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Blood, 15 June 2007, Vol. 109, No. 12, pp. 5422-5429.
Prepublished online as a Blood First Edition Paper on March 1, 2007; DOI 10.1182/blood-2006-11-057208.


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NEOPLASIA

Inactivation of RB1 in mantle-cell lymphoma detected by nonsense-mediated mRNA decay pathway inhibition and microarray analysis

Magda Pinyol1, Silvia Bea2, Laura Plà2, Vincent Ribrag3, Jacques Bosq4, Andreas Rosenwald5, Elias Campo2, and Pedro Jares1

1 Genomics Unit 2 Hematopathology Unit, Department of Pathology, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; Departments of 3 Medicine and 4 Pathology, Institut Gustave Roussy, Villejuif, France; and 5 Institute of Pathology, University of Wüerzburg, Wüerzburg, Germany

Mantle-cell lymphoma (MCL) is genetically characterized by the translocation t(11;14)(q13;q32) and a high number of secondary chromosomal abnormalities. To identify genes inactivated in this lymphoma, we examined 5 MCL cell lines following a strategy previously described in tumors with microsatellite instability that is based on the combined inhibition of the nonsense-mediated mRNA decay pathway and gene-expression profiling. This approach, together with the design of a conservative algorithm for analysis of the results, allowed the identification of 3 genes carrying premature stop codons. These genes were p53 with a mutation previously described in JEKO-1, the leukocyte-derived arginine aminopeptidase (LRAP) gene in REC-1 that showed a new splicing isoform generating a premature stop codon, and RB1 in UPN-1 that contained an intragenic homozygous deletion resulting in a truncated transcript and total loss of protein expression. The new LRAP isoform was detected also in 2 primary MCLs, whereas inactivating intragenic deletions of RB1 were found in the primary tumor from which UPN-1 was derived and 1 additional blastoid MCL. These tumors carried a concomitant inactivation of p53, whereas p16INK4a was wild type. These results indicate for the first time that RB1 may be inactivated in aggressive MCL by intragenic deletions.


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