Nucleotide sequence, transcription map, and mutation analysis of the 13q14 chromosomal region deleted in B-cell chronic lymphocytic leukemia.
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 the CAR 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. (Blood. 2001;97:2098-2104)
Institute of Cancer Genetics, Columbia University, New York, New York 10032, USA.
A
A
Migliazza
F
F
Bosch
H
H
Komatsu
E
E
Cayanis
S
S
Martinotti
E
E
Toniato
E
E
Guccione
X
X
Qu
M
M
Chien
V V
VV
Murty
G
G
Gaidano
G
G
Inghirami
P
P
Zhang
S
S
Fischer
S M
SM
Kalachikov
J
J
Russo
I
I
Edelman
A
A
Efstratiadis
R
R
Dalla-Favera
D000818:Animals; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002874:Chromosome Mapping; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics* / Q000648:ultrastructure; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics*; D020224:Expressed Sequence Tags; D015973:Gene Expression Regulation, Leukemic; D016147:Genes, Tumor Suppressor; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D011506:Proteins / Q000235:genetics; D011544:Pseudogenes; D062085:RNA, Long Noncoding; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D017384:Sequence Deletion; D014158:Transcription, Genetic; D014166:Transferases; D025521:Tumor Suppressor Proteins
C109421:DLEU1 lncRNA, human; C109420:DLEU2 lncRNA, human; D018076:DNA, Complementary; D004273:DNA, Neoplasm; D011506:Proteins; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D025521:Tumor Suppressor Proteins; C486375:Dleu2 protein, mouse; D014166:Transferases