Intrinsic inhibition of transcription factor E2A by HLH proteins ABF-1 and Id2 mediates reprogramming of neoplastic B cells in Hodgkin lymphoma Stephan Mathas 1,2,5 , Martin Janz 1,2,5 , Franziska Hummel 2 , Michael Hummel 3 , Brigitte Wollert-Wulf 2 , Simone Lusatis 2 , Ioannis Anagnostopoulos 3 , Andreas Lietz 2 , Mikael Sigvardsson 4 , Franziska Jundt 1,2 , Korinna Jo ¨hrens 3 , Kurt Bommert 2 , Harald Stein 3 & Bernd Do ¨rken 1,2 B cell differentiation is controlled by a complex network of lineage-restricted transcription factors. How perturbations to this network alter B cell fate remains poorly understood. Here we show that classical Hodgkin lymphoma tumor cells, which originate from mature B cells, have lost the B cell phenotype as a result of aberrant expression of transcriptional regulators. The B cell–specific transcription factor program was disrupted by overexpression of the helix-loop-helix proteins ABF-1 and Id2. Both factors antagonized the function of the B cell–determining transcription factor E2A. As a result, expression of genes specific to B cells was lost and expression of genes not normally associated with the B lineage was upregulated. These data demonstrate the plasticity of mature human lymphoid cells and offer an explanation for the unique classical Hodgkin lymphoma phenotype. The plasticity of the pluripotent hematopoietic stem cell requires tight transcriptional control for the generation of different hematopoietic lineages. Differentiation toward the B lymphoid cell type is controlled by a complex network of transcription factors, which includes E2A, early B cell factor (EBF) and Pax5 (ref. 1). The E2A gene (TCF3) encodes two basic helix-loop-helix (bHLH) transcription factors, E12 and E47 (ref. 2). Mice deficient in E2A show a block in B cell development at an early stage, and B lineage–specific transcripts are substantially reduced 3 . E2A and EBF are critically involved in B cell differentiation through the pro– and pre–B cell stage 1,3–5 . E2A and EBF initiate the differentiation program in the common lymphoid pro- genitor cell, whereas Pax5 has been proposed to act ‘downstream’ of these factors in the genetic hierarchy of B cell development and is required for commitment to and maintenance of the B cell phenotype 1 . E2A proteins form homodimers and heterodimers with other bHLH proteins, resulting in tissue-specific and cell type–specific regulation of their activity 6,7 . E2A activity is negatively regulated by the inhibitor of differentiation (Id) protein family 7 . Id proteins contain a helix-loop- helix (HLH) dimerization motif, but lack the basic region required for DNA binding. Thus, interaction of Id proteins with bHLH transcrip- tion factors prevents binding to DNA and inhibits gene transcription that is dependent on E-box recognition by E2A proteins 7 . Id1- transgenic mice develop a block in early B cell development 8 , and overexpression of Id2 and Id3 interferes with E2A- and Pax5-dependent expression of B cell–specific genes 7,9–11 . These observations support a model in which Id proteins influence lineage fates and maturation in the hematopoietic system by modulating E2A and, potentially, Pax5 activity 12 . In addition to Id proteins, the bHLH protein activated B cell factor 1 (ABF-1) has been identified as a dimerization partner of E- proteins in B cells 13 . ABF-1 contains a transcriptional repression domain and inhibits the transcriptional activity of E47 (refs. 13,14). The physiological function of ABF-1 is unclear. Previous hypotheses have stated that a differentiated cell loses its ability to change its fate. The lymphoid system served as model system for studying the transcription factor networks required for a multistep differentiation process and for evaluating the differentiation potential of committed cells. Thus, conditional inactivation of Pax5 in early and late B lymphopoiesis results in a loss of the committed B cell phenotype 1,15,16 , and Pax5 –/– B cells can differentiate into several hematopoietic lineages 17,18 . Similarly, E2A-deficient progenitor cells can develop into different hematopoietic cell types 19 . In addition, enforced expression of C/EBP transcription factors in committed B cells allows transdifferentiation of these cells into macrophages 20 . Those data indicate that slight alterations in the transcription factor program of B cells might have considerable consequences regarding changes in their cellular fate, thereby challenging the previous rigid Received 23 June; accepted 26 October; published online 20 December 2005; corrected 4 January 2006 (details online); doi:10.1038/ni1285 1 Max-Delbru ¨ck-Center for Molecular Medicine, 13125 Berlin, Germany. 2 Hematology, Oncology and Tumorimmunology, Charite ´, Medical University Berlin, Campus Virchow-Klinikum, Campus Berlin-Buch, 13353 Berlin, Germany. 3 Institute for Pathology, Charite ´, Medical University Berlin, Campus Benjamin Franklin, 12200 Berlin, Germany. 4 Department for Hematopoietic Stemcell Biology, Stemcell Center, Lund University, S221 84 Lund, Sweden. 5 These authors contributed equally to this work. Correspondence should be addressed to S.M. (smathas@mdc-berlin.de). NATURE IMMUNOLOGY VOLUME 7 NUMBER 2 FEBRUARY 2006 207 ARTICLES © 2006 Nature Publishing Group http://www.nature.com/natureimmunology