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Tryptophan in Molecular Hematopoiesis

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Book cover Tryptophan Metabolism: Implications for Biological Processes, Health and Disease

Part of the book series: Molecular and Integrative Toxicology ((MOLECUL))

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Abstract

The localizations of tryptophan residues are evident in membrane-binding proteins that are functional in hematopoiesis. Tryptophan at the transmembrane–cytosolic junction modulates the main cytokine of megakaryothrombocytopoiesis, the thrombopoietin receptor (TpoR), dimerization, and activation. Tryptophan is absolutely required at juxtamembrane position 515 to maintain the unliganded TpoR inactive. Tryptophan is located in the bone marrow microenvironment for the modulation of hematopoiesis. Likewise, endonexin also has a tryptophan residue that interacts strongly with membrane phospholipids. Tryptophan and tryptophan metabolism could have a role in the development of hematological neoplastic disorders. For instance, modulation of the tryptophan catabolism by human leukemic cells results in the conversion of CD25– into CD25+ T regulatory cells. The expression of indoleamine 2,3-dioxygenase (IDO), which is induced by interferon-gamma (IFN-gamma) and catalyzes the conversion from tryptophan to kynurenine, has been identified as a T-cell inhibitory effector pathway in professional antigen-presenting cells in the marrow stroma. Human acute monoblastic leukemia (AML-M5) and acute lymphoblastic leukemia (ALL) express IDO, and both can be treated by 1-methyltryptophan in mice. Tryptophan metabolism is deregulated in the pathobiology of numerous hematological disorders including myeloid leukemia, plasma cell myeloma, lymphoma, immune thrombocytopenic purpura (ITP), and graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation (HSCT). The aim of this chapter is to outline the status of tryptophan and tryptophan metabolism in normal and neoplastic hematopoiesis. Pharmacological and cellular therapeutics are being developed for the modulation of tryptophan metabolism for the better management of the patients with hematological neoplastic diseases.

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References

  • Alcock RS (1933) The role of tryptophan in blood development. Biochem J 27:754

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bagnost T, Ma L, da Silva RF et al (2010) Cardiovascular effects of arginase inhibition in spontaneously hypertensive rats with fully developed hypertension. Cardiovasc Res 87:569–577

    Article  CAS  PubMed  Google Scholar 

  • Barge RM, de Koning JP, Pouwels K, Dong F, Lowenberg B, Touw IP (1996) Tryptophan 650 of human granulocyte colony-stimulating factor (G-CSF) receptor, implicated in the activation of JAK2, is also required for G-CSF-mediated activation of signaling complexes of the p21ras route. Blood 87:2148–2153

    CAS  PubMed  Google Scholar 

  • Baris S, Celkan T, Batar B et al (2009) Association between genetic polymorphism in DNA repair genes and risk of B-cell lymphoma. Pediatr Hematol Oncol 26:467–472

    Article  CAS  PubMed  Google Scholar 

  • Barnes NA, Stephenson SJ, Tooze RM, Doody GM (2009) Amino acid deprivation links BLIMP-1 to the immunomodulatory enzyme indoleamine 2,3-dioxygenase. J Immunol 183:5768–5777

    Article  CAS  PubMed  Google Scholar 

  • Berthon C, Fontenay M, Corm S et al (2013) Metabolites of tryptophan catabolism are elevated in sera of patients with myelodysplastic syndromes and inhibit hematopoietic progenitor amplification. Leukemia Res 37:573–579

    Article  CAS  Google Scholar 

  • Bracher NA, Lyons CA, Wessels G, Mansvelt E, Coetzer TL (2001) Band 3 Cape Town (E90K) causes severe hereditary spherocytosis in combination with band 3 Prague III. Br J Haematol 113:689–693

    Article  CAS  PubMed  Google Scholar 

  • Camilleri RS, Cohen H, Mackie IJ et al (2008) Prevalence of the ADAMTS-13 missense mutation R1060W in late onset adult thrombotic thrombocytopenic purpura. J Thromb Haemost 6:331–338

    Article  CAS  PubMed  Google Scholar 

  • Chamuleau ME, van de Loosdrecht AA, Hess CJ et al (2008) High INDO (indoleamine 2,3-dioxygenase) mRNA level in blasts of acute myeloid leukemic patients predicts poor clinical outcome. Haematologica 93:1894–1898

    Article  CAS  PubMed  Google Scholar 

  • Chen J, Williams IR, Kutok JL et al (2004) Positive and negative regulatory roles of the WW-like domain in TEL-PDGFbetaR transformation. Blood 104:535–542

    Article  CAS  PubMed  Google Scholar 

  • Chen W, Liang X, Peterson AJ, Munn DH, Blazar BR (2008) The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation. J Immunol 181:5396–5404

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chiesa MD, Carlomagno S, Frumento G et al (2006) The tryptophan catabolite l-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function. Blood 108:4118–4125

    Article  PubMed  Google Scholar 

  • Curti A, Pandolfi S, Valzasina B et al (2007) Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25- into CD25+ T regulatory cells. Blood 109:2871–2877

    CAS  PubMed  Google Scholar 

  • Curti A, Trabanelli S, Salvestrini V, Baccarani M, Lemoli RM (2009) The role of indoleamine 2,3-dioxygenase in the induction of immune tolerance: focus on hematology. Blood 113:2394–2401

    Article  CAS  PubMed  Google Scholar 

  • Curti A, Trabanelli S, Onofri C et al (2010) Indoleamine 2,3-dioxygenase-expressing leukemic dendritic cells impair a leukemia-specific immune response by inducing potent T regulatory cells. Haematologica 95:2022–2030

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Damm F, Thol F, Hollink I et al (2011) Prevalence and prognostic value of IDH1 and IDH2 mutations in childhood AML: a study of the AML-BFM and DCOG study groups. Leukemia 25:1704–1710

    Article  CAS  PubMed  Google Scholar 

  • De Ravin SS, Zarember KA, Long-Priel D et al (2010) Tryptophan/kynurenine metabolism in human leukocytes is independent of superoxide and is fully maintained in chronic granulomatous disease. Blood 116:1755–1760

    Article  PubMed Central  PubMed  Google Scholar 

  • Defour JP, Itaya M, Gryshkova V et al (2013) Tryptophan at the transmembrane-cytosolic junction modulates thrombopoietin receptor dimerization and activation. Proc Natl Acad Sci U S A 110:2540–2545

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Doig RG, Begley CG, McGrath KM (1994) Hereditary protein C deficiency associated with mutations in exon IX of the protein C gene. Thromb Haemost 72:203–208

    CAS  PubMed  Google Scholar 

  • Ebuehi OA, Olaosebikan O, Renner JK (2009) Blood chemistry, hematology and tryptophan level in cerebral malaria children. Nig Q J Hosp Med 19:142–144

    CAS  PubMed  Google Scholar 

  • Falini B, Bolli N, Shan J et al (2006a) Both carboxy-terminus NES motif and mutated tryptophan(s) are crucial for aberrant nuclear export of nucleophosmin leukemic mutants in NPMc+ AML. Blood 107:4514–4523

    Article  CAS  PubMed  Google Scholar 

  • Falini B, Martelli MP, Bolli N et al (2006b) Immunohistochemistry predicts nucleophosmin (NPM) mutations in acute myeloid leukemia. Blood 108:1999–2005

    Article  CAS  PubMed  Google Scholar 

  • Falini B, Nicoletti I, Martelli MF, Mecucci C (2007) Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features. Blood 109:874–885

    Article  CAS  PubMed  Google Scholar 

  • Gajewski TF (2004) Overcoming immune resistance in the tumor microenvironment by blockade of indoleamine 2,3-dioxygenase and programmed death ligand 1. Curr Opin Investig Drugs 5:1279–1283

    CAS  PubMed  Google Scholar 

  • Gieseke F, Schutt B, Viebahn S et al (2007) Human multipotent mesenchymal stromal cells inhibit proliferation of PBMCs independently of IFNgammaR1 signaling and IDO expression. Blood 110:2197–2200

    Article  CAS  PubMed  Google Scholar 

  • Goker H, Haznedaroglu IC, Chao NJ (2001) Acute graft-vs-host disease: pathobiology and management. Exp Hematol 29:259–277

    Article  CAS  PubMed  Google Scholar 

  • Hadrup S, Donia M, Thor Straten P (2013) Effector CD4 and CD8 T cells and their role in the tumor microenvironment. Cancer Microenviron Off J Int Cancer Microenviron Soc: 6:123–133

    Google Scholar 

  • Hainz U, Obexer P, Winkler C et al (2005) Monocyte-mediated T-cell suppression and augmented monocyte tryptophan catabolism after human hematopoietic stem-cell transplantation. Blood 105:4127–4134

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Haznedaroglu IC, Beyazit Y (2010) Pathobiological aspects of the local bone marrow renin-angiotensin system: a review. J Renin Angiotensin Aldosterone Syst 11:205–213

    Article  CAS  PubMed  Google Scholar 

  • Haznedaroglu IC, Beyazit Y (2013) Local bone marrow renin-angiotensin system in primitive, definitive and neoplastic haematopoiesis. Clin Sci 124:307–323

    Article  CAS  PubMed  Google Scholar 

  • Haznedaroglu IC, Arici M, Buyukasik Y (2000) A unifying hypothesis for the renin-angiotensin system and hematopoiesis: sticking the pieces together with the JAK-STAT pathway. Med Hypotheses 54:80–83

    Article  CAS  PubMed  Google Scholar 

  • Haznedaroglu IC, Goker H, Turgut M, Buyukasik Y, Benekli M (2002) Thrombopoietin as a drug: biologic expectations, clinical realities, and future directions. Clin Appl Thromb Hemost 8:193–212

    Article  CAS  PubMed  Google Scholar 

  • Heitger A, Juergens B, Hainz U, Fuchs D (2006) Potential tolerizing capacity of human dendritic cells featuring high levels of expression and activity of the tryptophan metabolizing enzyme indoleamine 2,3 dioxygenase. ASH Ann Meet Abstr 108:623

    Google Scholar 

  • Hoshi M, Ito H, Fujigaki H et al (2009) Indoleamine 2,3-dioxygenase is highly expressed in human adult T-cell leukemia/lymphoma and chemotherapy changes tryptophan catabolism in serum and reduced activity. Leuk Res 33:39–45

    Article  CAS  PubMed  Google Scholar 

  • Hou DY, Muller AJ, Sharma MD et al (2007) Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. Cancer Res 67:792–801

    Article  CAS  PubMed  Google Scholar 

  • Jia L, Schweikart K, Tomaszewski J et al (2008) Toxicology and pharmacokinetics of 1-methyl-d-tryptophan: absence of toxicity due to saturating absorption. Food Chem Toxicol 46:203–211

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kizaki M, Miller CW, Selsted ME, Koeffler HP (1994) Myeloperoxidase (MPO) gene mutation in hereditary MPO deficiency. Blood 83:1935–1940

    CAS  PubMed  Google Scholar 

  • Landfried K, Zhu W, Waldhier MC et al (2011) Tryptophan catabolism is associated with acute GVHD after human allogeneic stem cell transplantation and indicates activation of indoleamine 2,3-dioxygenase. Blood 118:6971–6974

    Article  CAS  PubMed  Google Scholar 

  • Lankhof H, Damas C, Schiphorst ME et al (1997) Functional studies on platelet adhesion with recombinant von Willebrand factor type 2B mutants R543Q and R543W under conditions of flow. Blood 89:2766–2772

    CAS  PubMed  Google Scholar 

  • Lankhof H, Damas C, Schiphorst ME et al (1999) Recombinant vWF type 2A mutants R834Q and R834W show a defect in mediating platelet adhesion to collagen, independent of enhanced sensitivity to a plasma protease. Thromb Haemost 81:976–983

    CAS  PubMed  Google Scholar 

  • Laurence A, Edbury SM, Marinaki AM et al (2007) 4-pyridone-3-carboxamide ribonucleoside triphosphate accumulating in erythrocytes in end stage renal failure originates from tryptophan metabolism. Clin Exp Med 7:135–141

    Article  CAS  PubMed  Google Scholar 

  • Lob S, Konigsrainer A, Schafer R, Rammensee H-G, Opelz G, Terness P (2008) Levo- but not dextro-1-methyl tryptophan abrogates the IDO activity of human dendritic cells. Blood 111:2152–2154

    Article  CAS  PubMed  Google Scholar 

  • Lob S, Konigsrainer A, Rammensee HG, Opelz G, Terness P (2009) Inhibitors of indoleamine-2,3-dioxygenase for cancer therapy: can we see the wood for the trees? Nat Rev Cancer 9:445–452

    Article  PubMed  Google Scholar 

  • Meers P (1990) Location of tryptophans in membrane-bound annexins. Biochemistry 29:3325–3330

    Article  CAS  PubMed  Google Scholar 

  • Meisel R, Zibert A, Laryea M, Göbel U, Däubener W, Dilloo D (2004) Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase–mediated tryptophan degradation. Blood 103:4619–4621

    Article  CAS  PubMed  Google Scholar 

  • Meisel R, Brockers S, Heseler K et al (2011) Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase. Leukemia 25:648–654

    Article  CAS  PubMed  Google Scholar 

  • Mussai F, De Santo C, Abu-Dayyeh I et al (2013) Acute myeloid leukemia creates an arginase-dependent immunosuppressive microenvironment. Blood 122:749–758

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ninomiya S, Tsurumi H, Hara T et al (2010) Tryptophan catabolism is associated with clinical outcome of patients with malignant lymphoma. ASH Annu Meeting Abstr 116:4146

    Google Scholar 

  • Noda M, Fujimura K, Takafuta T et al (1995) Heterogeneous expression of glycoprotein Ib, IX and V in platelets from two patients with Bernard-Soulier syndrome caused by different genetic abnormalities. Thromb Haemost 74:1411–1415

    CAS  PubMed  Google Scholar 

  • Nowak EC, de Vries VC, Wasiuk A et al (2012) Tryptophan hydroxylase-1 regulates immune tolerance and inflammation. J Exp Med 209:2127–2135

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ogasawara N, Oguro T, Sakabe T et al (2009) Hemoglobin induces the expression of indoleamine 2,3-dioxygenase in dendritic cells through the activation of PI3K, PKC, and NF-kappaB and the generation of reactive oxygen species. J Cell Biochem 108:716–725

    Article  CAS  PubMed  Google Scholar 

  • Pardanani AD, Levine RL, Lasho T et al (2006) MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 108:3472–3476

    Article  CAS  PubMed  Google Scholar 

  • Pastore YD, Jelinek J, Ang S et al (2003) Mutations in the VHL gene in sporadic apparently congenital polycythemia. Blood 101:1591–1595

    Article  CAS  PubMed  Google Scholar 

  • Peng W, Quinn-Allen MA, Kim SW, Alexander KA, Kane WH (2004) Trp 2063 and Trp2064 in the factor Va C2 domain are required for high-affinity binding to phospholipid membranes but not for assembly of the prothrombinase complex. Biochemistry 43:4385–4393

    Article  CAS  PubMed  Google Scholar 

  • Pfeifer S, Schreder M, Bolomsky A et al (2012) Induction of indoleamine-2,3 dioxygenase in bone marrow stromal cells inhibits myeloma cell growth. J Cancer Res Clin Oncol 138:1821–1830

    Article  CAS  PubMed  Google Scholar 

  • Pieneman WC, Fay P, Briet E, Reitsma PH, Bertina RM (1998) Partial reconstitution of factor VIII activity from a mild Crm+ hemophilia A patient by replacement of the defective A2 domain. Thromb Haemost 79:943–948

    CAS  PubMed  Google Scholar 

  • Poort SR, Landolfi R, Bertina RM (1997) Compound heterozygosity for two novel missense mutations in the prothrombin gene in a patient with a severe bleeding tendency. Thromb Haemost 77:610–615

    CAS  PubMed  Google Scholar 

  • Rosenblatt J, Bissonnette A, Ahmad R et al (2010) Immunomodulatory effects of vitamin D: implications for GVHD. Bone Marrow Transplant 45:1463–1468

    Article  CAS  PubMed  Google Scholar 

  • Rutella S, Bonanno G, De Cristofaro R (2009) Targeting indoleamine 2,3-dioxygenase (IDO) to counteract tumour-induced immune dysfunction: from biochemistry to clinical development. Endocr Metab Immune Disord Drug Targets 9:151–177

    Article  CAS  PubMed  Google Scholar 

  • Shatanawi A, Romero MJ, Iddings JA et al (2011) Angiotensin II-induced vascular endothelial dysfunction through RhoA/Rho kinase/p38 mitogen-activated protein kinase/arginase pathway. Am J Physiol Cell Physiol 300:C1181–C1192

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sorensen RB, Kollgaard T, Andersen RS et al (2011) Spontaneous cytotoxic T-cell reactivity against indoleamine 2,3-dioxygenase-2. Cancer Res 71:2038–2044

    Article  CAS  PubMed  Google Scholar 

  • Stover EH, Chen J, Folens C et al (2006) Activation of FIP1L1-PDGFRalpha requires disruption of the juxtamembrane domain of PDGFRalpha and is FIP1L1-independent. Proc Natl Acad Sci U S A 103:8078–8083

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sun JX, Zhang WG, Chen YX et al (2007) Indoleamine 2, 3-dioxygenase expression in cells of human acute monocyte leukemia (M(5)) and acute lymphocyte leukemia and therapeutic effect of its inhibitor 1-methyl tryptophan. Zhongguo shi yan xue ye xue za zhi Zhongguo bing li sheng li xue hui J Exp Hematol Chin Assoc Pathophysiol 15:478–482

    CAS  Google Scholar 

  • Trabanelli S, Ocadlikova D, Evangelisti C, Parisi S, Curti A (2011) Induction of regulatory T cells by dendritic cells through indoleamine 2,3-dioxygenase: a potent mechanism of acquired peripheral tolerance. Curr Med Chem 18:2234–2239

    Article  CAS  PubMed  Google Scholar 

  • von Bergwelt-Baildon MS, Popov A, Saric T et al (2006) CD25 and indoleamine 2,3-dioxygenase are up-regulated by prostaglandin E2 and expressed by tumor-associated dendritic cells in vivo: additional mechanisms of T-cell inhibition. Blood 108:228–237

    Article  Google Scholar 

  • Wang CY, Shi Y, Min YN et al (2011) Decreased IDO activity and increased TTS expression break immune tolerance in patients with immune thrombocytopenia. J Clin Immunol 31:643–649

    Article  CAS  PubMed  Google Scholar 

  • Xu SQ, Wang CY, Zhu XJ et al (2012) Decreased indoleamine 2,3-dioxygenase expression in dendritic cells and role of indoleamine 2,3-dioxygenase-expressing dendritic cells in immune thrombocytopenia. Ann Hematol 91:1623–1631

    Article  CAS  PubMed  Google Scholar 

  • Xu J, Wei J, Zhu X et al (2013) Increased plasma indoleamine 2,3-dioxygenase activity and interferon-gamma levels correlate with the severity of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant: J Am Soc Blood Marrow Transplant 19:196–201

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Hematology, Hacettepe University, Medical School, Hacettepe Mh., 06230, Ankara, Turkey

    Ibrahim C. Haznedaroglu M.D.

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  1. Ibrahim C. Haznedaroglu M.D.
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Correspondence to Ibrahim C. Haznedaroglu M.D. .

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  1. Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey

    Atilla Engin

  2. Faculty of Pharmacy, Department of Toxicology, Gazi University, Hipodrom, Ankara, Turkey

    Ayse Basak Engin

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Haznedaroglu, I.C. (2015). Tryptophan in Molecular Hematopoiesis. In: Engin, A., Engin, A. (eds) Tryptophan Metabolism: Implications for Biological Processes, Health and Disease. Molecular and Integrative Toxicology. Humana Press, Cham. https://doi.org/10.1007/978-3-319-15630-9_11

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