Abstract
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. © 2004 Wiley‐Liss, Inc.