Die molekulare Pathogenese des klassischen Hodgkin-Lymphoms

Zusammenfassung

Obwohl das klassische Hodgkin-Lymphom (HL) als Erkrankung erstmalig vor über 170 Jahren beschrieben wurde, konnten erst in den letzten 15 Jahren wesentliche Fortschritte zu zentralen Fragen seiner molekularen Pathogenese erzielt werden. Der Mangel eines spezifischen Markerprofils in Kombination mit der geringen Anzahl der malignen einkernigen Hodgkin- und mehrkernigen Reed-Sternberg-(HRS-)Zellen in dem betroffenen Gewebe verhinderte lange Zeit sowohl die Identifikation des zellulären Urspungs als auch die Beschreibung genomischer und molekularer Defekte. Durch die Entwicklung von Techniken zur Analyse von Einzelzellen konnte gezeigt werden, dass HRS-Zellen von B-Zellen abstammen. Es ist allerdings deutlich geworden, dass das nomale B-Zell-spezifische Genexpressionsprogramm in HRS-Zellen durch verschiedene molekulare Defekte nachhaltig gestört ist. Zudem konnten in den letzten Jahren molekulare und genomische Defekte verschiedener Signalwege in HRS-Zellen identifiziert werden, u. a. der NF-κB, JAK/STAT und MAPK/AP-1 Signalwege, durch die die HRS-Zellen vor dem programmierten Zelltod geschützt werden. Trotz guter Erfolge in der klinischen Behandlung des HL erfordert die erhebliche Spättoxizität konventioneller Therapien die Entwicklung neuer nicht-genotoxischer Therapiestrategien. Es wird deshalb ein wesentliches Ziel der nächsten Jahre sein, die Kenntnisse zur molekularen Pathogenese klinisch nutzbar zu machen und in die bisherigen Behandlungskonzepte einzubinden.

Summary

Despite the fact that classical Hodgkin lymphoma (HL) has been described more than 170 years ago, only over the last 15 years significant advances regarding its molecular pathogenesis have been achieved. The lack of a specific lineage profile in combination with the low number of the malignant mononuclear Hodgkin- and multinucleated Reed-Sternberg- (HRS-) cells in the affected lymph nodes prevented for a long time both the identification of its cell of origin and of genomic and molecular defects. The development of methods for the analysis of micromanipulated single cells made it possible to demonstrate a B cell origin of HRS cells. However, it has become clear that the normal B cell-specific gene expression program in HRS cells is disrupted by various molecular lesions. Furthermore, molecular and genomic defects of various signaling pathways could be identified in HRS cells, including the NF-κB, JAK/STAT and MAPK-AP-1 signaling pathways, which protect HRS cells from apoptotic cell death. Despite significant advances in the treatment of HL, the considerable long term toxicity of conventional therapies requires the development of new non-genotoxic therapeutic strategies. Therefore, it will be a central aim to develop new treatment strategies based on these insights into HL pathogenesis.

Schlüsselwörter

Hodgkin-Lymphom - HRS-Zellen - B-Zell-Differenzierung - Apoptose

Keywords

Hodgkin lymphoma - HRS cells - B cell differentiation - apoptosis

Literatur

• 1 Atayar C, Poppema S, Blokzijl T, Harms G, Boot M, van den Berg A. Expression of the T-cell transcription factors, GATA-3 and T-bet, in the neoplastic cells of Hodgkin lymphomas.  Am J Pathol. 2005;  166 127-134
• 2 Bargou R C, Emmerich F, Krappmann D. et al . Constitutive nuclear factor-kappaB-RelA activation is required for proliferation and survival of Hodgkin’s disease tumor cells.  J Clin Invest. 1997;  100 2961-2969
• 3 Bräuninger A, Hansmann M L, Strickler J G. et al . Identification of common germinal-center B-cell precursors in two patients with both Hodgkin’s disease and non-Hodgkin’s lymphoma.  N Engl J Med. 1999;  340 1239-1247
• 4 Cobaleda C, Jochum W, Busslinger M. Conversion of mature B cells into T cells by dedifferentiation to uncommitted progenitors.  Nature. 2007;  449 473-477
• 5 Fiumara P, Snell V, Li Y. et al . Functional expression of receptor activator of nuclear factor kappaB in Hodgkin disease cell lines.  Blood. 2001;  98 2784-2790
• 6 Gandhi M K, Lambley E, Duraiswamy J. et al . Expression of LAG-3 by tumor-infiltrating lymphocytes is coincident with the suppression of latent membrane antigen-specific CD8+ T-cell function in Hodgkin lymphoma patients.  Blood. 2006;  108 2280-2289
• 7 Hertel C B, Zhou X G, Hamilton-Dutoit S J, Junker S. Loss of B cell identity correlates with loss of B cell-specific transcription factors in Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma.  Oncogene. 2002;  21 4908-4920
• 8 Hinz M, Lemke P, Anagnostopoulos I. et al . Nuclear factor kappaB-dependent gene expression profiling of Hodgkin’s disease tumor cells, pathogenetic significance, and link to constitutive signal transducer and activator of transcription 5a activity.  J Exp Med. 2002;  196 605-617
• 9 Holtick U, Vockerodt M, Pinkert D. et al . STAT3 is essential for Hodgkin lymphoma cell proliferation and is a target of tyrphostin AG17 which confers sensitization for apoptosis.  Leukemia. 2005;  19 936-944
• 10 Ishida T, Ishii T, Inagaki A. et al . Specific recruitment of CC chemokine receptor 4-positive regulatory T cells in Hodgkin lymphoma fosters immune privilege.  Cancer Res. 2006;  66 5716-5722
• 11 Joos S, Küpper M, Ohl S. et al . Genomic imbalances including amplification of the tyrosine kinase gene JAK2 in CD30+ Hodgkin cells.  Cancer Res. 2000;  60 549-552
• 12 Jundt F, Acikgöz Ö, Kwon S H. et al . Aberrant expression of Notch1 interferes with the B-lymphoid phenotype of neoplastic B cells in classical Hodgkin lymphoma.  Leukemia. 2008;  22 1587-1594
• 13 Jundt F, Anagnostopoulos I, Bommert K. et al . Hodgkin/Reed-Sternberg cells induce fibroblasts to secrete eotaxin, a potent chemoattractant for T cells and eosinophils.  Blood. 1999;  94 2065-2071
• 14 Jundt F, Anagnostopoulos I, Förster R, Mathas S, Stein H, Dörken B. Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma.  Blood. 2002;  99 3398-3403
• 15 Jundt F, Kley K, Anagnostopoulos I. et al . Loss of PU.1 expression is associated with defective immunoglobulin transcription in Hodgkin and Reed-Sternberg cells of classical Hodgkin disease.  Blood. 2002;  99 3060-3062
• 16 Juszczynski P, Ouyang J, Monti S. et al . The AP1-dependent secretion of galectin-1 by Reed Sternberg cells fosters immune privilege in classical Hodgkin lymphoma.  Proc Natl Acad Sci U S A. 2007;  104 13 134-13 139
• 17 Kanzler H, Küppers R, Hansmann M L, Rajewsky K. Hodgkin and Reed-Sternberg cells in Hodgkin’s disease represent the outgrowth of a dominant tumor clone derived from (crippled) germinal center B cells.  J Exp Med. 1996;  184 1495-1505
• 18 Karin M, Liu Z, Zandi E. AP-1 function and regulation.  Curr Opin Cell Biol. 1997;  9 240-246
• 19 Klein U, Dalla-Favera R. Germinal centres: role in B-cell physiology and malignancy.  Nat Rev Immunol. 2008;  8 22-33
• 20 Krappmann D, Emmerich F, Kordes U, Scharschmidt E, Dörken B, Scheidereit C. Molecular mechanisms of constitutive NF-kappaB/Rel activation in Hodgkin/Reed-Sternberg cells.  Oncogene. 1999;  18 943-953
• 21 Küppers R. The biology of Hodgkin’s lymphoma.  Nat Rev Cancer. 2009;  9 15-27
• 22 Küppers R, Dalla-Favera R. Mechanisms of chromosomal translocations in B cell lymphomas.  Oncogene. 2001;  20 5580-5594
• 23 Küppers R, Klein U, Schwering I. et al . Identification of Hodgkin and Reed-Sternberg cell-specific genes by gene expression profiling.  J Clin Invest. 2003;  111 529-537
• 24 Küppers R, Rajewsky K. The origin of Hodgkin and Reed/Sternberg cells in Hodgkin’s disease.  Annu Rev Immunol. 1998;  16 471-493
• 25 Marafioti T, Hummel M, Anagnostopoulos I, Foss H D, Huhn D, Stein H. Classical Hodgkin’s disease and follicular lymphoma originating from the same germinal center B cell.  J Clin Oncol. 1999;  17 3804-3809
• 26 Marafioti T, Hummel M, Foss H D. et al . Hodgkin and Reed-Sternberg cells represent an expansion of a single clone originating from a germinal center B-cell with functional immunoglobulin gene rearrangements but defective immunoglobulin transcription.  Blood. 2000;  95 1443-1450
• 27 Mathas S, Hinz M, Anagnostopoulos I. et al . Aberrantly expressed c-Jun and JunB are a hallmark of Hodgkin lymphoma cells, stimulate proliferation and synergize with NF-kappa B.  Embo J. 2002;  21 4104-4113
• 28 Mathas S, Janz M, Hummel F. et al . Intrinsic inhibition of transcription factor E2A by HLH proteins ABF-1 and Id2 mediates reprogramming of neoplastic B cells in Hodgkin lymphoma.  Nat Immunol. 2006;  7 207-215
• 29 Mathas S, Lietz A, Janz M. et al . Inhibition of NF-kappaB essentially contributes to arsenic-induced apoptosis.  Blood. 2003;  102 1028-1034
• 30 Mullighan C G, Goorha S, Radtke I. et al . Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia.  Nature. 2007;  446 758-764
• 31 Müschen M, Rajewsky K, Bräuninger A. et al . Rare occurrence of classical Hodgkin’s disease as a T cell lymphoma.  J Exp Med. 2000;  191 387-394
• 32 Portis T, Dyck P, Longnecker R. Epstein-Barr Virus (EBV) LMP2A induces alterations in gene transcription similar to those observed in Reed-Sternberg cells of Hodgkin lymphoma.  Blood. 2003;  102 4166-4178
• 33 Renné C, Martin-Subero J I, Eickernjäger M. et al . Aberrant expression of ID2, a suppressor of B-cell-specific gene expression, in Hodgkin’s lymphoma.  Am J Pathol. 2006;  169 655-664
• 34 Rothenberg E V, Moore J E, Yui M A. Launching the T-cell-lineage developmental programme.  Nat Rev Immunol. 2008;  8 9-21
• 35 Scheeren F A, Diehl S A, Smit L A. et al . IL-21 is expressed in Hodgkin Lymphoma and activates STAT5; evidence that activated STAT5 is required for Hodgkin Lymphomagenesis.  Blood. 2008;  111 4706-4715
• 36 Skinnider B F, Elia A J, Gascoyne R D. et al . Signal transducer and activator of transcription 6 is frequently activated in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma.  Blood. 2002;  99 618-626
• 37 Skinnider B F, Elia A J, Gascoyne R D. et al . Interleukin 13 and interleukin 13 receptor are frequently expressed by Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma.  Blood. 2001;  97 250-255
• 38 Souabni A, Jochum W, Busslinger M. Oncogenic role of Pax5 in the T-lymphoid lineage upon ectopic expression from the immunoglobulin heavy-chain locus.  Blood. 2007;  109 281-289
• 39 Stein H, Delsol G, Pileri S. . In: Jaffe ES, Harris NL, Stein H, Vardiman JW, World Health Organization Classification of Tumors: Pathology and Genetics of Tumors of Haematopoietic and Lymphoid tissues. Lyon; IARC Press 2001: 244-253
• 40 Stein H, Marafioti T, Foss H D. et al . Down-regulation of BOB.1/OBF.1 and Oct2 in classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with immunoglobulin transcription.  Blood. 2001;  97 496-501
• 41 Trieu Y, Wen X Y, Skinnider B F. et al . Soluble interleukin-13Ralpha2 decoy receptor inhibits Hodgkin’s lymphoma growth in vitro and in vivo.  Cancer Res. 2004;  64 3271-3275
• 42 Ushmorov A, Leithäuser F, Sakk O. et al . Epigenetic processes play a major role in B-cell-specific gene silencing in classical Hodgkin lymphoma.  Blood. 2006;  107 2493-2500
• 43 Vallabhapurapu S, Karin M. Regulation and function of NF-kappaB transcription factors in the immune system.  Annu Rev Immunol. 2009;  27 693-733
• 44 van den Berg A, Visser L, Poppema S. High expression of the CC chemokine TARC in Reed-Sternberg cells. A possible explanation for the characteristic T-cell infiltratein Hodgkin’s lymphoma.  Am J Pathol. 1999;  154 1685-1691
• 45 Vockerodt M, Morgan S L, Kuo M. et al . The Epstein-Barr virus oncoprotein, latent membrane protein-1, reprograms germinal centre B cells towards a Hodgkin’s Reed-Sternberg-like phenotype.  J Pathol. 2008;  216 83-92
• 46 Watanabe M, Sasaki M, Itoh K. et al . JunB induced by constitutive CD30-extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase signaling activates the CD30 promoter in anaplastic large cell lymphoma and reed-sternberg cells of Hodgkin lymphoma.  Cancer Res. 2005;  65 7628-7634
• 47 Weniger M A, Melzner I, Menz C K. et al . Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation.  Oncogene. 2006;  25 2679-2684