Expression profile of shelterin components in plasma cell disorders. Clinical significance of POT1 overexpression.
The core complex of telomere-associated proteins, named the shelterin complex, plays a critical role in telomere protection and telomere length (TL) homeostasis. In this study, we have explored changes in the expression of telomere-associated genes POT1, TIN2, RAP1 and TPP1, in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). A total of 154 patients: 70 with MGUS and 84 with MM were studied. Real-time quantitative PCR was used to quantify gene expression. TL was evaluated by Terminal Restriction Fragments. Our data showed increased expression of POT1, TPP1, TIN2 and RAP1 in MM with respect to MGUS patients, with significant differences for POT1 gene (p=0.002). In MM, the correlation of gene expression profiles with clinical characteristics highlighted POT1 for its significant association with advanced clinical stages, high calcium and β2-microglobulin levels (p=0.02) and bone lesions (p=0.009). In multivariate analysis, POT1 expression (p=0.04) was a significant independent prognostic factor for overall survival as well as the staging system (ISS) (p<0.02). Our findings suggest for the first time the participation of POT1 in the transformation process from MGUS to MM, and provide evidence of this gene as a useful prognostic factor in MM as well as a possible molecular target to design new therapeutic strategies.
Laboratorio de Genética de Neoplasias Linfoides, Instituto de Medicina Experimental, CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina.
Julieta
J
Panero
División Patología Molecular, Instituto de Investigaciones Hematológicas "Mariano R. Castex", Academia Nacional de Medicina, Buenos Aires, Argentina.
Carmen
C
Stanganelli
Departamento de Clínica Médica, Sección Hematología, Hospital Italiano de Buenos Aires, Argentina.
Jorge
J
Arbelbide
Departamento de Clínica Médica, Sección Hematología, Hospital Italiano de Buenos Aires, Argentina.
Dorotea Beatriz
DB
Fantl
Servicio de Anatomía Patológica, Hospital Italiano de Buenos Aires, Argentina.
Dana
D
Kohan
Servicio de Anatomía Patológica, Hospital Italiano de Buenos Aires, Argentina.
Hernán
H
García Rivello
Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental-CONICET, Buenos Aires, Argentina; Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
Gabriel A
GA
Rabinovich
Laboratorio de Genética de Neoplasias Linfoides, Instituto de Medicina Experimental, CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina. Electronic address: islavutsky@hematologia.anm.edu.ar.
Irma
I
Slavutsky
D000368:Aged; D000369:Aged, 80 and over; D019175:DNA Methylation; D005500:Follow-Up Studies; D037483:Galectin 1 / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D008875:Middle Aged; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic; D000089804:Shelterin Complex; D019098:Telomerase / Q000235:genetics; D034501:Telomere-Binding Proteins / Q000235:genetics*
C495876:ACD protein, human; D037483:Galectin 1; C440849:POT1 protein, human; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D019098:Telomerase
MGUS; Multiple myeloma; POT1 expression; Telomere associated genes