INVESTIGADORES
MORANDE Pablo ElÍas
congresos y reuniones científicas
Título:
Lipoprotein lipase expression in unmutated CLL patients is the consequence of a demethylation process induced by the microenvironment
Autor/es:
ABREU CECILIA; MORENO PILAR; BORGE MERCEDES; PALACIOS FLORENCIA; MORANDE PABLO; PEGAZZANO MARIANA; BIANCHI SERGIO; LANDONI ANA INÉS; AGRELO RUBEN; GIORDANO MIRTA; DIGHIERO GUILLERMO; GAMBERALE ROMINA; OPPEZZO PABLO
Lugar:
Cologne
Reunión:
Encuentro; VIIth Annual CLL Young Investigators' Meeting; 2012
Resumen:
We have previously demonstrated that lipoprotein lipase (LPL) is associated to an unmutated (Um) immunoglobulin profile and clinical poor outcome in Chronic Lymphocytic Leukemia (CLL). Despite the usefulness of LPL for CLL prognosis, its functional role and the molecular mechanism regulating its expression remain elusive. LPL plays a central role in lipid metabolism by catalyzing the hydrolysis of chylomicrons and very-low-density lipoproteins. In addition to its catalytic function, LPL acts as a bridging protein between cell surface proteins and lipoproteins, through its interaction with heparan sulfate-proteoglycan. In CLL B-cells, LPL expression has been related to functional pathways involved in fatty acid degradation and signaling which may influence CLL biology and clinical outcome. Since interaction of CLL B-cells with tissue microenvironment favors disease progression by promoting malignant B-cell growth and considering that tissue methylation can be altered by environmental factors, we investigated the methylation status of LPL gene and the possibility that its over-expression could be associated to microenvironment signals. To gain insight into the molecular mechanisms responsible for the high LPL expression in Um CLL B-cells we investigated the methylation status of the CpG island from this gene in 26 CLL cases. Moreover, we explored the possibility that LPL expression could be related to specific signals delivered from an activated CLL microenvironment. Our results suggest that demethylated status of LPL gene involving Exon1/Intron1 region is responsible for the anomalous expression of this prognostic marker in Um CLL. We also found that demethylation of this CpG island and expression of LPL gene, can be induced in the leukemic clone by specific microenvironment signals, delivered by CD40L/IL-4 and anti-IgM, but not by T-independent related signals delivered through TLR receptors. Overall, these results suggest that an epigenetic mechanism, triggered by the microenvironment, regulates LPL expression in Um patients and supports previous results, about the functional role of LPL expression in the lipid metabolism from CLL B-cells.