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Molecular and transcriptional characterization of 17p loss in B-cell chronic lymphocytic leukemia

✍ Scribed by Sonia Fabris; Laura Mosca; Katia Todoerti; Giovanna Cutrona; Marta Lionetti; Daniela Intini; Serena Matis; Monica Colombo; Luca Agnelli; Massimo Gentile; Mauro Spriano; Vincenzo Callea; Gianluca Festini; Stefano Molica; Giorgio Lambertenghi Deliliers; Fortunato Morabito; Manlio Ferrarini; Antonino Neri

Publisher
John Wiley and Sons
Year
2008
Tongue
English
Weight
960 KB
Volume
47
Category
Article
ISSN
1045-2257

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✦ Synopsis

Abstract

Distinct genetic abnormalities, such as TP53 deletion at 17p13.1, have been identified as having adverse prognostic relevance in B‐cell chronic lymphocytic leukemia (B‐CLL), and conventional cytogenetic studies have shown that TP53 deletion in B‐CLL is mainly associated with the loss of 17p due to complex chromosomal rearrangements. We used an integrative genomic approach to investigate the significance of 17p loss in 18 B‐CLLs in Binet stage A, carrying a TP53 monoallelic deletion detected by means of fluorescence in situ hybridization (FISH). Genome‐wide DNA analysis using single nucleotide polymorphism (SNP) arrays of 12 of 18 samples showed 17p loss in 11 cases, with breakpoints scattered along the 17p11.2 region. FISH analysis confirmed these findings and revealed 17p loss in a small fraction of leukemic cells in the remaining TP53‐deleted case, and it also indicated 17p loss in the six cases not investigated by means of SNP arrays. Mutations in exons 2–11 of the remaining TP53 allele were found in 9 of 12 deleted samples. Gene‐expression profiling of 60 B‐CLLs, including seven patients with 17p loss, identified 40 differentially expressed genes in 17p‐ versus 17p normal samples, 35 of which were downregulated in 17p‐tumors. The majority (30 of 35) of these transcripts, including putative tumor suppressor genes, mapped to 17p, thus indicating a remarkable gene‐dosage effect. Our data provide evidence that 17p loss may play an additional pathogenetic role in B‐CLL and suggest that the concomitant loss of multiple tumor suppressor genes could be responsible for the highly adverse prognostic relevance associated with TP53 loss. © 2008 Wiley‐Liss, Inc.

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