13 May 2020

A newly found gene mutation linked to chronic graft-versus-host disease (cGvHD) could help understand the mechanisms of the disease, scientists have reported.

A research project led by Professor Satu Mustjoki, from the University of Helsinki, Finland, investigated the role of somatic mutations in T cells in cGvHD. Somatic mutations are common in cancer cells, but little is known about their existence and significance in other cells, such as immune cells.

This study, published in Nature Communications, identifies for the first time in a cGvHD patient an activating somatic mutation the mTOR gene, which regulates cell growth and cell survival.

Prof Mustjoki and team went on to screen blood samples from an international cohort of 135 cGvHD patients and 54 healthy blood donors. Using next generation sequencing, they found two additional people with cGvHD harboured cells with the same mutation in mTOR, meaning the mutation has a prevalence of 2.2% in their cohort. None of the healthy blood donors had the mutation.

“What makes our finding particularly significant is that the mutation now found was recurrent, meaning that the same mutation was found in several patients with chronic GvHD,” Mustjoki said.

“Our previous studies in rheumatoid arthritis had shown that acquired mutations could be found in T cells, but in these studies, the mutations had been isolated and the same mutations had not been found in more than one patient.”

The researchers used single-cell RNA sequencing and T cell receptor sequencing on samples collected from the index patient. The found that the mTOR‑mutated CD4+ T cell clone expanded during the GvHD, despite immunosuppressive treatment. The team believe this suggests that the mutation contributed to the disease pathogenesis.

They also found that the mutation was restricted to cytotoxic T cells, which were able to damage the body’s own cells.

When the research team investigated the mTOR mutation in more detail by introducing it into a human cell line, the activating mTOR mutation promoted cell proliferation and cell survival.

The researchers performed a high-throughput drug screen with 527 drugs to identify potential targeted therapies. The index patient’s CD4+ T cells were sensitive to HSP90 inhibitors, indicating these drugs may have potential for the treatment of GvHD.

They say that further studies using larger cohorts of GvHD are needed to understand if clonal mutations in T cells modify GvHD severity, drug responses and clinical outcome.

Source: Kim D, Park G, Huuhtanen J, Lundgren S, Khajuria RK, Hurtado AM, Muñoz-Calleja C, Cardeñoso L, Gómez-García de Soria V, Chen-Liang TH, Eldfors S, Ellonen P, Hannula S, Kankainen M, Bruck O, Kreutzman A, Salmenniemi U, Lönnberg T, Jerez A, Itälä-Remes M, Myllymäki M, Keränen MAI, Mustjoki S (2020) “Somatic mTOR mutation in clonally expanded T lymphocytes associated with chronic graft versus host disease”, Nature Communications, doi: 10.1038/s41467-020-16115-w


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