The methylthioadenosine phosphorylase gene is frequently co-deleted with the p16INK4a gene in acute type adult T-cell leukemia.

Adult T-cell leukemia (ATL) is a retrovirus-associated leukemia with poor prognosis and often has deletions of the p16INK4a and p15INK4b genes on chromosome 9p21. The gene for methylthioadenosine phosphorylase (MTAP), a purine and methionine metabolic enzyme, resides approximately 100 Kb telomeric to the p16INK4a gene and is frequently co-deleted with the tumor suppressor gene in a variety of cancers. This enzyme deficiency can be exploited for selective chemotherapy with de novo purine synthesis inhibitors and/or methionine depletion.

Detection of p16 gene deletions in gliomas: a comparison of fluorescence in situ hybridization (FISH) versus quantitative PCR.

The p16 protein plays a key role in cell cycle control by preventing CDK4 from inactivating the retinoblastoma protein (pRb). The corresponding tumor suppressor gene (p16/MTS1/CDKN2) has recently been implicated in malignant progression of astrocytomas and could potentially serve as an important marker for patient prognosis and for guiding specific therapeutic strategies. We have undertaken a study to evaluate 2 methods of detecting p16 deletion.

In vitro effects of sho-saiko-to on production of granulocyte colony-stimulating factor by mononuclear cells from patients with chronic hepatitis C.

During the past 2 years, drug-induced interstitial pneumonia was reported in 66 Japanese patients, mainly among chronic hepatitis C patients, undergoing treatment with the Japanese herbal medicine "Sho-saiko-to" (TJ-9). As interstitial pneumonia is also induced by granulocyte colony-stimulating factor (G-CSF), we examined the effects of TJ-9 on G-CSF production in peripheral blood mononuclear cells. In patients with hepatitis B or C, G-CSF production in the absence of any stimulation was significantly lower than healthy controls (p < 0.

p16INK4 and p15INK4B alterations in primary gynecologic malignancy.

Chromosome 9 abnormalities have been found in primary tumors and cell lines from human gynecologic malignancy. Alterations of p16INK4 and p15INK4B genes mapped on the band p21 of chromosome 9 have been detected in various human tumors, but the role of these genes as tumor suppressors in vivo appear to be dependent on tumor type. Polymerase chain reaction (PCR)-based analysis was performed to search for lesions of these genes in 202 primary gynecologic malignancies.

Genomic organization and chromosomal localization of the human casein gene family.

Five yeast artificial chromosome (YAC) clones containing the human casein gene family were isolated and characterized to study the control mechanisms for the expression of these genes. Partial restriction analysis in conjunction with the chromosomal fragmentation method and fluorescence in situ hybridization (FISH) analysis were performed to construct a detailed physical map of the casein gene family and to determine the chromosomal localization of these genes. The isolated YAC clones 748F3, 750D11, 882G11, 886B3 and 960D2 were 1.

Frequent and selective methylation of p15 and deletion of both p15 and p16 in T-cell acute lymphoblastic leukemia.

Frequent deletion of chromosome 9p21 in many cancers has suggested the presence of tumor suppressor genes in this region. Two genes mapping to 9p21, p15 and p16, encode inhibitors for cyclin-dependent kinases 4 and 6. We recently found that in T-cell acute lymphoblastic leukemia (T-ALL), both the p15 and p16 genes are deleted at a high frequency, with p16 gene deletion occurring slightly more frequently than p15 gene deletion.

Molecular cloning of the human methylthioadenosine phosphorylase processed pseudogene and localization to 3q28.

Human methylthioadenosine phosphorylase (MTAP) is a purine and methionine metabolic enzyme present ubiquitously in all normal tissues, but often deleted in many types of cancer. The gene for this enzyme maps to chromosome 9 at band p21 where the cyclin-dependent kinase inhibitor genes for p16 and p15 also reside. During our efforts to clone this gene we also isolated a phage clone containing a processed pseudogene of MTAP.

Effect of long-term depletion of plasma methionine on the growth and survival of human brain tumor xenografts in athymic mice.

Depletion of plasma methionine is expected to inhibit or reverse growth of methionine-dependent tumors; however, modulation of methionine and other sulfur amino acids is not a trivial task in experimental animals. L-Methioninase from Pseudomonas putida at 1,000 U/kg causes acute reduction of plasma methionine by 80% in mice, but recovery occurs within 14 hours. Restriction of dietary choline and replacement of dietary methionine with homocystine results in 50% chronic reduction of plasma methionine.

Methylthioadenosine phosphorylase cDNA transfection alters sensitivity to depletion of purine and methionine in A549 lung cancer cells.

Methylthioadenosine phosphorylase (MTAP), an enzyme involved in purine and methionine metabolism, is present in all normal tissues but is frequently deficient in a variety of cancers. It has been suggested that this metabolic difference between normal and cancer cells may be exploited to selectively treat MTAP-negative cancers by inhibiting de novo purine synthesis and by depleting L-methionine. However, these therapeutic strategies have only been tested in naturally occurring MTAP-positive and -negative cell lines, which might have additional genetic alterations that affect chemotherapeutic sensitivity.

Frequent deletion in the methylthioadenosine phosphorylase gene in T-cell acute lymphoblastic leukemia: strategies for enzyme-targeted therapy.

Methylthioadenosine phosphorylase (MTAP), an enzyme essential for the salvage of adenine and methionine, is deficient in a variety of cancers, including acute lymphoblastic leukemia (ALL). Because the MTAP gene is located adjacent to the tumor-suppressor gene p16 on chromosome 9p21 and more than 60% of T-cell ALL (T-ALL) patients have deletion in the p16 gene, we examined the status of the MTAP gene in T-ALL patients. Quantitative polymerase chain reaction amplification of exon 8 of MTAP showed a deletion in 16 of 48 (33.

Identification of human tumour suppressor genes by monochromosome transfer: rapid growth-arrest response mapped to 9p21 is mediated solely by the cyclin-D-dependent kinase inhibitor gene, CDKN2A (p16INK4A).

Microcell transfer of intact normal human chromosomes into immortal mouse and hamster fibroblast cell lines has revealed growth suppressive activity associated with a small sub-set of the human complement. Here, we describe the results of a detailed study aimed at identifying the gene or genes responsible for the rapid growth-arrest response obtained with human chromosome-9. Initially, STS-PCR deletion mapping of segregants arising in monochromosome transfer experiments was used successfully to localize the active sub-chromosomal region to 9p21.

Chromosome 9 related aberrations and deletions of the CDKN2 and MTS2 putative tumor suppressor genes in human chondrosarcomas.

Deletions on the short arm of chromosome 9 (9p21 region) have been reported in a number of hematopoietic and solid tumors. These aberrations on 9p have been previously associated with the loss of the interferon gene cluster and the gene for methylthioadenosine phosphorylase (MTAP), localized to the 9p21-22 region. Recently, two putative tumor suppressor gene(s) CDKN2 and MTS2 have been mapped to the 9p21 region, and shown to be deleted in a large number of tumors including leukemias, melanomas, bladder cancers and brain tumors.

Partial deletions of the CDKN2 and MTS2 putative tumor suppressor genes in a myxoid chondrosarcoma.

Cytogenetic abnormalities of chromosome 9 (9p21) have been reported in a large number of tumors that include malignant melanomas, gliomas, lung cancers and leukemias. These aberrations on 9p have been previously shown to involve the loss of the interferon gene cluster and the gene for methylthioadenosine phosphorylase (MTAP), both of which have been mapped to the 9p21 region. Recently, two putative tumor suppressor gene(s) CDKN2 and MTS2, have been mapped to the 9p21 region, and have been shown to be deleted in a large number of hematopoietic and solid malignancies.

Homozygous deletions of p16/MTS1 and p15/MTS2 genes are frequent in t(1;19)-negative but not in t(1;19)-positive B precursor acute lymphoblastic leukemia in childhood.

We analyzed 60 B precursor acute lymphoblastic leukemia (ALL) primary samples and 15 cell lines for homozygous deletions of p16 and p15 genes and mutations of p16 gene. These included five cell lines and 13 primary samples with the t(1;19)(q23;pl3), and eight primary samples with the t(9;22)(q34;qll). Of 10 cell lines without t(1;19), homozygous deletion of both p16 and p15 genes was found in eight cell lines (80%), and a rearrangement of p16 in one cell line (10%).

Purification and characterization of recombinant human 5'-methylthioadenosine phosphorylase: definite identification of coding cDNA.

5'-Methylthioadenosine phosphorylase gene maps on the 9p21 chromosome, strictly linked to the important tumor suppressor gene p16INK4A. Chromosomal deletions encompassing both the phosphorylase and p16INK4A genes cause the complete absence of the enzymatic activity in a large number of tumors, thus resulting in well-defined metabolic differences between malignant and normal cells. Recently, the cloning of the phosphorylase gene has been reported on the basis of indirect evidence.

Genomic cloning of methylthioadenosine phosphorylase: a purine metabolic enzyme deficient in multiple different cancers.

5'-Deoxy-5'-methylthioadenosine phosphorylase (methylthioadeno-sine: ortho-phosphate methylthioribosyltransferase, EC 24.2.28; MTAP) plays a role in purine and polyamine metabolism and in the regulation of transmethylation reactions.

[A case report of congenital stapes fixation accompanied by symphalangism and hypermetropia].

A 32-year-old female with bilateral congenital stapes fixation accompanied by bilateral proximal symphalangism and bilateral hypermetropia is reported. This is the 19th case of congenital stapes fixation and symphalangism in Japan. Hypermetropia was speculated to be one of the cardinal symptoms of the disease based on the present case and cases previously reported.

Gene cloning and characterization of Pseudomonas putida L-methionine-alpha-deamino-gamma-mercaptomethane-lyase.

Methionine dependency has been reported in cancer cell lines and primary tumors. Thus, L-methionine deprivation might have potential value for the treatment of human cancers with a methionine requirement. L-Methionine-alpha-deamino-gamma-mercaptomethane-lyase has been reported to decrease plasma methionine levels and to inhibit tumor growth in experimental animals but has not been studied extensively because sufficient homogeneous enzyme was not available.

Expression of the p16 and p15 cyclin-dependent kinase inhibitors in lymphocyte activation and neuronal differentiation.

The cyclin-dependent kinase inhibitors p16INK4/MTS1 and p15INK4B/MTS2 have been mapped to a region in chromosome 9 (921) that is deleted frequently in acute lymphoblastic leukemias and malignant gliomas. To gain insight into the functions of these inhibitors in lymphocytes and neuronal cells, we studied the expression of p15 and p16 during lymphocyte mitogenesis and neuronal differentiation. Expression of p15 was extinguished during lymphocyte activation, concomitant with an increase in retinoblastoma kinase activity.

Homozygous deletions of p16/MTS1 gene are frequent but mutations are infrequent in childhood T-cell acute lymphoblastic leukemia.

Fifty-six primary childhood T-cell acute lymphoblastic leukemia (T-ALL) samples and 17 T-ALL cell lines were examined for mutations and homozygous deletions of the p16/MTS1 gene using polymerase chain reaction single-strand conformation polymorphism and Southern blot analysis. Homozygous deletions were found in 22 primary samples (39%) and in 10 cell lines (59%). In contrast, mutations including small deletions and/or insertions were identified in only 4 primary samples (7%) and in 2 cell lines (12%).

p16 alterations and deletion mapping of 9p21-p22 in malignant mesothelioma.

To determine whether p16 is altered in human malignant mesothelioma (MM), molecular analysis of multiple 9p loci was performed on 40 cell lines and 23 primary tumors from 42 MM patients. We identified homozygous deletions of p16 in 34 (85%) cell lines and a point mutation in 1 line. Down-regulation of p16 was observed in 4 of the remaining cell lines, 1 of which displayed a DNA rearrangement of p16.

Higher frequency of alterations in the p16/CDKN2 gene in squamous cell carcinoma cell lines than in primary tumors of the head and neck.

Sixty-eight primary head and neck squamous cell carcinomas and nine head and neck squamous cell carcinoma cell lines were examined for mutations and homozygous deletions of the p16/CDKN2 gene. Homozygous deletions of the p16/CDKN2 gene were found in three lines, and a mutation was detected in another cell line. In contrast, none of the primary tumors showed homozygous deletions and 11 of 68 tumors had missense or nonsense base changes.

Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers.

Cytogenetic abnormalities of chromosome 9p21 are characteristic of malignant melanomas, gliomas, lung cancers and leukaemias. From a panel of 46 human malignant cell lines, we localized by positional cloning the most frequently deleted region on 9p21. Sequence analysis of the isolated fragment reveals two open reading frames identical to the recently described complementary DNA for the inhibitor of cyclin-dependent kinase 4 (CDK4).

Distinct deletions of chromosome 9p associated with melanoma versus glioma, lung cancer, and leukemia.

Deletions of DNA on chromosome 9p21-22 are frequently observed in cells derived from melanomas, gliomas, non-small cell lung cancers, and acute lymphoblastic leukemia. The minimal deletion shared by the latter three cancers extends from the interferon-alpha locus towards the centromere; its centromeric end is flanked by the gene encoding methylthioadenosine phosphorylase. We have determined that the telomeric end of the minimal homozygous deletion shared by two melanoma cell lines does not include the methylthioadenosine phosphorylase locus.