BACKGROUND: Hodgkin lymphoma (HL) is predominantly composed of reactive, non-neoplastic cells surrounding scarcely distributed tumor cells, that is, so-called Hodgkin and Reed-Sternberg (HRS) or lymphocyte predominant (LP) cells. This scarcity impeded the analysis of the tumor cell genomes for a long time, but recently developed methods (especially laser capture microdissection, flow cytometry/fluorescence-activated cell sorting) facilitated molecular investigation, elucidating the pathophysiological principles of "Hodgkin lymphomagenesis". METHODS: We reviewed the relevant literature of the last three decades focusing on the genomic landscape of classic and nodular lymphocyte predominant HL (NLPHL) and summarized molecular cornerstones. RESULTS: Firstly, the malignant cells of HL evade the immune system by altered expression of PDL1/2, B2M and MHC class I and II due to various genetic alterations. Secondly, tumor growth is promoted by permanently activated JAK/STAT signaling due to pervasive mutations of multiple genes involved in the pathway. Thirdly, apoptosis of neoplastic cells is prevented by alterations of NF-κB compounds and the PI3K/AKT/mTOR axis. Additionally, Epstein-Barr virus infection can simultaneously activate JAK/STAT and NF-κB, similarly leading to enhanced survival and evasion of apoptosis. Finally, epigenetic phenomena such as promoter hypermethylation lead to the downregulation of B-lineage-specific, tumor-suppressor and immune regulation genes. CONCLUSION: The blueprint of HL genomics has been laid, paving the way for future investigations into its complex pathophysiology.
BACKGROUND:Hodgkin lymphoma (HL) is predominantly composed of reactive, non-neoplastic cells surrounding scarcely distributed tumor cells, that is, so-called Hodgkin and Reed-Sternberg (HRS) or lymphocyte predominant (LP) cells. This scarcity impeded the analysis of the tumor cell genomes for a long time, but recently developed methods (especially laser capture microdissection, flow cytometry/fluorescence-activated cell sorting) facilitated molecular investigation, elucidating the pathophysiological principles of "Hodgkin lymphomagenesis". METHODS: We reviewed the relevant literature of the last three decades focusing on the genomic landscape of classic and nodular lymphocyte predominant HL (NLPHL) and summarized molecular cornerstones. RESULTS: Firstly, the malignant cells of HL evade the immune system by altered expression of PDL1/2, B2M and MHC class I and II due to various genetic alterations. Secondly, tumor growth is promoted by permanently activated JAK/STAT signaling due to pervasive mutations of multiple genes involved in the pathway. Thirdly, apoptosis of neoplastic cells is prevented by alterations of NF-κB compounds and the PI3K/AKT/mTOR axis. Additionally, Epstein-Barr virus infection can simultaneously activate JAK/STAT and NF-κB, similarly leading to enhanced survival and evasion of apoptosis. Finally, epigenetic phenomena such as promoter hypermethylation lead to the downregulation of B-lineage-specific, tumor-suppressor and immune regulation genes. CONCLUSION: The blueprint of HL genomics has been laid, paving the way for future investigations into its complex pathophysiology.
Authors: S Hartmann; B Schuhmacher; T Rausch; L Fuller; C Döring; M Weniger; A Lollies; C Weiser; L Thurner; B Rengstl; U Brunnberg; M Vornanen; M Pfreundschuh; V Benes; R Küppers; S Newrzela; M-L Hansmann Journal: Leukemia Date: 2015-12-10 Impact factor: 11.528
Authors: Michael R Green; Scott Rodig; Przemyslaw Juszczynski; Jing Ouyang; Papiya Sinha; Evan O'Donnell; Donna Neuberg; Margaret A Shipp Journal: Clin Cancer Res Date: 2012-01-23 Impact factor: 12.531
Authors: Margaretha G M Roemer; Ranjana H Advani; Robert A Redd; Geraldine S Pinkus; Yasodha Natkunam; Azra H Ligon; Courtney F Connelly; Christine J Pak; Christopher D Carey; Sarah E Daadi; Bjoern Chapuy; Daphne de Jong; Richard T Hoppe; Donna S Neuberg; Margaret A Shipp; Scott J Rodig Journal: Cancer Immunol Res Date: 2016-10-13 Impact factor: 11.151
Authors: R Küppers; K Rajewsky; M Zhao; G Simons; R Laumann; R Fischer; M L Hansmann Journal: Proc Natl Acad Sci U S A Date: 1994-11-08 Impact factor: 11.205
Authors: Sylvia Hartmann; José I Martin-Subero; Stefan Gesk; Julia Hüsken; Maciej Giefing; Inga Nagel; Jennifer Riemke; Andreas Chott; Wolfram Klapper; Marie Parrens; Jean-Philippe Merlio; Ralf Küppers; Andreas Bräuninger; Reiner Siebert; Martin-Leo Hansmann Journal: Haematologica Date: 2008-07-18 Impact factor: 9.941
Authors: Ann-Kathrin Desch; Kristin Hartung; Ante Botzen; Alexander Brobeil; Mathias Rummel; Lars Kurch; Thomas Georgi; Theresa Jox; Stefan Bielack; Stefan Burdach; Carl Friedrich Classen; Alexander Claviez; Klaus-Michael Debatin; Martin Ebinger; Angelika Eggert; Jörg Faber; Christian Flotho; Michael Frühwald; Norbert Graf; Norbert Jorch; Udo Kontny; Christof Kramm; Andreas Kulozik; Joachim Kühr; Karl-Walter Sykora; Markus Metzler; Hermann L Müller; Michaela Nathrath; Thomas Nüßlein; Michael Paulussen; Arnulf Pekrun; Dirk Reinhardt; Harald Reinhard; Claudia Rössig; Axel Sauerbrey; Paul-Gerhardt Schlegel; Dominik T Schneider; Wolfram Scheurlen; Lothar Schweigerer; Thorsten Simon; Meinolf Suttorp; Peter Vorwerk; Roland Schmitz; Regine Kluge; Christine Mauz-Körholz; Dieter Körholz; Stefan Gattenlöhner; Andreas Bräuninger Journal: Leukemia Date: 2019-08-20 Impact factor: 11.528
Authors: Diede A G van Bladel; Wendy B C Stevens; Michiel van den Brand; Leonie I Kroeze; Patricia J T A Groenen; J Han J M van Krieken; Konnie M Hebeda; Blanca Scheijen Journal: Cancers (Basel) Date: 2022-06-30 Impact factor: 6.575