Thyroid hormones maintain the proliferative phenotype in T cell lymphomas through nuclear and membrane-initiated transcriptional programs

CAYROL F; FERNANDO T; DIAZ FLAQUÉ MC; GENARO AM; FARÍAS RN; CERCHIETTI L; CREMASCHI GA

Washington DC

Congreso; AACR Annual Meeting 2013; 2013

The American Association of Cancer Research

T cell non-Hodgkin lymphomas (T-NHL) are a heterogeneous group of lymphoproliferative disorders with aggressive clinical course and no specific treatments. Thyroid Hormones (TH) are crucial regulators of differentiation, growth and metabolism. TH modulate these functions by activating canonical nuclear (TR) and membrane receptors (mTR, for most cells represented by RGD integrin dimers). Recent studies of us showed that TH stimulate the proliferation of T-NHLs through complimentary intracellular pathways involving both TH receptors, thus suggesting that both pathways are co-opted by malignant T cells to maintain proliferation and survival. This could represent a specific way to target these lymphoma subtypes. To characterize their participation on the T-NHL malignant phenotype, we analyzed the effect of TH through TR and mTR in 8 human cell lines representing the spectrum of immature and peripheral T-NHLs (CUTLL-1, Jurkat, Hut78, Mac-2A, OCI-Ly12, OCI-Ly13.2, SUDHL-1, Karpas299). Compared to normal T cells, T-NHL expressed higher levels of TRα and TRβ, and mTR (integrins with RGD site). To discriminate between nuclear vs. membrane-initiated effects, T-NHL cells were treated with physiological concentrations of free and cell impermeable agarose-bound T3/T4 (TH-AG), for 1 to 5 days. In these conditions, both free and TH-AG increased the proliferation of T-NHL (doubling time increased between 24 to 43%), PCNA and CCNDs proliferation markers and ERK phosphorylation. To further characterize TR and mTR initiated transcriptional programs, CUTLL1 cells were exposed to Free TH and TH-AG for 24 h and 96 h and mRNA extracted for RNA-sequencing in triplicates. We found 16 and 174 transcripts were significantly (p