Nucleotide sequence, transcription map, and mutation analysis of the 13q14 chromosomal region deleted in B-cell chronic lymphocytic leukemia

Author:

Migliazza Anna1,Bosch Francesc1,Komatsu Hirokazu1,Cayanis Eftihia1,Martinotti Stefano1,Toniato Elena1,Guccione Ernesto1,Qu Xiaoyan1,Chien Minchen1,Murty V. V. V.1,Gaidano Gianluca1,Inghirami Giorgio1,Zhang Peisen1,Fischer Stuart1,Kalachikov Sergey M.1,Russo James1,Edelman Isidore1,Efstratiadis Argiris1,Dalla-Favera Riccardo1

Affiliation:

1. From the Institute of Cancer Genetics, the Departments of Pathology and Genetics & Development, and the Genome Center, Columbia University, New York; the Department of Medical Sciences, A. Avogadro University of Eastern Piedmont, Novara, Italy; and the Department of Pathology, New York University Medical Center, New York.

Abstract

Abstract Deletions of the 13q14 chromosome region are associated with B-cell chronic lymphocytic leukemia (B-CLL) and several other types of cancer, suggesting the presence of a tumor suppressor gene. In previous studies the minimal region of deletion (MDR) was mapped to a less than 300-kilobase (kb) interval bordered by the markers 173a12-82 and 138G4/1.3R. For the identification of the putative tumor suppressor gene, the entire MDR (approximately 347 kb) has been sequenced, and transcribed regions have been identified by exon trapping, EST-based full-length complementary DNA cloning, database homology searches, and computer-assisted gene prediction analyses. The MDR contains 2 pseudogenes and 3 transcribed genes: CAR, encoding a putative RING-finger containing protein; 1B4/Leu2, generating noncoding transcripts; and EST70/Leu1, probably representing another noncoding gene (longest open reading frame of 78 codons). These genes have been sequenced in 20 B-CLL cases with 13q14 hemizygous deletion, and no mutations were found. Moreover, no somatic variants were found in the entire MDR analyzed for nucleotide substitutions by a combination of direct sequencing and fluorescence-assisted mismatch analysis in 5 B-CLL cases displaying 13q14-monoallelic deletion. The nondeleted allele of theCAR and EST70/Leu1 genes was expressed in B-CLL specimens, including those with monoallelic loss, whereas no expression of 1B4/Leu2 was detectable in B-CLL, regardless of the 13q14 status. These results indicate that allelic loss and mutation of a gene within the MDR is an unlikely pathogenetic mechanism for B-CLL. However, haplo-insufficiency of one of the identified genes may contribute to tumorigenesis.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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