BATF3 in ALCL cells

New approach to therapy at rare leukaemia type on the horizon

The anaplastic large cell lymphoma is a type of leukaemia whose development is significantly influenced by the transcription factor BATF3 and its target genes. An international research team, including scientists from Berlin, has now described a new approach to therapy in "Nature Communications".

The malignant lymphoma is the most frequent form of lymphatic cancer and develops if the lymphocytes belonging to the immune system divide uncontrolled. Differentiation is made between the Hodgkin lymphoma and non-Hodgkin lymphomas, which also include the less frequent anaplastic large cell lymphomas (ALCL), a malignant T-cell lymphoma, which particularly affects children and young adults. Chemotherapy is used as the standard therapy, but relapses often occur.

We were able to demonstrate that the transcription factor BATF3 and its target genes play a key role in tumor cell growth.
Stephan Mathas
Stephan Mathas Head of the Lab "Biology of Malignant Lymphomas"

A group of researchers of MedUni Vienna around Professor Olaf Merkel and Professor Lukas Kenner (also at the University of Veterinary Medicine Vienna) of the Clinical Institute for Pathology in cooperation with the research group of Professor Stephan Mathas of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), the Charité – Universitätsmedizin Berlin and the Experimental and Clinical Research Center (ECRC ) from the MDC and Charité now examined the role of the transcription factors BATF3 in case of ALCL.

The interest of the researchers in BATF3 had been aroused by the fact that this factor is very strongly expressed in ALCL. Above that, the growth of ALCL cells slows down when BATF3 is switched off which indicates that this protein plays an important role in this illness. “We were able to demonstrate that the transcription factor BATF3 and its target genes play a key role in tumor cell growth,” said co-last author Stephan Mathas, summarizing the results of the study, which appeared in the journal Nature Communications. “This could serve as a starting point for the development of new therapies.”

Super-Enhancer region discovered

The group around Stephan Mathas had been able to demonstrate in earlier cooperation projects that a group of AP-1 transcription factors, among them BATF3, is severely expressed in ALCL. In view of the significance of BATF3 for the illness and its high expression, the researchers assumed that it could be located in a so-called super enhancer region of the genome. Super enhancers are areas in the genome which are of pivotal significance for gene regulation and cell identity. The genomic analysis executed together with the laboratory of Professor Tom Look in Boston confirmed that BATF3 is indeed located in a super enhancer region in all cell lines, and importantly also in primary ALCL patient samples.

Furthermore, the researchers also conducted a genome-wide binding test for BATF3, a BATF3 ChIP, and ascertained that BATF3 binds to its own promotor and thus generates a positive feedback loop. “While we observed the genes, whose expression was altered by a BATF3-knock-out, the genes of the Interleukin-2 (IL-2) receptor system were among the most conspicuous,” explains Olaf Merkel, “which prompted us to closely examine the members of the trimeric IL-2 receptor in terms of expression and function.”

Basis for clinical trials in humans

Representative IHC images of the respective IL-2R subunits and H&E staining in 22 ALCL, ALK+ tissue samples measured.

The researchers determined that all three sub-units of the IL-2 receptor complex in ALCL are severely activated and that IL-2Rα and IL-2Rβ are direct targets of BATF3. “IL-2 is the most important interleukin released after the activation of T-cells”, explains Merkel, “and we were able to demonstrate that IL-2 was able to promote the growth of ALCL tumour cells. The view that IL-2 has an essential function for ALCL growth is supported by the high activation of all three IL-2 receptor subunits in more than 80 percent of ALCL patients, which, together with the functional analyses, indicates the high importance of IL-2 signalling in ALCL.” Another closely related cytokine known to share two subunits with the IL-2 receptor is IL-15. The researchers were able to show a growth-promoting effect on the ALCL cells here as well.

In view to a possible therapeutic approach, the researchers investigated the effect of an armed antibody directed against an IL-2 receptor subunit that is coupled to a cell toxin against ALCL cells. Even a single administration of this antibody cell toxin conjugate massively reduces tumour growth of ALCL cells in animal models, which could be the basis for clinical trials in humans.

 

About the study

 

The study was promoted by the European Union's Horizon 2020 Marie Skłodowska-Curie Innovative Training Networks (ITN-ETN) for a project entitled “ALKATRAS” (ALK Activation as a target of TRAnslational Science).

 

Further information

 

Literature

Huan-Chang Liang et al. (2021): “Super-enhancer-based identification of a BATF3/ IL-2R−module reveals vulnerabilities in anaplastic large cell lymphoma”, Nature Communications, DOI: doi.org/10.1038/s41467-021-25379-9