In vitro und in vivo Modelle zur Analyse Helix-Loop-Helix Protein-vermittelter Reprogrammierung und maligner Transformation lymphatischer Zellen
Zellbiologie
Zusammenfassung der Projektergebnisse
Malignant transformation is closely linked to profound alterations in the cellular differentiation program. The most prominent example in the lymphoid system is classical Hodgkin lymphoma (cHL), a germinal center B cell-derived malignancy that is characterized by a striking loss of the B cell phenotype accompanied by the widespread upregulation of non-B cell lineage genes. Based on previous work, we postulated that the inhibition of the B cell transcription factor E2A by its antagonists ID2 and ABF1 is a central event that connects loss of differentiation, lineage infidelity and cellular reprogramming to oncogenic transformation. In the proposed project we aimed to investigate the phenotype of Id2 and Abf1 transgenic mice and its impat on malignant transformation, and to gain insights into the mechanisms of ABF1 and ID2 up-regulation as well as the role of lineage infidelity and cellular reprogramming, mediated by the lost E2A activity, for growth and survival of malignant lymphoma cells. Our in vivo experiments performed during the reported period show that both Id2 and Abf1 have detrimental effects on B cell differentiation. Both factors act as strong inhibitors of B cell differentiation at several stages, including later stages that are relevant for cHL. In addition, they can shift the transcriptional program of B cells towards a cHL-related gene signature. Although Id2 and Abf1 are not sufficient to induce the full cHL phenotype, our observations indicate that they are critical factors for shaping central features of cHL (i.e. downregulation of B cell-specific genes and upregulation of alternative hematopoietic lineage gens). In an extension of our previous in vitro experiments we fully characterized the HL- specific chromatin landscape and performed an unbiased genome-wide search for TF binding motifs enriched within HRS-specific accessible chromatin. By this approach, we confirmed not only the importance of know HL-specific transcription factor alterations, such as high-level NF-κB or AP-1 activities, but also charactirued IRF5 as master regulator for the HL-specific gene expression program, including extinction of the B cell phenotype and upregulation of ABF-1 and ID2, as well as up-regulation of various cytokines and chemokines including LTA. LTA in turn was identified as major autocrine and paracrine factor resulting in the constitutive NF-κB activity in HRS cells and to contribute to the lymphoid-myeloid lineage switching of HRS cells. Finally, we propose that the aberrant CD74 expression in ALCL cells provides an alternative mechanism of ALCL cells to circumvent the consequences of lost E2A activity and subsequent lost T cell-associated gene expression. Together, apart from the insights into HL and ALCL pathogenesis, our data identified key regulators such as IRF5 to extend our in vivo models in future experiments.
Projektbezogene Publikationen (Auswahl)
- Mapping of transcription factor motifs in active chromatin identifies IRF5 as key regulator in classical Hodgkin lymphoma. Proc Natl Acad Sci USA. 2014;111(42):E4513-22
Kreher S, Bouhlel MA, Cauchy P, Lamprecht B, Li S, Grau M, Hummel F, Köchert K, Anagnostopoulos I, Jöhrens K, Hummel M, Hiscott J, Wenzel SS, Lenz P, Schneider M, Küppers R, Scheidereit C, Giefing M, Siebert R, Rajewsky K, Lenz G, Cockerill PN, Janz M, Dörken B, Bonifer C, Mathas S
(Siehe online unter https://doi.org/10.1073/pnas.1406985111) - Cytokine and proinflammatory gene expression in classical Hodgkin lymphoma: its more than NF-κB! Cytokine. 2015;72(1):115-7
Kreher S, Cauchy P, Bonifer C, Mathas S
(Siehe online unter https://doi.org/10.1016/j.cyto.2014.12.012) - The IL-15 cytokine system provides growth and survival signals in Hodgkin lymphoma and enhances the inflammatory phenotype of HRS cells. Leukemia. 2015;29(5):1213-8
Ullrich K, Blumenthal-Barby F, Lamprecht B, Köchert K, Lenze D, Hummel M, Mathas S, Dörken B, Janz M
(Siehe online unter https://doi.org/10.1038/leu.2014.345) - The origins of ALK translocations. Front Biosci (Schol Ed). 2015;7:260-8
Roukos V, Mathas S
(Siehe online unter https://doi.org/10.2741/439) - Canonical NF-κB signaling is uniquely required for the long-term persistence of functional mature B cells. Proc Natl Acad Sci USA. 2016;113(18):5065-70
Derudder E, Herzog S, Labi V, Yasuda T, Köchert K, Janz M, Villunger A, Schmidt-Supprian M, Rajewsky K
(Siehe online unter https://doi.org/10.1073/pnas.1604529113) - Hodgkin lymphoma: Pathology and biology. Semin Hematol. 2016;53(3):139-47
Mathas S, Hartmann S, Küppers R
(Siehe online unter https://doi.org/10.1053/j.seminhematol.2016.05.007) - Inactivation of the putative ubiquitin-E3 ligase PDLIM2 in classical Hodgkin and anaplastic large cell lymphoma. Leukemia. 2017;31(3):602-613
Wurster KD, Hummel F, Richter J, Giefing M, Hartmann S, Hansmann ML, Kreher S, Köchert K, Krappmann D, Klapper W, Hummel M, Wenzel SS, Lenz G, Janz M, Dörken B, Siebert R, Mathas S
(Siehe online unter https://doi.org/10.1038/leu.2016.238) - The AP-1-BATF and -BATF3 module is essential for growth, survival and TH17/ILC3 skewing of anaplastic large cell lymphoma. Leukemia. 2018;32(9):1994-2007
Schleussner N, Merkel O, Costanza M, Liang HC, Hummel F, Romagnani C, Durek P, Anagnostopoulos I, Hummel M, Jöhrens K, Niedobitek A, Griffin PR, Piva R, Sczakiel HL, Woessmann W, Damm-Welk C, Hinze C, Stoiber D, Gillissen B, Turner SD, Kaergel E, von Hoff L, Grau M, Lenz G, Dörken B, Scheidereit C, Kenner L, Janz M, Mathas S
(Siehe online unter https://doi.org/10.1038/s41375-018-0045-9) - Autocrine LTA signaling drives NF-κB and JAK-STAT activity and myeloid gene expression in Hodgkin lymphoma. Blood. 2019;133(13):1489-1494
von Hoff L, Kärgel E, Franke V, McShane E, Schulz-Beiss KW, Patone G, Schleussner N, Kolesnichenko M, Hübner N, Daumke O, Selbach M, Akalin A, Mathas S, Scheidereit C
(Siehe online unter https://doi.org/10.1182/blood-2018-08-871293)
