EFFECT OF THYROID HORMONE MEMBRANE RECEPTOR INHIBITION IN THE TREATMENT WITH REXINOIDS OF CUTANEOUS T CELL LYMPHOMA

CAYROL M.F.; REVUELTA M.V.; DEBERNARDI M.; DIAZ FLAQUÉ C.; PAULAZO M.A.; STERLE H.A.; CERCHIETTI L; CREMASCHI G.A.

Mar del Plata

Congreso; SAIC; 2016

Cutaneous T Cell Lymphomas 􀀊CTCL􀀋 are neoplasms of matureT cells 􀁙ith clinical presentations from discrete s􀁍in lesionsto visceral disease. CTCL are exposed to a complex paracrineand endocrine environment that influence their development.􀀴ecently 􀁙e found that both nuclear 􀀊T􀀴􀀋 and membrane 􀀊mT􀀴,integrin a􀀸b􀀕􀀋 TH receptors regulate transcriptional programsrequired for the survival and proliferation of TCL, including CTCL.For CTCL treatment the most used rexinoid, bexarotene 􀀊􀀤E􀀺A􀀋,is associated 􀁙ith hypothyroidism being patients candidate for THreplacement therapy. The consequences of TH administration onthe activity of 􀀤E􀀺A in CTCL cells are un􀁍no􀁙n. 􀀱ur aim 􀁙asto study the effect of TH and their genetic programs on the anti􀀏lymphoma activity of rexinoids. To accomplish this, 􀁙e performfunctional assays andnext generation sequencing studies in CTLC􀀤E􀀺A􀀏treated cells 􀀊HuT􀀙􀀚 and 􀀯􀀬􀀋 inthe presence or absence ofT􀀴 or mT􀀴. 􀀴esults sho􀁙, that 􀀤E􀀺A activity decreaseon both,conventional or 􀀕􀀦 CTCL cell cultures, in the presence ofphysiologicalconcentrations of TH. 􀀱nthe other hand, in vivo assaysperformed on C􀀗􀀙􀀤L/􀀘 mice sho􀁙 that C􀀦􀀕􀀍 population, mainlythe C􀀦􀀚􀀍 cells, decrease due to 􀀤E􀀺A􀀏induced hypothyroidism,as TH replacement revert this effect. Considering this, 􀁙e evaluatedthe effect in vitro of mT􀀴 inhibition in combination 􀁙ith 􀀤E􀀺Atreatment. 􀀹e found that either, using silencing 􀀴􀀰A or pharmacologicalinhibitors of mT􀀴, the anti􀀏lymphoma activity of 􀀤E􀀺Aincreases. The improvement of 􀀤E􀀺A activity could be explainedby the increase of cell apoptosis and the inhibition of cell cyclemar􀁍ers. 􀀴􀀰Aseq results support the latest, sho􀁙ing that inhibitionof mT􀀴 in cells treated 􀁙ith 􀀤E􀀺A, increases the regulationof genes involved in cell cycle, apoptosis and tumorigénesis 􀀊􀀴EL,􀀫􀀦􀀔, L􀀩ALS􀀓, 􀀼C􀀕H􀀓􀀔, among others􀀋. 􀀤ased on our results, 􀁙eproposed that mT􀀴 inhibition could be a ne􀁙 strategy to improverexinoid treatment in CTCL patients.