Translocation t(X;11)(q13;q23) in B-cell chronic lymphocytic leukemia disrupts two novel genes.
Deletion of chromosome region 11q22-q23 defines a subgroup of patients with B-cell chronic lymphocytic leukemia (B-CLL) characterized by poor survival. Although the tumor-suppressor gene ATM in the consensus deletion region was found to be biallelically inactivated in about one third of B-CLL cases, in the majority of those who have this deletion, inactivation of the remaining ATM allele was not observed. To identify a second disease-associated gene, we investigated two B-CLL cases with translocation breakpoints in the critical 11q23 deletion region. In one case, a t(X;11)(q13;q23) was cloned and two novel genes were isolated. The breakpoint on 11q23 affected the ARHGAP20 gene, which encodes a protein predicted to be involved in the regulation of Rho family GTPases. The breakpoint on Xq13 occurred in BRWD3, which codes for a putative novel transcription factor. The rearrangement of ARHGAP20 and BRWD3 did not result in fusion transcripts, but it disrupted both genes. Mutation analysis of 28 B-CLL samples with monoallelic deletions and two B-CLL samples with 11q23 translocations detected no deleterious mutation in the remaining copy of ARHGAP20. Quantitative expression analysis in 22 B-CLLs revealed significant up-regulation of ARHGAP20 in CLL B cells, whereas BRWD3 was slightly down-regulated. Thus, deregulation of ARHGAP20 by altered gene expression or by gene disruption (but not point mutation) might be a general molecular mechanism of B-CLL leukemogenesis.
Kalla
Claudia
C
Abteilung Molekulare Genetik, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Nentwich
Hagen
H
Schlotter
Magdalena
M
Mertens
Daniel
D
Wildenberger
Kathrin
K
Döhner
Hartmut
H
Stilgenbauer
Stephan
S
Lichter
Peter
P
D002871:Chromosome Banding / Q000379:methods; D019457:Chromosome Breakage / Q000235:genetics; D002872:Chromosome Deletion; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D041321:Chromosomes, Human, X / Q000235:genetics*; D003001:Cloning, Molecular / Q000379:methods; D004252:DNA Mutational Analysis / Q000379:methods; D004273:DNA, Neoplasm / Q000235:genetics; D005091:Exons / Q000235:genetics; D020690:GTPase-Activating Proteins; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology; D014178:Translocation, Genetic / Q000235:genetics*; D000092468:Bromodomain Containing Proteins
D004273:DNA, Neoplasm; D020690:GTPase-Activating Proteins; D015514:Oncogene Proteins, Fusion; D022821:RNA Splice Sites; D014157:Transcription Factors; C502036:ARHGAP20 protein, human; C502037:BRWD3 protein, human; D000092468:Bromodomain Containing Proteins