Inhibition of T-cell Receptor Signaling for Treatment of Adult T-cell Leukemia Lymphoma

Abstract – Inhibition of T-Cell Receptor Signaling for Treatment of Adult T-Cell Leukemia Lymphoma Human T-cell leukemia virus type 1 (HTLV-1)-associated adult T-cell leukemia-lymphoma (ATLL) is an aggressive lymphoproliferative malignancy. Despite aggressive chemotherapy, this disorder is fatal in almost all individuals. Our preliminary results, and those of others, uncovered a high rate of mutations in the T-cell receptor (TCR) signaling pathway in ATLL, with frequent mutations in phospholipase Cγ, protein kinase Cβ (PKCβ), and caspase recruitment domain containing protein 11 (CARD11) leading to activation of transcription factors nuclear factor κB (NFκB) and interferon-regulatory factor 4 (IRF4). We hypothesize that this pathway drives ATLL development and/or progression and targeted therapy against this pathway will synergize with combination chemotherapy. We also suggest that lenalidomide represses IRF4 expression in ATLL. We propose to assess: Aim 1: Role of IRF4 activation in ATLL through RNAseq and functional analysis of IRF4-dependent gene targets. We will also determine if repression of IRF4 mediates the cytotoxic effects of lenalidomide in ATLL. Aim 2: Phase 1 study of lenalidomide in combination with EPOCH chemotherapy for HTLV-ATLL is conducted through the ETCTN, and correlative studies performed in the current project to assess whether efficacy of lenalidomide is mediated through effects on IRF4, and depend on mutations in TCR pathway components. HTLV load, expression, and clonality assays will be used to monitor the efficacy of therapy. Aim 3: Role of PKCβ activation in ATLL will be examined as an alternative therapeutic target, based on sensitivity of ATLL cells to inhibitors, enzastaurin and midostaurin. We will assess whether sensitivity to these inhibitors are affected by mutations in PKCβ or CARD11, which often co-occur in ATLL. This study will provide in-depth knowledge of the role of TCR signaling in ATLL, and new therapeutic targets.