Expression profile of shelterin components in plasma cell disorders. Clinical significance of POT1 overexpression

Abstract

In this study we analyzed the expression profile and the interactions of all shelterin components in patients with MM and MGUS, and correlated the results with hTERT expression, telomere length (TL) and clinical characteristics of the diseases. Bone marrow samples of 154 patients: 70 with MGUS and 84 with MM were studied. Gene expression was determined by real-time quantitative RT-PCR and TL was evaluated by terminal restriction fragments. A significant overexpression of TRF2, POT1 and hTERT in MM compared to MGUS was observed (p<0.03). Due to the great heterogeneity in hTERT levels, patients were divided into three groups of expression: GI (low), GII (intermediate) and GIII (high). This classification showed an upregulation of TRF2 and RAP1 in MGUS (GIII vs. GI: p<0.01), and an increased expression of TRF2 and TPP1 in MM (GIII vs. GI and GII: p<0.04). In addition, a significant over-expression of LGALS1 (encoding galectin-1, a multifunctional β-galactoside binding protein) was observed in GII/III respect to GI (p=0.013). TL was inversely correlated with telomerase expression (GII vs. GI: p=0.02). In MM, POT1 were positively correlated with β2microglobulin (β2M), advanced DS stages, high calcium levels and bone lesions (p=0.009), whereas TL was correlated positively with hemoglobin levels and negatively with β2M (p=0.02). Our findings provide the first evidence of a global modification in the expression of the six shelterin subunits, their interactions and the correlation between hTERT and LSGAL1 in plasma cell disorders. The strong association of POT1 with different parameters of adverse clinical outcome suggests its importance as a target for novel therapeutic strategies.