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• W152007997 abstract "Uterine leiomyomata, or fibroids, are smooth muscle tumors well known to the practicing gynecologist, women's pathologist, and a large number of women primarily of reproductive age. Their characteristic benign nature has resulted perhaps in a low profile as tumors of intense research interest. However, in the past few years positional cloning efforts have been used successfully to begin to approach an understanding of genes involved in the pathobiology of fibroids. Knowledge of these genes and their role in tumor biology may provide valuable insight into the molecular events that differentiate benign and malignant tumors, in addition to possibly impacting development of medical treatment for uterine fibroids. Uterine leiomyomata are the most common pelvic tumors in women and are associated with a variety of symptoms including abnormal uterine bleeding, pelvic pain, urinary frequency, impaired fertility, and spontaneous abortion. It is obvious that many of these symptoms are due to the anatomic location of the tumors but other findings, such as impaired fertility, may result from presently unknown biochemical alterations in the endometrium mediated by a fibroid. Estrogen and progesterone undoubtedly play an important role in growth and development of these tumors, which are not seen before puberty, undergo a rapid increase in size during pregnancy, and then regress postmenopausally. The role of oral contraceptives in stimulating the growth of fibroids remains somewhat controversial and we have yet to know what effects hormone replacement therapy might have on these tumors. Fibroids occur in 20–25% of women of reproductive age, but this percentage may be a gross underestimate as studies by Drs. Cramer and Patel,1Cramer SF Patel A The frequency of uterine leiomyomas.Am J Clin Pathol. 1990; 94: 435-438Crossref PubMed Scopus (769) Google Scholar looking at the presence of uterine leiomyomata in serial sections from 100 hysterectomies indicated a prevalence rate of 77%. Lastly, but most importantly, these tumors are a major public health problem. Fibroids are the primary indication for greater than a third of all hysterectomies, accounting for more than 200,000 procedures in the United States annually and for an estimated one in five visits to the gynecologist. Fibroids are benign tumors with less than 0.1% estimated to progress to malignancy. Rigorous studies of these tumors might provide insight into the molecular events that differentiate benign and malignant tumors. For example, in the case of leiomyomata and their presumed malignant counterpart, leiomyosarcomas, it remains to be determined whether these two neoplasms are in the same genetic pathway. One consideration for the observed low progression of the incredibly prevalent leiomyomata to the rare leiomyosarcoma is that there are so many additional genetic events that must occur that a malignant tumor rarely arises. Histologically, uterine leiomyomata are characterized by well-differentiated whirling bundles of smooth muscle cells that comprise fairly distinct nodules. Consistent with their benign nature, mitoses are scant and normal in appearance. In comparison to the normal myometrium the fibroid appears more cellular, although in tissue culture the two are indistinguishable. Fibroids can be found in intramural, subserosal, or submucosal locations in the uterus. An average uterus contains six or seven fibroids, which have often been referred to as “potato-like” due to the diversity in shape and form of these tumors. It is estimated that there is a threefold to ninefold greater prevalence of uterine leiomyomata among black females than white females, and a roughly threefold increase has been confirmed recently in an analysis of data from the Nurses' Health Study II.2Marshall LM Spiegelman D Barbieri RL Goldman MB Manson JE Colditz GA Willett WC Hunter DJ Variation in the incidence of uterine leiomyomata among premenopausal women by age and race.Obstet Gynecol. 1997; 90: 967-973Crossref PubMed Scopus (639) Google Scholar This finding indicates that there might be some genetic factor which predisposes one to develop fibroids. A genome-wide scan could be performed to look for a major susceptibility locus for fibroids, similar to that reported for prostate cancer for which a locus on chromosome 1 was identified.3Smith JR Frieje D Carpten JD Gronberg H Xu J Isaacs SD Brownstein MJ Bova GS Guo H Bujnovszky P Nusskern DR Damber JE Bergh A Emanuelsson M Kallioniemi OP Walker-Daniels J Bailey-Wilson JE Beaty TH Meyers DA Walsh PC Collins FS Trent JM Isaacs WB Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search.Science. 1996; 274: 1371-1374Crossref PubMed Scopus (667) Google Scholar Interestingly, twin pair correlations for hysterectomy in monozygotic twins are about twice that reported in dizygous twins,4Treloar SA Martin NG Dennerstein L Raphael B Heath AC Pathways to hysterectomy: Insights from longitudinal twin research.Am J Obstet Gynecol. 1992; 167: 82-88Abstract Full Text PDF PubMed Scopus (80) Google Scholar consistent with the genetic relationship between monozygotic and dizygotic twins, indicating that there is a genetic liability for hysterectomy. Because fibroids are the most common indication for hysterectomy, it seems likely that they play a role in this correlation although there may be other factors as well. Concerning biochemical and molecular studies, G6PD isozyme analysis has been used to establish clonality of these tumors5Townsend DE Sparkes RS Baluda MC McClelland G Unicellular histogenesis of uterine leiomyomas as determined by electrophoresis of glucose-6-phosphate dehydrogenase.Am J Obstet Gynecol. 1970; 107: 1168-1173Abstract Full Text PDF PubMed Scopus (192) Google Scholar and we have used the polymorphic androgen receptor locus (HUMARA) to confirm those studies and to make some additional observations.6Mashal RD Fejzo MS Friedman AJ Mitchner N Nowak RA Rein MS Morton CC Sklar J Analysis of androgen receptor DNA reveals the independent clonal origins of uterine leiomyomata and the secondary nature of cytogenetic aberrations in the development of leiomyomata.Genes Chromosomes Cancer. 1992; 11: 1-6Crossref Scopus (141) Google Scholar Clonality was evaluated in 36 fibroids from 16 patients. Twenty-seven of the 36 fibroids had been karyotyped previously and these tumors fell into three groups: normal 46,XX tumors, karyotypically abnormal, and mosaic tumors of 46,XX and karyotypically abnormal cells. The assay takes advantage of the facts that essentially one X chromosome in a normal human female is inactivated and that there is a methylation sensitive restriction enzyme site upstream of the polymorphic CAG repeat in the gene. Oligonucleotide primer pairs were designed flanking these repeats and used to amplify the tumor DNA. In informative individuals (ie those with different numbers of CAG repeats), clonality was determined following digestion of the amplified DNA withHhaI. In a monoclonal tumor, DNA from only the inactive X chromosome would remain whereas in a polyclonal tumor, products from either X chromosome would be found, representing either the maternal or paternal X chromosome randomly inactivated. In addition to confirming the monoclonal origin of uterine leiomyomata, we observed that tumors which were mosaics were also clonal.10Xing YP Powell WL Morton CC The del(7q) subgroup in uterine leiomyomata: Genetic and biologic characteristics.Cancer Genet Cytogenet. 1997; 98: 69-74Abstract Full Text PDF PubMed Scopus (49) Google Scholar This leads to the interesting interpretation that the cytogenetic aberrations may be secondary and that the clonal expansion of tumor cells occurs prior to the acquisition of the cytogenetic aberration. We and others have described tumor-specific chromosome aberrations in uterine leiomyomata7Rein MS Friedman AJ Barbieri RL Pavelka K Fletcher JA Morton CC Cytogenetic abnormalities in uterine leiomyomata.Obstet Gynecol. 1991; 77: 923-926PubMed Google Scholar, 8Nilbert M Heim S Uterine leiomyoma cytogenetics.Genes Chromosomes Cancer. 1990; 2: 3-13Crossref PubMed Scopus (192) Google Scholar and these aberrations have been invaluable in targeting areas of the genome in which genes involved in the pathobiology of these tumors might reside. About 40% of tumors are karyotypically abnormal, suggesting that genetic aberrations at the submicroscopic level might be present in karyotypically normal fibroids. A variety of cytogenetic subgroups have been described that predict different genetic mechanisms (Table 1). A trisomy (eg, trisomy 12) predicts a gene dosage mechanism whereas a translocation (eg, t(12;14)(q15;q23–24)) predicts a gain-of-function mutation in the form of a fusion protein, or potentially dysregulation of a particular gene product. A deletion (eg, del(7)(q22q32) is consistent with a loss-of-function mutation, typified by tumor suppressor genes. Thus, it appears that there are probably many different genetic pathways by which a fibroid can grow and develop.Table 1Cytogenetics of uterine leiomyomata60% are 46,XX40% are chromosomally abnormal del(7)(q22q32) t(12;14)(q15;q23-24) rearrangements of 6p21 trisomy 12 rearrangements of 10q22 rearrangements of 13q21-22 deletions of 3q Open table in a new tab Because fibroids are genetically heterogeneous, it is interesting to ask whether there are any phenotypic correlations among the different cytogenetic subgroups. Recently, we evaluated the possible relationship between the size of a tumor and its karyotype9Rein MS Powell WL Walters FC Weremowicz S Cantor RM Barbieri RL Morton CC Cytogenetic abnormalities in uterine myomas are associated with myoma size.Mol Hum Reprod. 1998; 4: 83-86Crossref PubMed Scopus (84) Google Scholar(Table 2). Our sample consisted of 73 karyotypically normal and 41 karyotypically abnormal tumors. Although a trend was noted for association of a larger tumor with an abnormal karyotype, there was not a statistically significantly difference. However, if the abnormal tumors were classified into tumors which were either mosaics or nonmosaics, a significant difference was observed between the normal and karyotypically abnormal nonmosaic tumors. Underlying this observation is the finding that most mosaic tumors involve the deletion 7 subgroup and are actually smaller in size than chromosomally normal tumors, although the difference is not statistically significant. It is possible that loss of genetic material from chromosome 7 results in less than optimal growth in a fibroid.10Xing YP Powell WL Morton CC The del(7q) subgroup in uterine leiomyomata: Genetic and biologic characteristics.Cancer Genet Cytogenet. 1997; 98: 69-74Abstract Full Text PDF PubMed Scopus (49) Google ScholarTable 2Summary of myoma size and cytogenetic analysisCytogenetic analysisMyoma diameter (cm), Mean ± SDMyoma diameter (cm), MedianCalculated myoma volume (cm3), Mean ± SDNormal (n = 73)5.9 ± 4.2aValues with the same superscripts were significantly different, P < 0.01.5.4334 ± 1123cValues with the same superscripts were significantly different, P < 0.01.Abnormal (n = 41)7.6 ± 5.37.0642 ± 1638Abnormal (mosaic) (n = 21)5.0 ± 3.0bValues with the same superscripts were significantly different, P < 0.01.4.5136 ± 165dValues with the same superscripts were significantly different, P < 0.01.Abnormal (non-mosaic) (n = 20)10.2 ± 5.9aValues with the same superscripts were significantly different, P < 0.01.,bValues with the same superscripts were significantly different, P < 0.01.10.01173 ± 2246cValues with the same superscripts were significantly different, P < 0.01.,dValues with the same superscripts were significantly different, P < 0.01.Reprinted by permission of the European Society of Human Reproduction and Embryology, from Molecular Human Reproduction 1998, 4:83–86 © Oxford University Press.a Values with the same superscripts were significantly different, P < 0.01.b Values with the same superscripts were significantly different, P < 0.01.c Values with the same superscripts were significantly different, P < 0.01.d Values with the same superscripts were significantly different, P < 0.01. Open table in a new tab Reprinted by permission of the European Society of Human Reproduction and Embryology, from Molecular Human Reproduction 1998, 4:83–86 © Oxford University Press. To begin to identify genes involved in fibroids, we undertook a positional cloning project focused on chromosome 12 in the q15 breakpoint region. This region was frequently rearranged in fibroids in a consistent translocation with chromosome 14 in q23-24. Of particular interest and potential relevance were numerous chromosome aberrations involving this region in a variety of other mesenchymal tumors including lipomas,11Sreekantaiah C Leong SPL Karakousis CP McGee DL Rappaport WD Villar HV Neal D Fleming S Wankel A Herrington PN Carmona R Sandberg A Cytogenetic profile of 109 lipomas.Cancer Res. 1991; 51: 422-433PubMed Google Scholar pulmonary chondroid hamartomas,12Dal Cin P Kools P De Jonge I Moerman P Van de Ven W Van den Berghe H Rearrangements of 12q14–15 in pulmonary chondroid hamartoma.Genes Chromosomes Cancer. 1993; 8: 131-133Crossref PubMed Scopus (45) Google Scholar, 13Fletcher JA Longtine J Wallace K Mentzer SJ Sugarbaker DJ Cytogenetic and histologic findings in 17 pulmonary chondroid hamartomas: evidence for a pathogenic relationship with lipomas and leiomyomas.Genes Chromosomes Cancer. 1995; 12: 220-223Crossref PubMed Scopus (64) Google Scholar and endometrial polyps14Walter TA Fan SX Medchill MT Berger CS Decker H-JH Sandberg AA inv(12)(p11.2q13) in an endometrial polyp.Cancer Genet Cytogenet. 1989; 41: 99-103Abstract Full Text PDF PubMed Scopus (33) Google Scholar, 15Vanni R Dal Cin P Marras S Moerman P Andria M Valdes E Deprest J Van den Berghe H Endometrial polyp: another benign tumor characterized by 12q13–q15 changes.Cancer Genet Cytogenet. 1993; 68: 32-33Abstract Full Text PDF PubMed Scopus (65) Google Scholar among others, suggesting either that this region contains a single gene involved in all of these tumors or that multiple genes involved in neoplasia reside within 12q15. To facilitate the positional cloning project it was necessary to develop a high-density physical map of this region of chromosome 12 and in this effort we collaborated with Drs. Donald Moir, Thomas Dorman, and Jen-i Mao (Genome Therapeutics Corp., Waltham, MA), and Drs. Raju Kucherlapati, Sung-Joo Yoon, Kate Montgomery, and Kenneth Krauter (Albert Einstein College of Medicine, New York, NY) who provided various yeast artificial chromosomes (YACs) and cosmids from chromosome 12, which we mapped using fluorescence in situ hybridization (FISH) on tumor metaphase chromosomes. Thirty-nine YACs and six cosmids were mapped with respect to t(12;14).16Schoenberg Fejzo M Yoon S-J Montgomery K Rein MS Weremowicz S Krauter KS Dorman TE Fletcher JA Mao J Moir DT Kucherlapati RS Morton CC Identification of a YAC spanning the translocation breakpoints in uterine leiomyomata, pulmonary chondroid hamartoma and lipoma: physical mapping of the 12q14–q15 breakpoint region in uterine leiomyomata.Genomics. 1995; 26: 265-271Crossref PubMed Scopus (52) Google Scholar YAC 981f11 was found to bridge the translocation breakpoints in uterine leiomyomata, pulmonary chondroid hamartoma, and lipoma, making it highly likely that this YAC would contain the DNA sequence of interest in these tumors. Following identification of YAC 981f11 at 12q15, we collaborated with Drs. Kucherlapati and Kiran Chada (University of Medicine and Dentistry of New Jersey, Piscataway, NJ) to evaluate a potential candidate gene, known as HMGIC, because it mapped within the YAC. Most studies of Hmgic had been conducted in the mouse, and many of the findings made this gene an especially attractive candidate. Interestingly, Hmgic was a very large gene spanning approximately 200 to 250 kb, and a large gene was consistent with a large target in which numerous tumors rearrange potentially. Insertional mutagenesis in a transgenic mouse, knocking out this gene in essence, resulted in a mini-mouse that was about 60% smaller than the wild-type littermate.17Xiang X Benson KF Chada K Mini-mouse: disruption of the pygmy locus in a transgenic insertional mutant.Science. 1990; 247: 967-969Crossref PubMed Scopus (79) Google Scholar The mini-mouse had a large reduction in adipose tissue,18Benson K Chada K Mini-mouse: phenotypic characterization of a transgenic insertional mutant allelic to pygmy.Genet Res. 1994; 64: 27-33Crossref PubMed Scopus (35) Google Scholar an intriguing finding with respect to frequent rearrangements in lipomas at 12q15.Hmgic was expressed at highest levels during embryonic days 12.5 to 14 in mesenchymal tissues, which was also of interest with regard to the various mesenchymal tumors under investigation.HMGIC encodes a member of a family of high mobility group proteins,19Grosschedl R Giese K Pagel J HMG domain proteins: architectural elements in the assembly of nucleoprotein structures.Trends Genet. 1994; 10: 94-100Abstract Full Text PDF PubMed Scopus (729) Google Scholar which are accessory transcription factors, and contains 109 amino acids with 5′ DNA-binding AT hook motifs and a 3′ acidic domain of unknown function.20Ashar HR Cherath L Przybysz KM Chada K Genomic characterization of human HMGIC, a member of the accessory transcription factor family found at translocation breakpoints in lipomas.Genomics. 1996; 31: 207-214Crossref PubMed Scopus (41) Google Scholar, 21Chau K-Y Patel UA Lee K-L Lam H-Y Crane-Robinson C The gene for the human architectural transcription factor HMGI-C consists of five exons coding for a distinct functional element.Nucleic Acids Res. 1995; 23: 4262-4266Crossref PubMed Scopus (72) Google Scholar A very highly homologous family member known as HMGIY is located on chromosome 6 in band p21,22Friedman M Holth LT Zoghbi HY Reeves R Organization, inducible-expression and chromosome localization of the human HMGI(Y) non-histone protein gene.Nucleic Acids Res. 1993; 21: 4259-4267Crossref PubMed Scopus (185) Google Scholar of note because one of the cytogenetic subgroups in fibroids involved 6p21. Probes from the 5′ and 3′ regions of HMGIC were used separately in FISH experiments to metaphases from three lipomas with rearrangements of one chromosome 12 homolog at 12q15;23Ashar HR Schoenberg Fejzo M Tkachenko A Zhou X Fletcher JA Weremowicz S Morton CC Chada K Disruption of the architectural factor HMGI-C: DNA-binding AT hook motifs fused in lipomas to distinct transcriptional regulatory domains.Cell. 1995; 82: 57-65Abstract Full Text PDF PubMed Scopus (407) Google Scholar the three lipomas included tumors with t(3;12)(q29;q15), t(12;13)(q14-22;q21-32) and t(12;15)(q15;q24). Hybridization signals for the 5′ and 3′ HMGIC probes were detected in each case on the normal chromosome 12 as expected. Additionally, signals were found on the derivative chromosome 12 with the 5′ probe in the t(3;12) and t(12;15) lipomas but the 3′ probe was present on the translocation partner chromosome, indicating an intragenic rearrangement inHMGIC. One of the lipomas, involving a t(12;13), turned out to have a more complex rearrangement such that the 5′ probe was detected on the der(13) and the 3′ probe was deleted. Thus, the rearrangement on chromosome 12 in the t(12;13) lipoma most likely occurred 5′ of the HMGIC gene. Two possible mechanisms were considered: a fusion transcript resulting from a chromosomal rearrangement and a truncation of the 3′ region of the gene by chromosomal rearrangement or gene deletion. 3′ RACE experiments identified fusion transcripts in both lipomas with intragenic rearrangements and, in both cases, an in frame splice had occurred precisely at the end of the third exon of HMGICfusing heterologous sequence from the partner chromosome with the 5′ region of HMGIC.23Ashar HR Schoenberg Fejzo M Tkachenko A Zhou X Fletcher JA Weremowicz S Morton CC Chada K Disruption of the architectural factor HMGI-C: DNA-binding AT hook motifs fused in lipomas to distinct transcriptional regulatory domains.Cell. 1995; 82: 57-65Abstract Full Text PDF PubMed Scopus (407) Google Scholar Monochromosomal somatic cell hybrids were used to confirm that the heterologous sequence was derived from the translocation partner chromosome, in these two lipomas either chromosome 3 or 15. Computer analysis of DNA sequence from the t(3;12) fusion transcript with HMGIC identified a motif known as a LIM domain. This was a very interesting domain for consideration in the fusion transcript. LIM domains are 50 to 60 amino acid motifs rich in cysteine and histidine organized into adjacent zinc fingers separated by a two-residue linker.24Sanchez-Garcia I Rabbitts T LIM domain proteins in leukemia and development.Semin Cancer Biol. 1993; 4: 349-358PubMed Google Scholar They are highly conserved among divergent species; were first identified in three proteins, lin11, ISL1, and MEC3;25Way JC Chalfie M mec-3, a homeobox-containing gene that specifies differentiation of the touch receptor neurons in C. elegans.Cell. 1988; 54: 5-16Abstract Full Text PDF PubMed Scopus (463) Google Scholar, 26Freyd G Kim SK Horvitz HR Novel cysteine-rich motif and homeodomain in the product of the Caenorhabditis elegans cell lineage gene lin-11.Nature. 1990; 344: 876-879Crossref PubMed Scopus (467) Google Scholar, 27Karlsson O Thor S Norbert T Ohlsson H Edlund T Insulin gene enhancer bindings protein Isl-1 is a member of a novel class of proteins containing both a homeo- and a Cys-His domain.Nature. 1990; 344: 879-882Crossref PubMed Scopus (575) Google Scholar and have important developmental functions including patterning, cell fate decision, and differentiation. Many LIM-containing proteins are presumed to be transcription factors with their activity thought to be regulated by protein-protein interactions through the LIM dimerization domain. Sequences of the two LIM domains from the chromosome 3-derived sequence were a perfect match with totally conserved cysteine, histidine, and aspartic acid residues seen in other proteins with LIM domains, in addition to being consistent with the presence of an aromatic residue adjacent to the first histidine and a leucin located carboxyl terminal to the central cluster of histidines and cysteines.23Ashar HR Schoenberg Fejzo M Tkachenko A Zhou X Fletcher JA Weremowicz S Morton CC Chada K Disruption of the architectural factor HMGI-C: DNA-binding AT hook motifs fused in lipomas to distinct transcriptional regulatory domains.Cell. 1995; 82: 57-65Abstract Full Text PDF PubMed Scopus (407) Google Scholar Interpretation of the sequence analysis of the chromosome 15 fusion transcript was not as straightforward as that of the chromosome 3 fusion transcript as no known motif was detected; however, the sequence is potentially a transactivation acidic domain. The carboxyl terminal end of the predicted protein is highly acidic and rich in serine and threonine residues, and such domains have been implicated in transcriptional activation. In summary, the two fusion transcripts had a very similar structure in that a heterologous sequence from either chromosome 3 or chromosome 15 was spliced in frame following exon 3 ofHMGIC. That splicing resulted in the 5′ portion ofHMGIC containing exons 1–3 with AT hook domains fused directly with a new 3′ region containing either a LIM domain or a putative transactivation domain.23Ashar HR Schoenberg Fejzo M Tkachenko A Zhou X Fletcher JA Weremowicz S Morton CC Chada K Disruption of the architectural factor HMGI-C: DNA-binding AT hook motifs fused in lipomas to distinct transcriptional regulatory domains.Cell. 1995; 82: 57-65Abstract Full Text PDF PubMed Scopus (407) Google Scholar FISH experiments with metaphase chromosomes from a uterine fibroid with a t(12;14) failed to detect any rearrangement. Both 5′ and 3′ probes were found on the derivative 14 chromosome, indicating that the breakpoint occurred proximal in HMGIC on chromosome 12 and might involve yet a different gene. However, following the observations in lipomas, we reconsidered our observations in uterine fibroids and reasoned that dysregulation of HMGIC might be mediated by an alteration in gene expression, either temporally or by elevated levels. A potentially relevant observation is that one of the characteristic cytogenetic aberrations in uterine fibroids is trisomy 12, which would potentially upregulate HMGIC expression by a gene dosage mechanism. In addition, one fibroid from our karyotyped series contained a copy of the derivative 14 chromosome from a t(12;14) rearrangement, but no copy of the derivative 12. Two cytogenetically normal copies of chromosome 12 were present and FISH experiments were consistent with three copies of HMGIC. Seven additional fibroids and one pulmonary chondroid hamartoma all with t(12;14) rearrangements were studied by FISH using a variety of genomic probes from the HMGIC locus. In all of these cases the translocation breakpoints were upstream of HMGIC and in one tumor a deletion of some of the 5′ sequences had occurred as well.28Schoenberg Fejzo M Ashar HR Krauter KS Powell WL Rein MS Weremowicz S Yoon S-J Kucherlapati RS Chada K Morton CC Translocation breakpoints upstream of the HMGIC gene in uterine leiomyomata suggest dysregulation of this gene by a mechanism different from that in lipomas.Genes Chromosomes Cancer. 1996; 17: 1-6Crossref PubMed Scopus (109) Google Scholar Breakpoints were found at 10 to >100 kb upstream of HMGIC. To substantiate a model predicting dysregulation of HMGIC expression, a Northern blot of RNA prepared from uncultured tissue from a series of five fibroids with t(12;14) rearrangements and their matched normal myometrium was performed. Expression of HMGIC was detected in four fibroids and in none of the matched myometrial RNAs. One fibroid containing a t(12;14) lacked a detectable signal but was a mosaic with normal 46,XX cells; decreased sensitivity to detect HMGIC expression accounted for this discrepancy as HMGIC message was detectable by subsequent RT-PRC experiments. In addition, no hybridization was found in a karyotypically normal fibroid. Recognition of a highly related family member, HMGIY, mapped to 6p21, a site of consistent chromosomal rearrangement in benign mesenchymal tumors now known to involve HMGIC, led to an evaluation of a uterine fibroid with a pericentric inversion involving 6p21, designated 46,XX, inv(6)(p21q15).29Williams AJ Powell WL Collins T Morton CC HMGI(Y) expression in human uterine leiomyomata: involvement of another HMG architectural factor in a benign neoplasm.Am J Pathol. 1997; 150: 911-918PubMed Google Scholar In collaboration with Amy Williams and Dr. Tucker Collins (Brigham and Women's Hospital, Boston, MA) a FISH probe was developed forHMGIY and it was possible to show that this probe was split in the copy of chromosome 6 in which the inversion had occurred. This indicated that the breakpoint was within the vicinity ofHMGIY. HMGIY is known to bind to specific AT-rich domains and promoters of several genes including the interferon β-1 promoter,30Thanos D Maniatis T The high mobility group protein HMGI(Y) is required for NF-κB-dependent virus induction of the human IFN-β gene.Cell. 1992; 71: 777-789Abstract Full Text PDF PubMed Scopus (557) Google Scholar, 31Du W Thanos D Maniatis T Mechanisms of transcriptional synergism between distinct virus-inducible enhancer elements.Cell. 1993; 74: 887-898Abstract Full Text PDF PubMed Scopus (396) Google Scholar E selectin,32Whitley MZ Thanos D Read MA Maniatis T Collins T A striking similarity in the organization of the E-selectin and β interferon gene promoters.Mol Cell Biol. 1994; 14: 6464-6475Crossref PubMed Scopus (177) Google Scholar the interleukin-2 receptor α-chain,33John S Reeves RB Lin JX Child R Leiden JM Thompson CB Leonard WJ Regulation of cell-type-specific interleukin-2 receptor α-chain gene expression: potential role of physical interactions between Elf-1, HMG-I(Y), and NF-κB family proteins.Mol Cell Biol. 1995; 15: 1786-1796Crossref PubMed Google Scholar the chemokine (MGSA/GRO,34Wood LD Farmer AA Richmond A HMGI(Y) and SP1 in addition to NF-κB regulate transcription of the MRSA/GROα gene.Nucleic Acids Res. 1995; 23: 4210-4219Crossref PubMed Scopus (80) Google Scholar and the class II major histocompatibility complex gene HLA-DRA,35Abdulkadir SA Krishna S Thanos D Maniatis T Strominger JL Ono SJ Functional roles of the transcription factor Oct-2A and the high mobility group protein I/Y in HLA-DRA gene expression.J Exp Med. 1995; 182: 487-500Crossref PubMed Scopus (59) Google Scholar and it is necessary for inducible gene expression. Also of interest, HMGIY suppresses transcription of several genes including interleukin-436Chuvpilo S Schomberg C Gerwig R Heinfling A Reeves R Grummt F Surfling E Multiple closely-linked NFAT/octamer and HMGI(Y) binding sites are part of the interleukin-4 promoter.Nucleic Acids Res. 1993; 21: 5694-5704Crossref PubMed Scopus (181) Google Scholar and the immunoglobulin ε-heavy chain gene.37Kim J Reeves R Rothman P Boothby M The non-histone chromosomal protein HMG-I(Y) contributes to repression of the immunoglobulin heavy chain germline ɛ RNA promoter.Eur J Immunol. 1995; 25: 798-808Crossref PubMed Scopus (42) Google Scholar Three binding sites for HMGIY are present in the interferon β-1 promoter; one is known as positive regulatory domain 2, and is located within the center of an NF-κB element. The other two sites flank ATF-2/c-jun sites and are known as positive regulatory domain.4Treloar SA Martin NG Dennerstein L Raphael B Heath AC Pathways to hysterectomy: Insights from longitudinal twin research.Am J Obstet Gynecol. 1992; 167: 82-88Abstract Full Text PDF PubMed Scopus (80) Google Scholar, 31Du W Thanos D Maniatis T Mechanisms of transcriptional synergism between distinct virus-inducible enhancer elements.Cell. 1993; 74: 887-898Abstract Full Text PDF PubMed Scopus (396) Google Scholar We developed an oligonucleotide to the positive regulatory domain 2 sequence, as well as a mutated oligonucleotide, to be used in electrophoretic mobility shift assays (EMSA) to detect HMGIY binding. In this assay a band was present following assay of protein from the leiomyoma with the inv(6) and no band was seen in protein from the myometrium (Figure 1). When the mutated oligonucleotide was used, the binding was almost completely abolished, whereas no diminution in band intensity was seen to the positive control sequence from the interferon β-1 promoter site. Matched leiomyomas and myometrium from nine different patients including a total of sixteen fibroids were studied for HMGIY expression. Interestingly, nine of these sixteen fibroids expressed HMGIY as shown by a band in the EMSA. Some fibroids from the same patient would express HMGIY whereas others would not, and an absolute correlation was seen with no expression of HMGIY in any of the myometrium. In summary, expression studies ofHMGIC by Northern blot and HMGIY by EMSA revealed no myometrium to express either HMGIC or HMGIY. Five uterine leiomyomas with t(12;14) expressed HMGIC. Nine of seventeen uterine leiomyoma had detectable HMGIY binding activity including both karyotypically normal and abnormal tumors with the highest expression seen in a fibroid with an inversion of chromosome 6. No uterine leiomyoma were found that expressed both HMGIC and HMGIY, and some tumors expressed neither. Thus, it is possible that there may be yet another gene which provides a similar function in these tumors as does HMGIC and HMGIY, accounting for the fact that neither have been found to be expressed in some. The finding that no tumors have been found to express both HMGIC and HMGIY may mean that these HMG proteins play similar, perhaps reciprocal, roles in the pathobiology of uterine fibroids. In conclusion, uterine leiomyomata are characterized by several distinct cytogenetic subgroups implying that there are multiple genetic pathways which may lead to these tumors. The frequent finding of chromosomally normal fibroids and the observation of clonality in karyotypically mosaic primary cell cultures and in uncultured fibroid tissue from mosaic cases indicate that the characteristic cytogenetic aberrations are unlikely to be the primary pathogenetic event. Also, rearrangement of 12q15 in uterine leiomyomata is likely to involve an alteration in expression of HMGIC, an architectural factor which is a member of a family of high-mobility group proteins thought to be involved in transcription. Translocations at 12q15 in lipomas, other benign mesenchymal tumors, result in chimeric genes in which the 5′ DNA-binding AT hook domains of HMGIC are fused with heterogeneous transcriptional regulatory domains. And lastly, rearrangement of 6p21 in uterine leiomyomata is likely to involve an alteration in expression of HMGIY, an architectural factor that is a family member of HMGIC." @default.
• W152007997 created "2016-06-24" @default.
• W152007997 creator A5082045576 @default.
• W152007997 date "1998-10-01" @default.
• W152007997 modified "2023-09-25" @default.
• W152007997 title "Many Tumors and Many Genes" @default.
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