Identification of candidate tumor suppressor genes from critical deletions of long arm of chromosome 6 in hematopoietic neoplasm

摘要

Deletion of the long arm of chromosome 6 has been frequently described in human lymphoid neoplasms as well as in other solid tumors, implicating the presence of tumor suppressor genes (TSGs) within this chromosomal segment. To isolate the relevant TSGs from the 6ql4-2.3 region, we performed deletion analysis for a large panel of hematopoietic tumor samples using fluorescent in situ hybridization (FISH), employing more than 50 PAC/BAC clones mapped in 6ql4-23 as probes, At least six critical regions (Dl to D6) existed within 6ql4-23 that underwent overlapping deletions, but were discretely separated from each other, indicating multiple tumor suppressor loci might reside in this region. Deletions were most frequently observed in the D2 region that was flanked by the genetic markers D6S449 and AFMA084ZE9, followed by the D3, the region between D6S447 and WI-5694. Although attempts to identify candidate TSGs from the latter two regions involving sequencing analysis of both regions failed, we found another locus showing homozygous deletion telomeric to the D3 region by FISH analysis using additional probes, Of 106 cell lines examined, 3 had homozygous deletion in this locus, and finally, the Blimp 1 gene was identified as the only gene that existed within the minimum overlapping homozygous deletion. Mutation analysis revealed that Blimpl was mutated in 3 out of 106 primary lymphoid tumors. Our findings indicated that Blimpl might be one of the target TSGs within 6q that was inactivated in human lymphoid neoplasms. ?2002 Elsevier Science B.V All rights reserved,