Methylation status regulates LPL expression in CLL

ABREU CECILIA; MORENO PILAR; PALACIOS FLORENCIA; BORGE MERCEDES; MORANDE PABLO; LANDONI ANA INÉS; GABÚS RAÚL; DIGHIERO G; GIORDANO MIRTA; GAMBERALE ROMINA; OPPEZZO PABLO

LEUKEMIA AND LYMPHOMA

TAYLOR & FRANCIS LTD

Lugar: Londres; Año: 2012

1042-8194

Although, it has traditionally been assumed that CLL is the consequence of long lived tumor cell accumulation, evidences indicate that disease evolution results from the balance between proliferating cells in specialized tissue microenvironment and circulating cells resisting apoptosis [13]. This equilibrium is finely tuned by a set of surface molecules expressed by CLL B cells and modulated in response to environment signals [14]. The high expression of LPL gene in Um CLL B-cells is a very interesting observation because there is no expression of LPL in normal B cells. This infidel expression, constitutes not only a suitable prognostic marker to study disease prognosis but could also be helpful to understand the heterogeneous proliferative behavior of  CLL disease. At physiological levels, the largest expression of LPL gene has been reported in adipose tissue, skeletal muscle, heart tissue, dendritic cells and CD33 myeloid cells [9]. LPL is a protein located on the luminal side of the vessel wall, where it is anchored to heparan sulfate proteoglycans and contains binding sites for heparan sulfate chains and apoproteins [15]. Furthermore, LPL has a bridging function in the formation of a trimolecular complex including a lipoprotein particle, LPL and heparan sulfate proteoglycans from different cells [15]. This role is an interesting characteristic, because independently of its catalytically function, LPL expression in Um CLL patients may be associated with cell spreading and migration functions of a tumoral proliferative cell subset [5,15]. If it is the case, LPL might also act as a crosstalk factor facilitating specific interactions with accessory cells in the tissue microenvironments.             In this study, we investigated whether LPL expression could be related to epigenetic changes in the CpG island of this gene and the putative role of microenvironment signaling in the induction of this epigenetic mechanism. The results present here connect tumoral cell proliferation with epigenetic changes on the CpG island of LPL DNA suggesting that LPL expression in CLL is related with microenvironment signals that appear to induce a demethylation process in the leukemic clone. This data is supported by the fact that anomalous LPL expression is a hallmark of Um CLL patients.             In conclusion, this work shows that an epigenetic mechanism, triggered by the microenvironment, is responsible for LPL expression in CLL disease.