Thyroid Hormones regulated transcriptional programs play a role in T-NHL survival and proliferation

CAYROL F; FERNANDO T; DIAZ FLAQUE MARIA C; GENARO A; FARIAS R; CREMASCHI G; CERCHIETTI LC

Florianópolis

Congreso; XV Latin American Thyroid Congress; 2013

BACKGROUND: T cell non-Hodgkin lymphomas (T-NHL) are a heterogeneous group of lymphoproliferative disorders with an aggressive clinical course and no specific treatments. Thyroid Hormones (THs) are important regulators of differentiation, growth and metabolism in normal T cells. Recent studies from our laboratory showed that THs stimulate the proliferation of T-NHLs through complimentary intracellular pathways involving both the canonical nuclear receptor (TR) and a membrane receptor (mTR) that for most cells are represented by RGD integrin dimers. OBJECTIVES: Characterize the THs regulated pathways and determine their relative influence on the T-NHL malignant phenotype. METHODS: We analyzed the effect of T3/T4 through TR and mTR in eight human cell lines representing the spectrum of T-NHLs. In order to discriminate between nuclear (total) vs. membrane-initiated effects of TH, T-NHL cells were treated with physiological concentrations of free T3/T4 and cell impermeable agarose-bound T3/T4 (TH-AG) at different time points. RESULTS: T-NHL expressed higher levels of TRs and putative mTRs genes compared to normal T cells. We found that both TH-free and TH-AG increased the proliferation of T-NHL and the proliferative intracellular signaling cascasde. . By RNA-sequencing in one of the cell lines we found activation by free THs of TR (including up-regulation of KLF9, BTEB, and NCOA7), TNFR and IL-2 pathways. While activation of the mTR receptor caused activation of genes involved in mitochondrial respiration, fatty-acid synthesis, angiogenesis and DNA replication CONCLUSIONS: Our data suggest that TH are important inducers of cell proliferation in T-NHLs tby transcriptionally regulating major survival pathways in these cells.