British Society for Haematology. Listening. Learning. Leading British Society for Haematology. Listening. Learning. Leading
10 September 2018

Scientists have identified a signalling pathway which is essential to the survival of anaplastic large-cell lymphoma cells.

Anaplastic large‑cell lymphoma is rare type of non-Hodgkin lymphoma, typically involving malignant T cells, which is diagnosed in around 160 people in the UK each year. It can be divided into two major subtypes, based on the presence or absence of a chromosome rearrangement involving the gene ALK, referred to as ‘ALK+’ or ‘ALK‑’ anaplastic large‑cell lymphoma, respectively.

The team, led by researchers from the Medical University of Austria, found that Tyrosine Kinase 2 (TYK2) prevents the death of the lymphoma cells by increasing the production of a protein called MCL1. Notably, this dependency on TYK2 was found to be common to both major forms of anaplastic large-cell lymphoma.

Dr Nicole Prutsch and colleagues used a mouse model of anaplastic large‑cell lymphoma in which the Tyk2 gene was deleted in T cells.  As the mice developed lymphoma, those in which Tyk2 had been deleted survived significantly longer than those which had the normal Tyk2 gene.

In addition, human lymphoma cell lines in which the TYK2 gene was either deleted or switched off grew significantly slower than cell lines with a normal TYK2 gene. Drugs which block TYK2 also reduced the survival and growth of human cell lines representing both ALK+ and ALK‑ anaplastic large‑cell lymphoma.

"We were therefore able to regard the tyrosine kinase 2 signals as the “Achilles’ heel” of anaplastic large-cell lymphoma, since both types of anaplastic large-cell lymphoma that we investigated relied on its activity to maintain the essential signal to protect against cell death” say Dr Olaf Merkel, who co-led the study with Prof Lukas Kenner.

Publishing their work in the journal Leukemia, the researchers report that TYK2 is "an attractive therapeutic target" for the treatment of anaplastic large‑cell lymphoma. TYK2-specific inhibitors are currently in the late stages of pre-clinical development.

Prof Kenner says: "We look forward to TYK2 inhibitors, which are currently being developed for treating immunological diseases, being available, since we urgently need better treatments for rare lymphomas." 


Source: Prutsch, N., Gurnhofer, E., Suske, T., Liang, H.C., Schlederer, M., Roos, S., Wu, L.C., Simonitsch-Klupp, I., Alvarez-Hernandez, A., Kornauth, C., Leone, D.A., Svinka, J., Eferl, R., Limberger, T., Aufinger, A., Shirsath, N., Wolf, P., Hielscher, T., Aberger, F., Schmoellerl, J., Stoiber, D., Strobl, B., Jäger, U., Staber, P.B., Grebien, F., Moriggl, R., Müller, M., Inghirami, G.G., Sanda, T., Look, A.T., Turner, S.D., Kenner, L., Merkel, O. (2018) ‘Dependency on the TYK2/STAT1/MCL1 axis in anaplastic large cell lymphoma’, Leukemia. Available at doi: 10.1038/s41375-018-0239-1

 

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