This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
好中球分化異常と疾患
平 位 秀 世
Key words : Granulopoiesis, Transcription factor, Granulocyte-Colony Stimulating Factor(G-CSF), Severe
Fig. 1 Differentiation and Maturation of Neutrophils in Bone Marrow.HSC: hematopoietic stem cells, HPC: hematopoietic progenitor cells, MMP9: matrixmetalloproteinase 9.
Fig. 3 G-CSF-mediated Homeostasis of Neutrophilic Granulopoiesis at Steady State.Neutrophils released from bone marrows are eventually ingested by macrophages.Macrophages regulate neutrophilic granulopoiesis at least partly through secretionof G-CSF. Pathogen-associated molecular patterns(PAMPs)like lipopolysacchar-ides(LPS)are recognized by pattern recognition receptors(PRRs)includingtoll-like receptors(TLRs), which are expressed by hematopoietic or non-hematopoietic cells. Stimulation of non-hematopoietic cells by LPS result inincreased plasma G-CSF level. Although not indispensable, G-CSF is required fordifferentiation, maturation and release of neutrophils in bone marrows.GI tract: gastrointestinal tract.
Fig. 5 Recently Identified Signaling Pathways Downstream of G-CSF Receptor.Interactions among HAX1, HCLS1, LEF1, C/EBPa are abrogated in SCNpatients with HAX1 or ELANE mutations.
められるような多彩なスペクトラムの分子が,時空間的
に互いに関連しあいながらダイナミックに好中球の分
化・成熟,増殖,アポトーシスおよび機能を制御してい
る。本稿で紹介しきれなかった多くの部分を含めても,
解明されたことはまだ限定的あり,今後新たな発見が続
くと予想される。本稿が,基礎研究および臨床で必要な
好中球造血の理解の一助になれば幸いである。
著者の COI(conflicts of interest)開示:本論文発表内容に関連
して特に申告なし
文 献
1)Borregaard N, Sørensen OE, Theilgaard-Mönch K. Neutro-phil granules: a library of innate immunity proteins. TrendsImmunol. 2007; 28: 340-345.
2)Summers C, Rankin SM, Condliffe AM, Singh N, Peters AM,Chilvers ER. Neutrophil kinetics in health and disease.Trends Immunol. 2010; 31: 318-324.
3)Furze RC, Rankin SM. The role of the bone marrow inneutrophil clearance under homeostatic conditions in themouse. FASEB J. 2008; 22: 3111-3119.
4)Savill JS, Wyllie AH, Henson JE, Walport MJ, Henson PM,Haslett C. Macrophage phagocytosis of aging neutrophils ininflammation. Programmed cell death in the neutrophil leadsto its recognition by macrophages. J Clin Invest. 1989; 83:865-875.
5)Stark MA, Huo Y, Burcin TL, Morris MA, Olson TS, Ley K.Phagocytosis of apoptotic neutrophils regulates granulopoie-sis via IL-23 and IL-17. Immunity. 2005; 22: 285-294.
6)Borregaard N. Neutrophils, from marrow to microbes.Immunity. 2010; 33: 657-670.
7)Panopoulos AD, Watowich SS. Granulocyte colony-stimulating factor: molecular mechanisms of action duringsteady state and CemergencyD hematopoiesis. Cytokine. 2008;42: 277-288.
8)Lieschke GJ, Grail D, Hodgson G, et al. Mice lackinggranulocyte colony-stimulating factor have chronic neutrope-nia, granulocyte and macrophage progenitor cell deficiency,and impaired neutrophil mobilization. Blood. 1994; 84: 1737-1746.
9)Liu F, Wu HY, Wesselschmidt R, Kornaga T, Link DC.Impaired production and increased apoptosis of neutrophilsin granulocyte colony-stimulating factor receptor-deficientmice. Immunity. 1996; 5: 491-501.
10)Richards MK, Liu F, Iwasaki H, Akashi K, Link DC. Pivotalrole of granulocyte colony-stimulating factor in the develop-ment of progenitors in the common myeloid pathway. Blood.2003; 102: 3562-3568.
11)Bugl S, Wirths S, Radsak MP, et al. Steady-state neutrophilhomeostasis is dependent on TLR4/TRIF signaling. Blood.
2013; 121: 723-733.12)Ohkubo T, Tsuda M, Suzuki S, El Borai N, Yamamura M.
Peripheral blood neutrophils of germ-free rats modified by invivo granulocyte-colony-stimulating factor and exposure tonatural environment. Scand J Immunol. 1999; 49: 73-77.
15)Zhan Y, Lieschke GJ, Grail D, Dunn AR, Cheers C. Essentialroles for granulocyte-macrophage colony-stimulating factor(GM-CSF) and G-CSF in the sustained hematopoieticresponse of Listeria monocytogenes-infected mice. Blood.1998; 91: 863-869.
16)Kimura A, Kinjyo I, Matsumura Y, et al. SOCS3 is aphysiological negative regulator for granulopoiesis andgranulocyte colony-stimulating factor receptor signaling. JBiol Chem. 2004; 279: 6905-6910.
17)Croker BA, Metcalf D, Robb L, et al. SOCS3 is a criticalphysiological negative regulator of G-CSF signaling andemergency granulopoiesis. Immunity. 2004; 20: 153-165.
18)Smith LT, Hohaus S, Gonzalez DA, Dziennis SE, Tenen DG.PU.1 (Spi-1) and C/EBP a regulate the granulocyte colony-stimulating factor receptor promoter in myeloid cells. Blood.1996; 88: 1234-1247.
19)Zhang P, Iwama A, Datta MW, Darlington GJ, Link DC,Tenen DG. Upregulation of interleukin 6 and granulocytecolony-stimulating factor receptors by transcription factorCCAAT enhancer binding protein a (C/EBP a) is critical forgranulopoiesis. J Exp Med. 1998; 188: 1173-1184.
20)Suzow J, Friedman AD. The murine myeloperoxidasepromoter contains several functional elements, one of whichbinds a cell type-restricted transcription factor, myeloidnuclear factor 1 (MyNF1). Mol Cell Biol. 1993; 13: 2141-2151.
21)Ford AM, Bennett CA, Healy LE, Towatari M, Greaves MF,Enver T. Regulation of the myeloperoxidase enhancerbinding proteins Pu1, C-EBPa, -b, and -d during granulocyte-lineage specification. Proc Natl Acad Sci U S A. 1996; 93:10838-10843.
22)Britos-Bray M, Friedman AD. Core binding factor cannotsynergistically activate the myeloperoxidase proximal en-hancer in immature myeloid cells without c-Myb. Mol CellBiol. 1997; 17: 5127-5135.
23)Nuchprayoon I, Meyers S, Scott LM, Suzow J, Hiebert S,Friedman AD. PEBP2/CBF, the murine homolog of thehuman myeloid AML1 and PEBP2 b/CBF b proto-oncoproteins, regulates the murine myeloperoxidase andneutrophil elastase genes in immature myeloid cells. Mol
臨 床 血 液 54:10
35(1581)
Cell Biol. 1994; 14: 5558-5568.24)Tidow N, Welte K. Advances in understanding postreceptor
signaling in response to granulocyte colony-stimulatingfactor. Curr Opin Hematol. 1997; 4: 171-175.
25)Avalos BR. Molecular analysis of the granulocyte colony-stimulating factor receptor. Blood. 1996; 88: 761-777.
26)De La Luz Sierra M, Gasperini P, McCormick PJ, Zhu J,Tosato G. Transcription factor Gfi-1 induced by G-CSF is anegative regulator of CXCR4 in myeloid cells. Blood. 2007;110: 2276-2285.
27)Nakajima H, Ihle JN. Granulocyte colony-stimulating factorregulates myeloid differentiation through CCAAT/enhancer-binding protein e. Blood. 2001; 98: 897-905.
28)Hirai H, Zhang P, Dayaram T, et al. C/EBPb is required forCemergencyD granulopoiesis. Nat Immunol. 2006; 7: 732-739.
29)Zhang DE, Zhang P, Wang ND, Hetherington CJ, DarlingtonGJ, Tenen DG. Absence of granulocyte colony-stimulatingfactor signaling and neutrophil development in CCAATenhancer binding protein alpha-deficient mice. Proc NatlAcad Sci U S A. 1997; 94: 569-574.
30)Zhang P, Iwasaki-Arai J, Iwasaki H, et al. Enhancement ofhematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor C/EBP a.Immunity. 2004; 21: 853-863.
31)Radomska HS, Huettner CS, Zhang P, Cheng T, Scadden DT,Tenen DG. CCAAT/enhancer binding protein a is aregulatory switch sufficient for induction of granulocyticdevelopment from bipotential myeloid progenitors. Mol CellBiol. 1998; 18: 4301-4314.
32)Porse BT, Pedersen TA, Xu X, et al. E2F repression by C/EBPa is required for adipogenesis and granulopoiesis invivo. Cell. 2001; 107: 247-258.
33)Johansen LM, Iwama A, Lodie TA, et al. c-Myc is a criticaltarget for c/EBPa in granulopoiesis. Mol Cell Biol. 2001; 21:3789-3806.
34)Wang H, Iakova P, Wilde M, et al. C/EBPa arrests cellproliferation through direct inhibition of Cdk2 and Cdk4. MolCell. 2001; 8: 817-828.
35)Pulikkan JA, Dengler V, Peramangalam PS, et al. Cell-cycleregulator E2F1 and microRNA-223 comprise an autoregulato-ry negative feedback loop in acute myeloid leukemia. Blood.2010; 115: 1768-1778.
36)Pulikkan JA, Peramangalam PS, Dengler V, et al. C/EBParegulated microRNA-34a targets E2F3 during granulopoiesisand is down-regulated in AML with CEBPAmutations. Blood.2010; 116: 5638-5649.
37)Akashi K, Traver D, Miyamoto T, Weissman IL. A clonogeniccommon myeloid progenitor that gives rise to all myeloidlineages. Nature. 2000; 404: 193-197.
38)Bjerregaard MD, Jurlander J, Klausen P, Borregaard N,Cowland JB. The in vivo profile of transcription factorsduring neutrophil differentiation in human bone marrow.
Blood. 2003; 101: 4322-4332.39)Nerlov C. C/EBPa mutations in acute myeloid leukaemias.
Nat Rev Cancer. 2004; 4: 394-400.40)Pabst T, Mueller BU, Harakawa N, et al. AML1-ETO
41)Zheng R, Friedman AD, Levis M, Li L, Weir EG, Small D.Internal tandem duplication mutation of FLT3 blocks myeloiddifferentiation through suppression of C/EBPa expression.Blood. 2004; 103: 1883-1890.
42)Guibal FC, Alberich-Jorda M, Hirai H, et al. Identification of amyeloid committed progenitor as the cancer-initiating cell inacute promyelocytic leukemia. Blood. 2009; 114: 5415-5425.
43)Perrotti D, Cesi V, Trotta R, et al. BCR-ABL suppresses C/EBPa expression through inhibitory action of hnRNP E2. NatGenet. 2002; 30: 48-58.
44)Scott EW, Simon MC, Anastasi J, Singh H. Requirement oftranscription factor PU. 1 in the development of multiplehematopoietic lineages. Science. 1994; 265: 1573-1577.
45)Scott EW, Fisher RC, Olson MC, Kehrli EW, Simon MC,Singh H. PU. 1 functions in a cell-autonomous manner tocontrol the differentiation of multipotential lymphoid-myeloid progenitors. Immunity. 1997; 6: 437-447.
46)Iwasaki H, Somoza C, Shigematsu H, et al. Distinctive andindispensable roles of PU.1 in maintenance of hematopoieticstem cells and their differentiation. Blood. 2005; 106: 1590-1600.
47)Zhang P, Zhang X, Iwama A, et al. PU.1 inhibits GATA-1 func-tion and erythroid differentiation by blocking GATA-1 DNAbinding. Blood. 2000; 96: 2641-2648.
48)Arinobu Y, Mizuno S, Chong Y, et al. Reciprocal activation ofGATA-1 and PU.1 marks initial specification of hematopoieticstem cells into myeloerythroid and myelolymphoid lineages.Cell Stem Cell. 2007; 1: 416-427.
49)Reddy VA, Iwama A, Iotzova G, et al. Granulocyte inducer C/EBPa inactivates the myeloid master regulator PU.1:possible role in lineage commitment decisions. Blood. 2002;100: 483-490.
50)Rosenbauer F, Wagner K, Kutok JL, et al. Acute myeloid leu-kemia induced by graded reduction of a lineage-specifictranscription factor, PU.1. Nat Genet. 2004; 36: 624-630.
51)Steidl U, Steidl C, Ebralidze A, et al. A distal single nucleotidepolymorphism alters long-range regulation of the PU.1 genein acute myeloid leukemia. J Clin Invest. 2007; 117: 2611-2620.
52)Bonadies N, Pabst T, Mueller BU. Heterozygous deletion ofthe PU.1 locus in human AML. Blood. 2010; 115: 331-334.
53)Okuda T, van Deursen J, Hiebert SW, Grosveld G, DowningJR. AML1, the target of multiple chromosomal translocationsin human leukemia, is essential for normal fetal liverhematopoiesis. Cell. 1996; 84: 321-330.
54)Ichikawa M, Asai T, Saito T, et al. AML-1 is required for
−臨 床 血 液−
36(1582)
megakaryocytic maturation and lymphocytic differentiation,but not for maintenance of hematopoietic stem cells in adulthematopoiesis. Nat Med. 2004; 10: 299-304.
55)Growney JD, Shigematsu H, Li Z, et al. Loss of Runx1perturbs adult hematopoiesis and is associated with amyeloproliferative phenotype. Blood. 2005; 106: 494-504.
56)Huang G, Zhang P, Hirai H, et al. PU.1 is a major downstreamtarget of AML1 (RUNX1) in adult mouse hematopoiesis. NatGenet. 2008; 40: 51-60.
57)Guo H, Ma O, Speck NA, Friedman AD. Runx1 deletion ordominant inhibition reduces Cebpa transcription via con-served promoter and distal enhancer sites to favor monopoie-sis over granulopoiesis. Blood. 2012; 119: 4408-4418.
58)Mangan JK, Speck NA. RUNX1 mutations in clonal myeloiddisorders: from conventional cytogenetics to next generationsequencing, a story 40 years in the making. Crit Rev Oncog.2011; 16: 77‒91.
60)Horman SR, Velu CS, Chaubey A, et al. Gfi1 integratesprogenitor versus granulocytic transcriptional programming.Blood. 2009; 113: 5466-5475.
61)Karsunky H, Zeng H, Schmidt T, et al. Inflammatoryreactions and severe neutropenia in mice lacking thetranscriptional repressor Gfi1. Nat Genet. 2002; 30: 295-300.
62)Hock H, Hamblen MJ, Rooke HM, et al. Intrinsic require-ment for zinc finger transcription factor Gfi-1 in neutrophildifferentiation. Immunity. 2003; 18: 109-120.
63)Zarebski A, Velu CS, Baktula AM, et al. Mutations in growthfactor independent-1 associated with human neutropeniablock murine granulopoiesis through colony stimulatingfactor-1. Immunity. 2008; 28: 370-380.
64)Velu CS, Baktula AM, Grimes HL. Gfi1 regulates miR-21 andmiR-196b to control myelopoiesis. Blood. 2009; 113: 4720-4728.
65)Person RE, Li FQ, Duan Z, et al. Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2.Nat Genet. 2003; 34: 308-312.
66)Khandanpour C, Thiede C, Valk PJ, et al. A variant allele ofGrowth Factor Independence 1 (GFI1) is associated withacute myeloid leukemia. Blood. 2010; 115: 2462-2472.
67)Yamanaka R, Kim GD, Radomska HS, et al. CCAAT/enhancerbinding protein e is preferentially up-regulated duringgranulocytic differentiation and its functional versatility isdetermined by alternative use of promoters and differentialsplicing. Proc Natl Acad Sci U S A. 1997; 94: 6462-6467.
68)Yamanaka R, Barlow C, Lekstrom-Himes J, et al. Impairedgranulopoiesis, myelodysplasia, and early lethality inCCAAT/enhancer binding protein e-deficient mice. Proc NatlAcad Sci U S A. 1997; 94: 13187-13192.
69)Gery S, Gombart AF, Fung YK, Koeffler HP. C/EBPe
interacts with retinoblastoma and E2F1 during granulopoie-sis. Blood. 2004; 103: 828-835.
70)Lekstrom-Himes JA, Dorman SE, Kopar P, Holland SM,Gallin JI. Neutrophil-specific granule deficiency results froma novel mutation with loss of function of the transcriptionfactor CCAAT/enhancer binding protein e. J Exp Med. 1999;189: 1847-1852.
71)Gombart AF, Shiohara M, Kwok SH, Agematsu K, KomiyamaA, Koeffler HP. Neutrophil-specific granule deficiency:homozygous recessive inheritance of a frameshift mutation inthe gene encoding transcription factor CCAAT/enhancerbinding protein-e. Blood. 2001; 97: 2561-2567.
72)Akagi T, Saitoh T, ODKelly J, Akira S, Gombart AF, KoefflerHP. Impaired response to GM-CSF and G-CSF, and enhancedapoptosis in C/EBPb-deficient hematopoietic cells. Blood.2008; 111: 2999-3004.
73)Zhang HY, Nguyen-Jackson H, Panopoulos A, Li HS, MurrayPJ, Watowich S. STAT3 controls neutrophil progenitorgrowth and differentiation during emergency granulopoiesis.Blood. 2009; 114: 1399. Abstract 3619.
74)Satake S, Hirai H, Hayashi Y, et al. C/EBPb is involved in theamplification of early granulocyte precursors duringcandidemia-induced“emergency” granulopoiesis. J Immu-nol. 2012; 189: 4546-4555.
75)Hall CJ, Flores MV, Oehlers SH, et al. Infection-responsiveexpansion of the hematopoietic stem and progenitor cellcompartment in zebrafish is dependent upon inducible nitricoxide. Cell Stem Cell. 2012; 10: 198-209.
76)Duprez E, Wagner K, Koch H, Tenen DG. C/EBPb: a majorPML-RARA-responsive gene in retinoic acid-induced differen-tiation of APL cells. EMBO J. 2003; 22: 5806-5816.
77)Hayashi Y, Hirai H, Kamio N, et al. C/EBPb promotes BCR-ABL-mediated myeloid expansion and leukemic stem cellexhaustion. Leukemia. 2013; 27: 619-628.
78)Watanabe-Okochi N, Yoshimi A, Sato T, et al. The shortestisoform of C/EBPb, liver inhibitory protein (LIP), collabo-rates with Evi1 to induce AML in a mouse BMT model.Blood. 2013; 121: 4142-4155.
79)Klein C. Genetic defects in severe congenital neutropenia:emerging insights into life and death of human neutrophilgranulocytes. Annu Rev Immunol. 2011; 29: 399-413.
80)Connelly JA, Choi SW, Levine JE. Hematopoietic stem celltransplantation for severe congenital neutropenia. Curr OpinHematol. 2012; 19: 44-51.
81)Zeidler C, Germeshausen M, Klein C, Welte K. Clinicalimplications of ELA2-,HAX1-, and G-CSF-receptor(CSF3R)mutations in severe congenital neutropenia. Br J Haematol.2009; 144: 459-467.
82)Horwitz M, Benson KF, Person RE, Aprikyan AG, Dale DC.Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nat Genet.1999; 23: 433-436.
臨 床 血 液 54:10
37(1583)
83)Dale DC, Person RE, Bolyard AA, et al. Mutations in the geneencoding neutrophil elastase in congenital and cyclicneutropenia. Blood. 2000; 96: 2317-2322.
84)Belaaouaj A, McCarthy R, Baumann M, et al. Mice lackingneutrophil elastase reveal impaired host defense againstgram negative bacterial sepsis. Nat Med. 1998; 4: 615-618.
85)Grenda DS, Johnson SE, Mayer JR, et al. Mice expressing aneutrophil elastase mutation derived from patients withsevere congenital neutropenia have normal granulopoiesis.Blood. 2002; 100: 3221-3228.
86)Benson KF, Li FQ, Person RE, et al. Mutations associatedwith neutropenia in dogs and humans disrupt intracellulartransport of neutrophil elastase. Nat Genet. 2003; 35: 90-96.
87)Grenda DS, Murakami M, Ghatak J, et al. Mutations of theELA2 gene found in patients with severe congenitalneutropenia induce the unfolded protein response andcellular apoptosis. Blood. 2007; 110: 4179-4187.
88)Skokowa J, Fobiwe JP, Dan L, Thakur BK, Welte K.Neutrophil elastase is severely down-regulated in severecongenital neutropenia independent of ELA2 or HAX1mutations but dependent on LEF-1. Blood. 2009; 114: 3044-3051.
89)Klein C, Grudzien M, Appaswamy G, et al. HAX1 deficiencycauses autosomal recessive severe congenital neutropenia(Kostmann disease). Nat Genet. 2007; 39: 86-92.
90)Chao JR, Parganas E, Boyd K, Hong CY, Opferman JT, IhleJN. Hax1-mediated processing of HtrA2 by Parl allowssurvival of lymphocytes and neurons. Nature. 2008; 452: 98-102.
91)Skokowa J, Klimiankou M, Klimenkova O, et al. Interactionsamong HCLS1, HAX1 and LEF-1 proteins are essential for G-CSF-triggered granulopoiesis. Nat Med. 2012; 18: 1550-1559.
92)Boztug K, Appaswamy G, Ashikov A, et al. A syndrome withcongenital neutropenia and mutations in G6PC3. N Engl JMed. 2009; 360: 32-43.
93)Cheung YY, Kim SY, Yiu WH, et al. Impaired neutrophilactivity and increased susceptibility to bacterial infection inmice lacking glucose-6-phosphatase-b. J Clin Invest. 2007;117: 784-793.
94)Kim SY, Jun HS, Mead PA, Mansfield BC, Chou JY.Neutrophil stress and apoptosis underlie myeloid dysfunc-tion in glycogen storage disease type Ib. Blood. 2008; 111:5704-5711.
95)Chen LY, Shieh JJ, Lin B, et al. Impaired glucose homeostasis,neutrophil trafficking and function in mice lacking theglucose-6-phosphate transporter. Hum Mol Genet. 2003; 12:2547-2558.
96)Devriendt K, Kim AS, Mathijs G, et al. Constitutivelyactivating mutation in WASP causes X-linked severecongenital neutropenia. Nat Genet. 2001; 27: 313-317.
97)Moulding DA, Blundell MP, Spiller DG, et al. Unregulatedactin polymerization by WASp causes defects of mitosis andcytokinesis in X-linked neutropenia. J Exp Med. 2007; 204:2213-2224.
98)Ancliff PJ, Blundell MP, Cory GO, et al. Two novel activatingmutations in the Wiskott-Aldrich syndrome protein result incongenital neutropenia. Blood. 2006; 108: 2182-2189.
99)Skokowa J, Cario G, Uenalan M, et al. LEF-1 is crucial forneutrophil granulocytopoiesis and its expression is severelyreduced in congenital neutropenia. Nat Med. 2006; 12: 1191-1197.
100)Skokowa J, Lan D, Thakur BK, et al. NAMPT is essential forthe G-CSF-induced myeloid differentiation via a NAD+-sirtuin-1-dependent pathway. Nat Med. 2009; 15: 151-158.