Lipoprotein lipase expression in unmutated CLL patients is the consequence of a demethylation process induced by the microenvironment

ABREU CECILIA; MORENO PILAR; BORGE MERCEDES; PALACIOS FLORENCIA; MORANDE PABLO; PEGAZZANO MARÍA; BIANCHI SERGIO; LANDONI ANA INÉS; AGRELO RUBÉN; GIORDANO MIRTA; DIGHIERO GUILLERMO; GAMBERALE ROMINA; OPPEZZO PABLO

Cologne

Encuentro; VI Young CLL Investigators´Meeting; 2012

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 mechanismregulating its expression remain elusive. LPL plays a central role in lipid metabolism by catalyzing thehydrolysis of chylomicrons and very-low-density lipoproteins. In addition to its catalytic function, LPLacts as a bridging protein between cell surface proteins and lipoproteins, through its interaction withheparan sulfate-proteoglycan. In CLL B-cells, LPL expression has been related to functional pathwaysinvolved 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 bypromoting malignant B-cell growth and considering that tissue methylation can be altered byenvironmental factors, we investigated the methylation status of LPL gene and the possibility that itsover-expression could be associated to microenvironment signals. To gain insight into the molecularmechanisms responsible for the high LPL expression in Um CLL B-cells we investigated themethylation status of the CpG island from this gene in 26 CLL cases. Moreover, we explored thepossibility that LPL expression could be related to specific signals delivered from an activated CLLmicroenvironment.Our results suggest that demethylated status of LPL gene involving Exon1/Intron1 region isresponsible for the anomalous expression of this prognostic marker in Um CLL. We also found thatdemethylation of this CpG island and expression of LPL gene, can be induced in the leukemic cloneby specific microenvironment signals, delivered by CD40L/IL-4 and anti-IgM, but not by T-independentrelated signals delivered through TLR receptors. Overall, these results suggest that an epigeneticmechanism, triggered by the microenvironment, regulates LPL expression in Um patients andsupports previous results, about the functional role of LPL expression in the lipid metabolism from CLLB-cells.