Phosphorylated ERK1/2 in CD4 T cells is associated with acute GVHD in allogeneic hematopoietic stem cell transplantation

To diagnose graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is sometimes difficult. We showed previously that MEK inhibitors selectively suppress murine GVHD while retaining antiviral and antitumor immunity. Here, we asked whether the RAS/MEK/ERK pathway is activated in human allo-HSCT recipients with GVHD, and whether the phosphorylated ERK1/2 can be a biomarker of GVHD. Peripheral blood was sequentially collected from 20 allo-HSCT recipients: 1 bone marrow transplant, 7 peripheral blood stem cell transplants (PBSCT), and 12 cord blood transplants. Ten of the 20 allo-HSCT recipients developed GVHD, and phosphorylation of ERK1/2 in T and B cells was analyzed by flow cytometry. Occurrence of acute GVHD was associated with phosphorylation of ERK1/2 in CD4+ T cells at day 30 (P < .001), which was suppressed by ex vivo exposure to a MEK inhibitor trametinib at clinically achievable concentrations. In particular, ERK1/2 was phosphorylated preferentially in naive/central memory CD4+ T cells. Notably, phosphorylation of ERK1/2 fell as GVHD improved. These results suggest that phosphorylation status of ERK1/2 in peripheral blood CD4+ T cells may be a future biomarker for diagnosing human GVHD, and the potential efficacy of MEK inhibitors against human GVHD

The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects

The efficacy of allogeneic hematopoietic stem cell transplantation for hematologic malignancies is limited by the difficulty in suppressing graft-versus-host disease (GVHD) without compromising graft-versus-tumor (GVT) effects. We previously showed that RAS/MEK/ERK signaling depends on memory differentiation in human T cells, which confers susceptibility to selective inhibition of naive T cells. Actually, antineoplastic MEK inhibitors selectively suppress alloreactive T cells, sparing virus-specific T cells in vitro. Here, we show that trametinib, a MEK inhibitor clinically approved for melanoma, suppresses GVHD safely without affecting GVT effects in vivo. Trametinib prolonged survival of GVHD mice and attenuated GVHD symptoms and pathology in the gut and skin. It inhibited ERK1/2 phosphorylation and expansion of donor T cells, sparing Tregs and B cells. Although high-dose trametinib inhibited myeloid cell engraftment, low-dose trametinib suppressed GVHD without severe adverse events. Notably, trametinib facilitated the survival of mice transplanted with allogeneic T cells and P815 tumor cells with no residual P815 cells observed in the livers and spleens, whereas tacrolimus resulted in P815 expansion. These results confirm that trametinib selectively suppresses GVHD-inducing T cells while sparing antitumor T cells in vivo, which makes it a promising candidate for translational studies aimed at preventing or treating GVHD. The antineoplastic MEK inhibitor trametinib selectively suppresses graft-versus-host disease–inducing T cells while sparing antitumor T cells

HTLV‐1 cell‐free DNA in plasma as a potential biomarker in HTLV‐1 carriers and adult T‐cell leukemia‐lymphoma

Abstract Viral cell‐free DNA (cfDNA) in plasma has been widely evaluated for detecting cancer and monitoring disease in virus‐associated tumors. We investigated whether the amount of cfDNA of human T‐cell leukemia virus type 1 (HTLV‐1) correlates with disease state in adult T‐cell leukemia‐lymphoma (ATL). HTLV‐1 cfDNA in aggressive ATL was significantly higher than that in indolent ATL and asymptomatic carriers. Notably, patients with lymphoma type represented higher HTLV‐1 cfDNA amount than chronic and smoldering subtypes, though they had no abnormal lymphocytes in the peripheral blood. HTLV‐1 cfDNA can be a universal biomarker that reflects the expansion of ATL clones