CONICET | Buscador de Institutos y Recursos Humanos

Chronic lymphoytic leukemia (CLL) is a clinically heterogeneous disease. Telomeres are essential structures that protect the ends of linear chromosomes, which functions depend on the telomerase enzyme and telomere associated proteins. Among them, H/ACA ribonucleoprotein (RNP) is composed of four evolutionary conserved proteins: Dyskerin (DKC1), NOP10, NHP2 and GAR1. We have evaluated the expression profile of the H/ACA RNP complex as well as hTERT and hTR telomerase subunits mRNA levels, in patients with CLL. Results were correlated with telomere length (TL), genetic alterations, IGHV mutational status, and clinicopathological characteristics of the disease. The study was performed on mononuclear cells from peripheral blood samples of 72 CLL patients at diagnosis (31 females; mean age: 67 years) and 14 normal controls. Gene expression and absolute TL measurement was carried out by q-PCR. IGHV mutational status were analyzed by RT-PCR and sequencing. Cytogenetic and FISH analysis were also performed. Gene expression analysis showed higher mRNA levels of hTERT, NHP2 and GAR1, as well as lower expression of hTR, DKC1 and NOP10 in patients compared to controls (p=0.043). A significant correlation between GAR1, NOP10 and NHP2 mRNA levels (p=0.008) was detected, supporting a strong interaction among them. Patients with short TL had increased hTERT and DKC1 expression (p=0.03). Higher mRNA levels of DKC1 and NHP2 in patients with two or more cytogenetic and FISH anomalies (p=0.04) compared to those with no/one alteration was observed. Increased hTERT expression in unmutated IGHV cases was also found (p=0.02). No association between gene expression and clinical parameters was found. Our findings show a global modification in the expression of telomere associated genes in CLL being, to our knowledge, the first analysis of hTR, NOP10, NHP2 and GAR1 in this pathology, suggesting a role for these genes in genomic instability and telomere dysfunction in CLL.