- Role of Protein Kinase C Mutations in Adult T-Cell Leukemia Human T-cell leukemia virus type 1 (HTLV-1) is the cause of a T cell lymphoproliferative disorder, designated adult T-cell leukemia lymphoma (ATL). This is a highly refractory malignancy, lacking effective treatment approaches, with a long-term survival rate of less than four percent. The current project exploits our exciting new discovery of frequent, recurrent mutations in ATL cells in mediators of the T cell receptor (TCR) pathway including phospholipase C ?1 (PLC?1), protein kinase C? (PRKC?), caspase recruitment domain family member 11 (CARD11), and interferon regulatory factor 4 (IRF4), and resultant nuclear factor ?B activation and high level expression of N-Myc. This proposal focuses specifically on possible gain-of-function mutations in PRKC? in ATL, the most frequent recurrently mutated gene in ATL, with mutation D427N accounting for more than 70% of these PRKC? mutations. First, we will determine 1) if PRKC? mutation D427N promotes proliferation of T cells in mice, if T cell proliferation in this setting can be inhibited with PRKC? inhibitor, midostaurin, and we will identify downstream gene targets of PRKC? activation in this setting. Second, we will determine if PRKC? D427N is critical for proliferation of ATL cells in immunodeficient mice, and if ATL growth in mice can be inhibited by midostaurin. We expect this study will provide promising new insights into effective therapy for ATL, which could have relevance to other lymphoproliferative disorders.
- Role of Protein Kinase C Mutations in Adult T-Cell Leukemia Human T-cell leukemia virus type 1-associated adult T-cell leukemia/lymphoma (ATL) is a highly aggressive and usually fatal malignancy despite the use of combination chemotherapy and antiviral agents. This application will characterize protein kinase C (PKC) as a key driver in this malignancy, and PKC inhibitor, midostaurin, as a potential therapeutic agent. Effects of midostaurin on T-cell receptor signaling gene targets in mouse and human T cells in vivo will be examined in order to define its therapeutic potential and assess the role of biomarkers in assessing its activity.
