PMID- 11156420 OWN - NLM STAT- MEDLINE DCOM- 20010222 LR - 20061115 IS - 0008-5472 (Print) IS - 0008-5472 (Linking) VI - 60 IP - 24 DP - 2000 Dec 15 TI - Inactivation of the human fragile histidine triad gene at 3p14.2 in monochromosomal human/mouse microcell hybrid-derived severe combined immunodeficient mouse tumors. PG - 7119-25 AB - We have previously shown that inoculation of human chromosome 3 (chr3)/A9 mouse fibrosarcoma microcell hybrids (MCHs) into severe combined immunodeficient (SCID) mice was followed by the regular elimination of some 3p regions whereas a 3q region was retained even after prolonged mouse passage. Using this approach, referred to as the elimination test (Et), we have defined a common eliminated region (CER) of approximately 7 cM at 3p21.3 that was absent in all of the 27 tumors generated from five MCHs. Later, CER was reduced to a 1-Mb region, designated as CER1. Another eliminated region (ER2) at 3p21.1-p14.2 was absent in 21 of the 27 tumors. ER2 borders at but does not include the fragile histidine triad (FHIT) gene, considered as a putative tumor suppressor gene. In the present work, two new and two previously studied MCHs, and 13 derived SCID mouse tumors were analyzed by fluorescence in situ hybridization (FISH) chromosome painting and by PCR, using 72 chr3p-specific and 11 chr3q-specific markers. Nine tumors generated from three MCHs that carried cytogenetically normal chr3, remained PCR-positive for all of the chr3 markers tested. Designated as "PCR+" tumors, they were examined by reverse transcription (RT)-PCR, together with four of six previously studied tumors derived from MCH910.7, which carried a del(3)(pter-p21.1), for the expression of 14 human genes: 5 genes within CER1 (LIMD1, CCR1, CCR2, CCR3, CCR5), 5 genes located within regions that were homozygously deleted in a variety of carcinomas (ITGA4L, LUCA1, PTPRG, FHIT, DUTT1), and 4 other genes in chr3p (VHL, MLH1, TGM4, UBE1L). We found that VHL, MLH1, ITGA4L, LIMD1, UBE1L, LUCA1, PTPRG, and DUTT1 were expressed in the MCH lines in vitro and also in the derived SCID tumors. No transcripts that originated from the four CCR genes or from TGM4 could be detected in any of the MCH lines. Alone among the 14 genes examined, FHIT showed a tumor growth-associated change. It was expressed in vitro in five of seven MCH lines. Nine of 13 derived tumors had no FHIT transcript. The remaining 4 expressed a truncated mRNA and a reduced amount of the full-length mRNA. We have previously found that FHIT was deleted at the DNA level in 17 of 21 tumors derived from four MCHs. The remaining 4 of 21 had no FHIT transcript. Our compiled data show that FHIT was either physically or functionally impaired in all 34 of the 34 analyzed tumors. Variants with deleted or down-regulated FHIT have a selective growth advantage. FAU - Kholodnyuk, I D AU - Kholodnyuk ID AD - Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden. FAU - Szeles, A AU - Szeles A FAU - Yang, Y AU - Yang Y FAU - Klein, G AU - Klein G FAU - Imreh, S AU - Imreh S LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Cancer Res JT - Cancer research JID - 2984705R RN - 0 (DNA, Complementary) RN - 0 (Neoplasm Proteins) RN - 0 (Proteins) RN - 0 (fragile histidine triad protein) RN - 9007-49-2 (DNA) RN - EC 3.6.- (Acid Anhydride Hydrolases) SB - IM MH - *Acid Anhydride Hydrolases MH - Animals MH - Carcinoma/genetics MH - Chromosome Painting MH - *Chromosomes, Human, Pair 3 MH - DNA/metabolism MH - DNA, Complementary/metabolism MH - Down-Regulation MH - Gene Deletion MH - Humans MH - Hybrid Cells MH - In Situ Hybridization, Fluorescence MH - Mice MH - Mice, SCID MH - Models, Genetic MH - *Neoplasm Proteins MH - Neoplasms, Experimental MH - Polymerase Chain Reaction MH - Proteins/*genetics MH - Reverse Transcriptase Polymerase Chain Reaction MH - Tumor Cells, Cultured EDAT- 2001/01/13 11:00 MHDA- 2001/03/03 10:01 CRDT- 2001/01/13 11:00 PHST- 2001/01/13 11:00 [pubmed] PHST- 2001/03/03 10:01 [medline] PHST- 2001/01/13 11:00 [entrez] PST - ppublish SO - Cancer Res. 2000 Dec 15;60(24):7119-25.