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Intrinsic inhibition of transcription factor E2A by HLH proteins ABF-1 and Id2 mediates reprogramming of neoplastic B cells in Hodgkin lymphoma

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Abstract

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.

* NOTE: In the version of this article initially published online, the directions to the panels for Figure 6e were incorrect in the legend and text. The legend for this panel should begin as follows: “Immunoblot (top), EMSA (bottom left) and RT-PCR (bottom right)….” The accompanying text should read as follows: “Transfection of L428 cells with a combination of these siRNAs efficiently reduced ABF-1 protein expression (Fig. 6e, top) and resulted in a substantial loss of E2A–ABF-1 DNA-binding activity (Fig. 6e, bottom left). After reduction of ABF-1 expression, we noted considerable downregulation of CSF1R and TCF7 expression and a moderate suppression of GATA3 expression (Fig. 6e, bottom right).” The error has been corrected for the HTML and print versions of the article.

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Figure 1: Analysis of Pax5, E2A and EBF expression in primary HRS cells.
Figure 2: Aberrant EBF and E2A protein-DNA complexes in HRS cell lines.
Figure 3: HRS cells display E2A ABF-1 heterodimers.
Figure 4: In HRS cells, overexpressed Id2 interacts with E2A.
Figure 5: ABF-1 and Id2 downregulate B cell–specific genes.
Figure 6: Upregulation of B lineage–inappropriate genes by intrinsic inhibition of E2A.

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  • 04 January 2006

    In the version of this article initially published online, the directions to the panels for Figure 6e were incorrect in the legend and text. The legend for this panel should begin as follows: “Immunoblot (top), EMSA (bottom left) and RT-PCR (bottom right)….” The accompanying text should read as follows: “Transfection of L428 cells with a combination of these siRNAs efficiently reduced ABF-1 protein expression (Fig. 6e, top) and resulted in a substantial loss of E2A–ABF-1 DNA-binding activity (Fig. 6e, bottom left). After reduction of ABF-1 expression, we noted considerable downregulation of CSF1R and TCF7 expression and a moderate suppression of GATA3 expression (Fig. 6e, bottom right).” The error has been corrected for the HTML and print versions of the article.

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Acknowledgements

We thank S. Meier for technical assistance; P. Rahn for cell sorting; A. Kather for the generation of BLCL cell lines; T. Tokino for the ID2 promoter reporter plasmids; C. Murre for the ABF-1–specific antiserum; and R. Agami for pSUPER siRNA expression plasmid. This work was supported by the Deutsche Forschungsgemeinschaft (Klinische Forschergruppe KFO 105), the Berliner Krebsgesellschaft, the Deutsche Krebshilfe and the National Genome Research Network.

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Correspondence to Stephan Mathas.

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Supplementary information

Supplementary Fig. 1

Expression of Pax5, EBF and E2A in HRS cell lines. (PDF 101 kb)

Supplementary Fig. 2

Characterization of E2A-E2A, E2A-ABF-1 and ABF-1-ABF-1 complexes by EMSA analysis. (PDF 185 kb)

Supplementary Fig. 3

Regulation of Id2 expression. (PDF 157 kb)

Supplementary Fig. 4

TCF-1 overexpression in L428 HRS cells. (PDF 40 kb)

Supplementary Note (PDF 28 kb)

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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 7, 207–215 (2006). https://doi.org/10.1038/ni1285

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