsel, T., Piacentini, M., and Cecconi, F. (2006). 5. Boztug, K., Appaswamy, G., Ashikov, A., Schäffer, Endoplasmic reticulum stress induces apoptosis A. A., Salzer, U., Diestelhorst, J., Germeshausen, by an apoptosome-dependent but caspase 12- M., Brandes, G., Lee-Gossler, J., Noyan, F., et al. independent mechanism. J Biol Chem 281, 2693- (2008a). A novel syndrome with severe congenital 2700. neutropenia is caused by mutations in G6PC3. N 16. Ferry, C., Ouachee, M., Leblanc, T., Michel, G., Engl J Med, in press. Notz-Carrere, A., Tabrizi, R., Flood, T., Lutz, P., Fischer, A., Gluckman, E., and Donadieu, J. 6. Boztug, K., Appaswamy, G., Ashikov, A., Schaffer, (2005). Hematopoietic stem cell transplantation in A. A., Salzer, U., Diestelhorst, J., Germeshausen, severe congenital neutropenia: experience of the M., Brandes, G., Lee-Gossler, J., Noyan, F., et al. French SCN register. Bone Marrow Transplant 35, (2009). A syndrome with congenital neutropenia 45-50. and mutations in G6PC3. N Engl J Med 360, 32- 43. 17. Germain, M., Milburn, J., and Duronio, V. (2008). MCL-1 inhibits BAX in the absence of MCL-1/BAX Interaction. J Biol Chem 283, 6384-6392. 7. Boztug, K., Welte, K., Zeidler, C., and Klein, C. (2008b). Congenital neutropenia syndromes. 18. Grenda, D. S., and Link, D. C. (2006). Mechanisms Immunol Allergy Clin North Am 28, 259-275, vii- of disordered granulopoiesis in congenital viii. neutropenia. Curr Top Dev Biol 74, 133-176.

7-10 Ekim 2009, Antalya 189 BOZTUĞ K. Congenital Neutropenia

19. Grenda, D. S., Murakami, M., Ghatak, J., Xia, J., 30. Person, R. E., Li, F. Q., Duan, Z., Benson, K. F., Boxer, L. A., Dale, D., Dinauer, M. C., and Link, Wechsler, J., Papadaki, H. A., Eliopoulos, G., D. C. (2007). Mutations of the ELA2 gene found Kaufman, C., Bertolone, S. J., Nakamoto, B., et al. in patients with severe congenital neutropenia (2003). Mutations in proto-oncogene GFI1 cause induce the unfolded protein response and cellular human neutropenia and target ELA2. Nat Genet apoptosis. Blood 110, 4179-4187. 34, 308-312. 20. Hetz, C., Bernasconi, P., Fisher, J., Lee, A. H., 31. Ron, D., and Walter, P. (2007). Signal integration Bassik, M. C., Antonsson, B., Brandt, G. S., in the endoplasmic reticulum unfolded protein Iwakoshi, N. N., Schinzel, A., Glimcher, L. H., and response. Nat Rev Mol Cell Biol 8, 519-529. Korsmeyer, S. J. (2006). Proapoptotic BAX and 32. Skokowa, J., Cario, G., Uenalan, M., Schambach, BAK modulate the unfolded protein response by A., Germeshausen, M., Battmer, K., Zeidler, C., a direct interaction with IRE1alpha. Science 312, Lehmann, U., Eder, M., Baum, C., et al. (2006). 572-576. LEF-1 is crucial for neutrophil granulocytopoiesis 21. Higashi, O. (1954). Congenital gigantism of and its expression is severely reduced in congenital peroxidase granules: the first case ever reported of neutropenia. Nat Med 12, 1191-1197. qualitative abnormity of peroxidase. Tohoku J Exp 33. Stinchcombe, J., Bossi, G., and Griffiths, G. M. Med 59, 315-332. (2004). Linking albinism and immunity: the secrets 22. Horwitz, M., Benson, K. F., Person, R. E., Aprikyan, of secretory lysosomes. Science 305, 55-59. A. G., and Dale, D. C. (1999). Mutations in ELA2, 34. Suzuki, Y., Demoliere, C., Kitamura, D., Takeshita, encoding neutrophil elastase, define a 21-day H., Deuschle, U., and Watanabe, T. (1997). biological clock in cyclic haematopoiesis. Nat Genet HAX-1, a novel intracellular protein, localized 23, 433-436. on mitochondria, directly associates with HS1, 23. Horwitz, M. S., Duan, Z., Korkmaz, B., Lee, H. a substrate of Src family tyrosine kinases. J H., Mealiffe, M. E., and Salipante, S. J. (2007). Immunol 158, 2736-2744. Neutrophil elastase in cyclic and severe congenital 35. Teis, D., Taub, N., Kurzbauer, R., Hilber, D., de neutropenia. Blood 109, 1817-1824. Araujo, M. E., Erlacher, M., Offterdinger, M., 24. Klein, C., Grudzien, M., Appaswamy, G., Villunger, A., Geley, S., Bohn, G., et al. (2006). Germeshausen, M., Sandrock, I., Schäffer, A. A., p14-MP1-MEK1 signaling regulates endosomal Rathinam, C., Boztug, K., Schwinzer, B., Rezaei, traffic and cellular proliferation during tissue B., et al. (2007). HAX1 deficiency causes autosomal homeostasis. J Cell Biol 175, 861-868. recessive severe congenital neutropenia (Kostmann 36. Todd, D. J., Lee, A. H., and Glimcher, L. H. (2008). disease). Nat Genet 39, 86-92. The endoplasmic reticulum stress response in 25. Köllner, I., Sodeik, B., Schreek, S., Heyn, H., immunity and autoimmunity. Nat Rev Immunol 8, von Neuhoff, N., Germeshausen, M., Zeidler, C., 663-674. Kruger, M., Schlegelberger, B., Welte, K., and 37. Welte, K., Zeidler, C., and Dale, D. C. (2006). Beger, C. (2006). Mutations in neutrophil elastase Severe congenital neutropenia. Semin Hematol 43, causing congenital neutropenia lead to cytoplasmic 189-195. protein accumulation and induction of the 38. Welte, K., Zeidler, C., Reiter, A., Muller, W., unfolded protein response. Blood 108, 493-500. Odenwald, E., Souza, L., and Riehm, H. (1990). 26. Kostmann, R. (1956). Infantile genetic Differential effects of granulocyte- agranulocytosis; agranulocytosis infantilis colony-stimulating factor and granulocyte hereditaria. Acta Paediatr 45 (Suppl 105), 1-78. colony-stimulating factor in children with severe 27. Kyas, U., Pietsch, T., and Welte, K. (1992). congenital neutropenia. Blood 75, 1056-1063. Expression of receptors for granulocyte colony- 39. Zeidler, C., Welte, K., Barak, Y., Barriga, F., stimulating factor on neutrophils from patients Bolyard, A. A., Boxer, L., Cornu, G., Cowan, M. with severe congenital neutropenia and cyclic J., Dale, D. C., Flood, T., et al. (2000). Stem cell neutropenia. Blood 79, 1144-1147. transplantation in patients with severe congenital 28. Lin, J. H., Walter, P., and Yen, T. S. (2008). neutropenia without evidence of leukemic Endoplasmic reticulum stress in disease transformation. Blood 95, 1195-1198. pathogenesis. Annu Rev Pathol 3, 399-425. 29. Mueller, B. U., and Pabst, T. (2006). C/EBPalpha and the pathophysiology of acute myeloid leukemia. Curr Opin Hematol 13, 7-14.

190 35. Ulusal Hematoloji Kongresi