Study deciphers the role of histone deacetylases in lymphoma development

Lymphomas belong to the group of malignant diseases of the immune system and mainly affect the organs of the lymphatic system. Anaplastic large cell lymphoma (ALCL) belongs to the subgroup of non-Hodgkin's lymphomas and is a rare but aggressive form of T-cell lymphoma that usually occurs in children and young adults. Research teams from the Medical University of Vienna at the Comprehensive Cancer Center of MedUni Vienna and University Hospital Vienna, in collaboration with the European Institute of Oncology (Turin, IT), Boston Children's Hospital and Harvard Medical School (US) and the University of Cambridge (UK), among others, have now been able to prove the function of epigenetic changes in the development of this cancer. The study has been published in the journal Leukemia.

Epigenetic processes, such as changes in DNA methylation or chromatin structure, are significantly involved in the development of various cancers, and mutations of epigenetic factors are among the most common genetic changes in tumours. Inhibitors that target epigenetic enzymes are already in clinical use and show a promising effect, especially in lymphoma diseases.

Blockade delays lymphoma development

In the current study, the research teams led by Gerda Egger and first author Maša Zrimšek, both from the Department of Pathology, were able to decipher the role of histone deacetylases (HDACs) in ALCL lymphoma development. HDACs are enzymes that regulate gene activity and are considered a target structure for modern cancer therapies. The influence of the drug entinostat, a so-called HDAC inhibitor that is currently undergoing clinical trials, was investigated in the mouse model. The pharmacological blockade of HDAC activity was able to significantly delay the development of lymphoma or, in some cases, even prevent it altogether. Entinostat also showed an effective effect in lymphoma cells from three patients who were resistant to previous therapies.

Enzyme shows protective function

Surprisingly, however, the targeted genetic silencing of HDAC1 in T cells significantly accelerated tumour growth in the mouse model - an indication of a previously underestimated protective function of the enzyme in certain stages of the disease.

Molecular analyses showed that the loss of HDAC1 profoundly changes the packaging of the genetic material and gene activity in T cells and, in particular, enhances signalling pathways such as PDGFRB-STAT5 or T cell receptor-associated mechanisms. These changes are suspected of promoting the development and spread of lymphomas.

Although the chances of a cure for ALK-positive ALCL are very good thanks to specific treatments, treatment resistance often occurs and additional treatment options are therefore urgently needed. The present results give hope for the use of HDAC inhibitors as an additional treatment option in the near future."

Gerda Egger, study leader, Medical University of Vienna

The results were obtained in collaboration with teams from MedUni Vienna (Center for Pathophysiology, Infectiology and Immunology; Center for Anatomy and Cell Biology), the European Institute of Oncology (Turin, IT), Boston Children's Hospital and Harvard Medical School (US) and the University of Cambridge (UK).

Background:

Anaplastic large cell lymphomas are rare but aggressive T-cell lymphomas. About 60-80 % of cases carry a gene fusion of the ALK gene, which drives tumour growth. Histone deacetylases (HDACs) are enzymes that regulate gene activity and are considered a target structure for modern cancer therapies.