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J J Yunis

Publications and source records attributed to J J Yunis.

At least 19 recordsLinked to original sources
PubMed1996

Cloning and transcription factor-binding sites of the human c-rel proto-oncogene promoter.

We report here the cloning, sequencing, functional analysis and DNase I footprinting of the human c-rel promoter region. The results revealed an 824-bp BsaAI-StuI minimal promoter region with a large number of NF-kappa B, Ap2 and Sp1-binding sites, some of them variants of known consensus sequences. This is the first promoter in the Rel/NF-kappa B/I kappa B family to be subjected to a detailed footprinting analysis for the binding of transcription activator proteins. Our finding of 14 Ap2-binding sites may indicate why the human c-rel promoter, unlike the chicken c-rel promoter, has a strong function and is highly responsive to phorbol esters. The presence of five NF-kappa B and six Sp1-binding sites in turn adds to growing evidence that, in mammals, the promoter of the Rel/NF-kappa B/I kappa B family may utilize multiple NF-kappa B- and Sp1-binding sites for their interactive regulation. Furthermore, there are putative binding sites for the PU.1 and Oct 1/2 transcription activator proteins, also present in the mouse c-rel promoter, which may help explain the preferential transcription of the c-rel gene in B- and T-lymphoid cells.

Amino Acid Sequence↗
PubMed1996

MLL tandem duplication and multiple splicing in adult acute myeloid leukemia with normal karyotype.

Rearrangement of the MLL (myeloid-lymphoid or mixed-lineage leukemia) gene through a reciprocal chromosomal translocation is found in 5% of adult acute myeloid (AML) and 10% of pediatric acute lymphoid (ALL) leukemia. More than 25 different reciprocal chromosomal translocations, with an 11q23 breakpoint, fuse the MLL gene (also named ALL-1, HRX and Htrx1) to a second partner gene. These leukemias have poor prognosis and frequently have a monocytic, lymphoid or biphenotypic (myeloid and lymphoid) antigen expression in blast cells. Approximately 20-30% of patients diagnosed as having adult de novo, AML have normal chromosomes by metaphase analysis and the majority of these patients have good prognosis. With the use of reverse transcriptase-polymerase chain reaction (RT-PCR) technique and Southern blot analysis, we found that seven of 34 such patients (21%) had a tandem partial duplication of exons 2 to 6 or 2 to 8 of the MLL gene. These seven patients showed a median survival of 2.7 months, compared to a 6.8 months median survival for all other patients in the study. If confirmed on a large series of patients, our findings may help differentiate AML with normal karyotype and poor prognosis from those with normal karyotype and a more favorable prognosis.

Acute Disease↗
PubMed1995

The major histocompatibility complex region marked by HSP70-1 and HSP70-2 variants is associated with clozapine-induced agranulocytosis in two different ethnic groups.

Genes of the major histocompatibility complex (MHC) have been associated with susceptibility to drug-induced adverse reactions. We previously found that clozapine-induced agranulocytosis (CA) is associated with the HLA-DRB1*0402, DRB4*0101, DQB1*0302, DQA1*0301 haplotype in Ashkenazi Jewish patients and with the HLA-DRB1*1601, DRB5*02, DQB1*0502, DQA1*0102 haplotype in non-Jewish patients. In the present study, we tested the hypothesis that the variants of the heat-shock protein 70 (HSP-70) encoded by the HSP-70 loci located within the MHC region and known to be involved in apoptosis and regulation of cell proliferation could play an important role in molecular mechanisms of CA. First, we analyzed HSP70-2 polymorphism in risk-associated haplotypes from HLA homozygous cells and normal individuals and confirmed that the HSP70-2 9-kb variant was associated invariably with DR4 (HLA-DRB1*0402, DQB1*0302) and DR2 (HLA-DRB1*01601, DQB1*0502, DQA1*0102 and HLA-DRB1*1501, DQB1*0602) haplotypes, which were the haplotypes found increased in Jewish and non-Jewish patients with CA, respectively. The 9.0-kb variant was also found to be associated with HLA-B44, DRB1*0401 and HLA-B44, DRB1*07 haplotypes. Second, in patients with CA (12 Ashkenazi Jewish and 20 non-Jewish patients), HSP70-1 A and HSP70-2 9.0-kb variants were associated with the MHC haplotypes found by us to be markers of susceptibility to CA. The clozapine-treated control group had an excess number of HSP70-1 C and HSP70-2 8.5-kb variants, consistent with genetic resistance to CA associated with those variants. This finding supports our hypothesis that a dominant gene within the MHC region (marked by HSP70-1 and HSP70-2), but not necessarily HLA, is associated with CA in two different ethnic groups.

Agranulocytosis↗
PubMed1995

HLA associations in clozapine-induced agranulocytosis.

We previously reported preliminary results of association of clozapine-induced agranulocytosis (CA) with HLA-B38, DR4, DQ3 in five Ashkenazi Jewish patients and with HLA-DR2, DQ1 in four non-Jewish patients. In the present study, 31 additional patients with CA, 10 Ashkenazi Jewish, and 21 of non-Jewish ancestry, were studied. HLA alleles and haplotypes were compared among 52 patients (33 Ashkenazi Jewish, 19 non-Jewish) matched for ethnic background and clinical status. Our results show two associations and define the HLA allele markers for the Ashkenazi Jewish and non-Jewish haplotypes associated with CA. The most important markers for susceptibility for CA in Ashkenazi Jewish patients were DRB1*0402, DQB1*0302, and DQA1*0301, and in non-Jewish patients, HLA-DR*02, DQB1*0502, and DQA1*0102. HLA-DRB1*011 and DQB1*0301 were underrepresented in Ashkenazi Jewish patients when compared with controls. We hypothesize that genes of the major histocompatability complex, other than class I and class II, are responsible for CA; among them are the variants of the heat-shock proteins 70 or the tumor necrosis factor loci.

Adult↗
PubMed1995

Ocular cicatricial pemphigoid. A case report of monozygotic twins discordant for the disease.

OBJECTIVE: To identify the major histocompatibility complex markers and the autoantibody associated with ocular cicatricial pemphigoid (OCP) in a proband, her unaffected cotwin, and the children of the cotwin. Ocular cicatricial pemphigoid is a chronic autoimmune disorder that affects the conjunctiva and other squamous epithelium. It is associated with the major histocompatibility complex class II alleles that are presumed to provide enhanced susceptibility to the disease. We encountered a pair of monozygotic female twins, one of whom has OCP. In addition to totally identical physical appearances since birth, the two sisters have identical blood groups. METHODS: The following studies were performed on the patient, her unaffected cotwin sister, and her children: (1) polymorphism of major histocompatibility complex class II genes by DNA typing, (2) sequence analysis of DQ beta gene second and third exons, and (3) serologic evaluation for the presence of anti-basement membrane zone autoantibodies specific for OCP by Western immunoblot with the use of skin and conjunctiva lysates as substrates. RESULT: Both monozygotic twins had the same HLA haplotypes. The sequence analysis of the second and third exons of DQ beta genes revealed no significant differences between the proband and her unaffected cotwin. Autoantibodies specific to OCP were detected only in the patient's serum. The serum of the unaffected cotwin and the other relatives did not demonstrate the presence of the OCP autoantibody. CONCLUSION: This isolated family study does not support a single-gene theory for the development of OCP. It is most likely due to a multigene effect and associated with environmental factors.

Aged↗
PubMed1994

Common major histocompatibility complex class II markers in clinical variants of cicatricial pemphigoid.

Cicatricial pemphigoid (CP) is a chronic autoimmune blistering disease affecting multiple mucous membranes derived from stratified squamous epithelium and occasionally the skin. CP has a wide spectrum of disease manifestations. Patients with oral pemphigoid (OP) have a benign self-limited disease in which pathological changes are restricted to the oral mucosa. On the other hand, patients with ocular cicatricial pemphigoid (OCP), a chronic condition marked with relapses and remissions, have ocular involvement and also perhaps involvement of other mucous membranes. All clinical subsets are characterized by the presence of a similar anti-basement zone autoantibody. The factors that determine the development of one form of CP or the other are not known. In a previous study, we described the association between OCP and the DQB1*0301 allele (P = 0.006). In this study, we have analyzed 22 Caucasian patients with OP and their family members for major histocompatibility complex DRB generic, DQA1, and DQB1 allele associations by PCR-sequence-specific oligonucleotide probe hybridization. The results were compared to those obtained from 17 Caucasian patients with OCP and to control Caucasian alleles and haplotypes. The DQB1*0301 allele frequency was 38.6% in OP, 52.9% in OCP, and 17.8% in controls. Statistically significant associations were detected between the DQB1*0301 allele and both OP (P = 0.0047) and OCP (P < 0.0001). In addition, DRB1*04 showed a statistically significant association (P = 0.005) with OCP when compared to controls. Analysis of major histocompatibility complex class II haplotypes showed significant statistical associations between both OCP and OP and the HLA-DRB1*04, DRB4*0101, DQA1*03, DQB1*0301 haplotype (P < 0.0001 and P = 0.0012, respectively). Our results indicate that DQB1*0301 is a marker of both oral and ocular forms of CP. The analysis of the amino acid sequence of the DQB1 alleles present in both OP and OCP suggested that amino acid residues at position 57 and positions 71-77 may also be markers of CP.

DNA Probes↗
PubMed1994

Major histocompatibility complex class II alleles and haplotypes and blood groups of four Amerindian tribes of northern Colombia.

MHC class II alleles and haplotypes were determined from unrelated individuals and families of the Arhuaco (n = 107), Kogi (n = 42), Arsario (n = 18), and Wayú (n = 88) tribes located in the northern part of Colombia. Class II DRB, DQA1, and DQB1 alleles were determined by PCR-SSO and PCR-RFLP based methods. Four haplotypes, [DRB1*0407, DRB4*0101, DQA1*03, DQB1*0302]; [DRB1*0403, DRB4*0101, DQA1*03, DQB1*0302]; [DRB1*1402/1406, DRB3*0101, DQA1*0501, DQB1*0301]; and [DRB1*0802, DQA1*0401, DQB1*0402], were observed among these four tribes. In addition to these haplotypes, the Wayú Indians showed a frequency of 21.3% for the [DRB1*1602, DRB5*02, DQA1*0501, DQB1*0301] haplotype, 13.1% for the [DRB1*0411, DRB4*0101, DQA1*03, DQB1*0302] haplotype, and 8.1% for the [DRB1*0411, DRB4*0101, DQA1*03, DQB1*0402] haplotype. Red cell antigen typing was used to calculate genetic admixture. The Kogi and Arsario showed no genetic admixture while the Arhuaco tribe showed admixture with genes of African origin and the Wayú showed admixture with Caucasians as well as genes of African origin. These findings were confirmed by the MHC class II allele and haplotype data obtained, as alleles and haplotypes of Caucasian and African origin were detected in the Wayú and Arhuaco and not in the Kogi or Arsario. These studies will be important in disease association and transplantation studies for Amerindian and colombian populations and for correlating genetic traits with the anthropologic and linguistic data available in order to better understand the Amerindian populations.

Alleles↗
PubMed1994

HSP70-2 9.0 kb variant is in linkage disequilibrium with the HLA-B and DRB1* alleles associated with clozapine-induced agranulocytosis.

In order to extend the analysis of the association between class I and class II HLA markers and HSP-70 alleles, we studied the genetic polymorphism of HSP70-2 genes by restriction fragment length polymorphism analysis in a panel of HLA-homozygous cell lines carrying the HLA-B alleles known to be associated with clozapine-induced agranulocytosis. We have found a linkage disequilibrium between the 9.0 kb variant of HSP70-2 with the class I antigens HLA-B7, B38, and B44 and with the class II antigens HLA-DR2 and DR4. We discuss the importance of analyzing the variants of HSP70-2 in patients with agranulocytosis to confirm that the 9.0 kb allele is a genetic marker for the disease. If that is the case, HSP-70 variants could explain the different associations of HLA alleles in individuals of Jewish and non-Jewish ancestry because the HLA alleles are in linkage disequilibrium with the 9.0 kb band. We postulate that HSP-70 molecules could also play a significant role in determining the molecular mechanisms that induce agranulocytosis by clozapine.

Agranulocytosis↗
PubMed1993

Major histocompatibility complex susceptibility genes for dermatitis herpetiformis compared with those for gluten-sensitive enteropathy.

Dermatitis herpetiformis (DH) shares some clinical features and major histocompatibility complex (MHC) markers with gluten-sensitive enteropathy (GSE). We compared MHC haplotypes in 27 patients with DH, 35 patients with GSE, and normal controls. As in GSE, the frequencies of two extended haplotypes, [HLA-B8, SC01, DR3] and [HLA-B44, FC31, DR7], were increased in patients with DH. Distributions of fragments of extended haplotypes, consisting of some but not all of the elements of complete extended haplotypes, were analyzed to attempt to localize a susceptibility gene. Besides complete extended susceptibility haplotypes, (DR3, DQ2) and (DR7, DQ2) fragments were most common in GSE. In contrast, DH showed only a few such fragments but many instances of the fragment (SC01). The differences in distribution of these fragments in the two diseases were highly significant (P < 0.002). HLA-DQ2 and DR3 had the highest odds ratios for GSE, but the highest odds ratio for DH was for the complotype SC01. These findings suggest that the MHC susceptibility gene for DH is between class II and complotype regions, closest to the complotype, whereas that for GSE is in the class II region.

Celiac Disease↗
PubMed1993

HLA-DQA1, DQB1 and DPB1 alleles on HLA-DQ2- and DQ9-carrying extended haplotypes.

DQA1, DQB1 and DPB1 alleles were investigated in a large panel of samples carrying HLA-DQ2- and HLA-DQ9-bearing extended haplotypes. Every instance of the [HLA-B8, SCO1, DR3, DQ2a] and [HLA-B18, F1C30, DR3, DQ2b] extended haplotypes carried the DQA1*0501 allele, while every instance of [HLA-B44, FC31, DR7, DQ2c], [HLA-B47, FC91,0, DR7, DQ2c] and [HLA-B57, SC61, DR7, DQ2d] carried the DQA1*0201 allele. All HLA-DR3, DQ2 and HLA-DR7, DQ2 extended haplotypes carried the DQB1*0201 allele. Every example of [HLA-B57, SC61, DR7, DQ9] carried the DQB1*0303 allele. Several associations between the DPB1 alleles and some HLA-DQ2- and DQ9-carrying extended haplotypes were identified. HLA-DPw2-encoding alleles, DPB1*0202 (50%, p < 0.001) and 0201 (30%), were found on the [HLA-B18, F1C30, DR3, DQ2b] extended haplotype. Every instance of the [HLA-B57, SC61, DR7, DQ9] extended haplotype carried the DPB1*0401 allele. Also, we have confirmed the associations of the DPB1*0101 and DPB1*0401 alleles with the [HLA-B8, SC01, DR3, DQ2a] extended haplotype. The analysis of homozygous typing cells carrying the [HLA-B44, FC31, DR7, DQ2c] extended haplotype showed that the DPB1*0401 and 0201 alleles were present at similar frequencies (37.5%), while the DPB1*1101 allele was found in only 25% of these haplotypes analyzed. Our results suggest that the constancy of the DNA of the HLA-B, DR, DQ regions may extend to the DP region and that the extent of such fixity varies, perhaps as the result of ethnic variability of the population studied.

Alleles↗
PubMed1993

Molecular mechanisms of hematologic malignancies.

This article reviews both the role of signal transduction in human cancer and the recently uncovered molecular mechanisms involved in a large number of human hematologic malignancies. Chronic myelogenous leukemia, follicular lymphoma, and colorectal carcinoma are used as models to illustrate the different, as well as partly convergent, molecular pathways involved in the multistep process of human neoplasias. Examples are also provided as to how unique molecular markers can be used as fast, sensitive, and precise tools for cancer prevention, early diagnosis, and the management of residual disease.

Base Sequence↗
PubMed1992

Human immunodeficiency virus gp120 binding C'C" ridge of CD4 domain 1 is also involved in interaction with class II major histocompatibility complex molecules.

Using site-directed mutagenesis informed by high-resolution CD4 structural data, we have investigated the role of residues of the C'C'' ridge region of human CD4 on class II major histocompatibility complex (MHC) binding. This C'C'' ridge is homologous to the CDR2 loop of an immunoglobulin variable domain and is known to contain the binding site for human immunodeficiency virus (HIV) coat glycoprotein gp120. Here we report that this region is also involved in interaction with class II MHC. Exposed positively charged residues Lys-35, Lys-46, and Arg-59 and the exposed hydrophobic residue Phe-43 contribute significantly to class II MHC binding. Moreover, mutations in the buried residues Trp-62 and Ser-49, which support the top and bottom of the C'C'' ridge, respectively, disrupt class II MHC interaction. The HIV binding region appears to involve a restricted area of the larger class II MHC binding site on CD4. Strategies of drug design aimed at interrupting CD4-HIV interaction will need to consider the extensive overlap between class II MHC and HIV gp120 binding surfaces in this region of CD4.

Animals↗
PubMed1992

Cloning, expression and localization of an RNA helicase gene from a human lymphoid cell line with chromosomal breakpoint 11q23.3.

A gene encoding a putative human RNA helicase, p54, has been cloned and mapped to the band q23.3 of chromosome 11. The predicted amino acid sequence shares a striking homology (75% identical) with the female germline-specific RNA helicase ME31B gene of Drosophila. Unlike ME31B, however, the new gene expresses an abundant transcript in a large number of adult tissues and its 5' non-coding region was found split in a t(11;14)(q23.3;q32.3) cell line from a diffuse large B-cell lymphoma.

Amino Acid Sequence↗
PubMed1992

Molecular quantification of residual disease in chronic myelogenous leukemia after bone marrow transplantation.

Residual disease remains a major problem in the treatment of human neoplasia. To effectively monitor minimal leukemic activity after bone marrow transplantation (BMT), we used a competitive polymerase chain reaction (PCR) amplification technique to quantify expression of the characteristic bcr-abl fusion message in patients with chronic myelogenous leukemia (CML). Quantitative results were obtained between the 0.001% and 0.1% level in control experiments. This represents a significant advantage over cytogenetic and Southern blotting techniques routinely used to diagnose CML, which may not be sensitive below the 1% level. To illustrate the potential clinical usefulness of the quantitative PCR strategy, we compared results of bcr-abl messenger RNA expression with those obtained using cytogenetic and Southern blotting techniques, in a study of consecutive BM and peripheral blood (PB) samples from two CML patients at high risk for relapse after BMT. One patient received a syngeneic transplant during the chronic phase of the disease and relapse was apparent at the molecular level 4.5 months after BMT, while the patient was in complete clinical remission. The second patient was treated with an allogeneic BMT during the accelerated phase of the disease. A slow, but progressive decrease in bcr-abl expression was observed during the first 12 months after BMT, and expression was undetectable thereafter. Our results indicate that the competitive PCR technique can be used to monitor disease activity in patients at high risk of relapse, while the patients are in complete clinical remission, which should facilitate the early detection of relapse or the identification of progressive disappearance of leukemic activity. The approach used may serve as a model for the study of residual disease in an increasing number of other hematologic malignancies that express cancer-specific RNAs.

Adult↗