Hodgkin Lymphoma: small cause - big effect

The exchange of a single amino acid in a transcription factor dramatically changes gene regulation to switch normal B-cells into cancer cells.

Microscope looking at slides.

The recent study which has involved University of Birmingham researchers and an international team led by Stephan Mathas from the Experimental and Clinical Research Center (ECRC) in Berlin has been published in Nature Communications.

Hodgkin Lymphoma (HL) is one of the most common forms of lymphoma of young adults. Its hallmarks are B cells of an abnormal size that carry markers of other immune cells on their surface, such as of macrophages or T-cells. The international team around Stephan Mathas from the Experimental and Clinical Research Center (ECRC), a research unit jointly run by the Max Delbrück Center and the Charité – University Medical School in Berlin has uncovered why this is the case and how these changes change cellular behaviour.

“We did know about a number of molecular changes in classic HL but we did not know which mutations in the genome are at the heart of driving the development of tumour cells”

Professor Stephan Mathas, Experimental and Clinical Research Center (ECRC)

To this end, the group collaborated with researchers of the Institutes of Human Genetics in Poznán (Poland) and Ulm (Germany) in search for recurrent mutations in the genome of HL patients and patient derived cells that could account for the observed changes – and were successful. 15% of patients had the same mutation in a gene that encoded the important transcriptional regulator protein IRF4. “The remarkable issue about this finding is that only one amino acid within this protein is changed” says Mathas. “This change completely alters the function of the protein. Instead of recognising the genetic code where it should and drive the activity of specific genes, it drives the activity of tumour-specific genes – which undermines the maturation of B cells to antibody producing cells.”

“This alteration of the binding features of the aberrant IRF4 protein leads to a global reprogramming of the chromosomal structure of normal B cells into a tumour specific state”

Professor Constanze Bonifer, University of Birmingham

The Bonifer lab from the University of Birmingham identified this feature.

This study might open the possibility to develop tools to interfere with such aberrant transcription factor activities. “Transcription factors such as IRF4 are difficult to target” says Mathas. “However, since we now know the precise alterations within the aberrant protein and how these alterations change its behaviour, we possibly can target these aberrant factors directly and leave the normal protein unaffected”.