Sphingosine Kinases (SK): Key Molecules Associated with the Activation, Proliferation and Ibrutinib-Induced Cell Death of Chronic Lympocytic Leukemia Cells

ALMEJÚN MARÍA BELÉN; BORGE MERCEDES; COLADO ANA; PODAZA ENRIQUE; RISNIK DENISE; BEZARES FERNANDO RAIMUNDO; FERNANDEZ GRECCO HORACIO; CABREJO MARÍA; BURGOS ANGEL; GIORDANO MIRTA; GAMBERALE ROMINA

Congreso; 57th ASH Meeting; 2015

Leukemic cells from CLL patients can survive and proliferate within lymphoid tissues where the supportive microenvironment favors their accumulation. We have previously reported that the activation of CLL cells reduces the expression of the main receptor for sphingosine 1-phosphate (S1P) (Borge M, J Immunol, 2014), a bioactive phospholipid that participates in lymphocyte egress from lymphoid tissues. S1P also mediates several biological functions, including cell growth stimulation and protection of apoptosis, through receptor independent intracellular mechanisms. S1P is generated by two isoforms of sphingosine kinases (SK1/2) and its levels are tightly controlled via degradation by intracellular S1P lyases (S1PL). Several studies have implicated the SK/S1P/S1PL pathway as an essential regulator of cell proliferation and survival in different cancer cells. The aims of our study were: a) to evaluate the expression of SK and S1PL in CLL cells, b) to assess whether key microenvironment signals are able to modulate this expression and c) to evaluate the effect of SK inhibitors on the activation and survival of the leukemic clone.We measured the basal expression of SK and S1PL by qRT-PCR on purified B cells from CLL patients (n=22) and aged-matched healthy donors (n=9), and found that CLL cells express high levels of SK1, favoring an increased SK1/S1PL ratio in the malignant clone compared to healthy B lymphocytes (p