STUDY OF AUTOPHAGY RESPONSE IN NEOPLASTIC CLL CELLS

ARROYO DANIELA S; RODRIGUEZ CECILIA M; BUSSI CLAUDIO; PERALTA-RAMOS JAVIER M; IRIBARREN PABLO

Congreso; LXIV Reunión Anual de la SAI; 2016

Chronic lymphocytic leukemia (CLL), a clonal expansion of B CD5+ cells, is the most common type of adult leukemia in western countries. Represent more than 40% of allleukemia in elderly patients (>67 years), with an age-adjusted incidence of 2-6 cases/100000 patients/year. The median age at diagnosis lies between 67 and 72 years. Twoprognostic staging systems exist, the Rai and Binet staging systems, which are established by physical examination and blood counts. Various biological and genetic markersalso have prognostic value. Comprehensive prognostic scores are currently being developed.Patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy. For physical fit patients, chemoimmunotherapy with fludarabine,cyclophosphamide, and rituximab remains the current standard therapy. Several new agents hold the potential to improve the outcome of patients with CLL.The accumulation of neoplastic B-cells is primarily caused by prolonged life-span of these cells due to specific genomic alterations causing the deletion of specific micro-RNAgenes and increasing the resistance of B cells toward apoptosis. In spite of numerous reports characterizing particular mechanisms of B-CLL cell apoptosis, still relatively little isknown about the complex regulation of this process. The pathway engaged in programmed cell death involves several Bcl-2 family proteins. Alternatively, Bcl-2?family proteinshave antiautophagic function. In cancer, autophagy plays dual roles, acting both as a tumor suppressor mechanism by preventing accumulation of damaged proteins andorganelles and as a prosurvival mechanism, promoting tumor growth.Autophagy is an intracellular process that plays a role in normal cell homeostasis. In this process, misfolded proteins, damaged/aged organelles, or other intracellularcomponents are sequestered inside a double-membrane vesicle called an 􀍞autophagosome,􀍟 which then fuses with lysosomes to allow degradation of its contents. In bothnormal and transformed cells, autophagy occurs after multiple different stimuli, including starvation, pharmacologic inhibition of mammalian target of rapamycin (mTOR) orclass I phosphatidylinositol 3-kinase (class I PI3K), etc.mTOR is a serine/threonine kinase that integrates a multiple of extracellular and intracellular signals to drive cellular growth, proliferation, autophagy or senescence.Numerous observations support the importance of mTOR pathway in cancer development, particularly oncogenic activation of mTOR signaling induces processes required forcancer cell proliferation. mTORC1 is a positive regulator of protein and lipid synthesis as well as energy metabolism and general negative regulator of autophagy and lysosomebiogenesis. Anticancer drugs inhibiting the activity of mTORC1 and mTORC2 complexes potentially can suppress cancer cell proliferation. PP242 is an inhibitor of kinase mTORdomain that suppress the activity of both TORC1 and TORC2 complexes. Given that autophagy has been described in the literature as an intracellular process that can act as asurvival strategy or a cell death mechanism depending upon cell type and circumstances, we performed a detailed analysis of this pathway in CLL cells. We investigated theautophagy machinery in CLL by testing a pharmacologic inhibitor of mTOR, PP242 (autophagy inducer), in combination with the CLL therapeutic agent fludarabine. Ourpreliminay findings might provide new insights into the role of mTOR function in the regulation of autophagy in neoplastic B lymphocytes.