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R S Lemons

Publications and source records attributed to R S Lemons.

At least 19 recordsLinked to original sources
PubMed2001

Retinoic acid-induced expression of autotaxin in N-myc-amplified neuroblastoma cells.

Neuroblastoma, the most common extracranial solid tumor in children, arises from precursors of the sympathetic nervous system. Neuroblastoma cell lines are responsive to the differentiation agent retinoic acid, which induces its effects by altering transcription rates of specific target genes. We identified autotaxin (ATX), which encodes an autocrine tumor motility-stimulating factor, as a gene whose expression is significantly induced by retinoic acid in neuroblastoma cells. ATX induction was specific for neuroblastoma cell lines that contain N-myc amplification, a cytogenetic feature commonly associated with aggressive neuroblastomas. Although ATX expression was associated with amplification of the N-myc locus, N-myc itself was neither sufficient nor required for ATX expression, suggesting that a coamplified gene is responsible. ATX induction by retinoic acid was due to increased transcription and required new protein synthesis.

Antineoplastic Agents↗
PubMed2001

Retinoid therapy of childhood cancer.

In vitro studies that showed RA could cause growth arrest and differentiation of myelogenous leukemia and neuroblastoma led to clinical trials of retinoids in APL and neuroblastoma that increased survival for both of those diseases. In the case of APL, ATRA has been the drug of choice, and preclinical and clinical data support direct combinations of ATRA with cytotoxic chemotherapy. For neuroblastoma, a phase I study defined a dose of 13-cis-RA, which was tolerable in patients after myeloablative therapy, and a phase III trial that showed postconsolidation therapy with 13-cis-RA improved EFS for patients with high-risk neuroblastoma. Preclinical studies in neuroblastoma indicate that ATRA or 13-cis-RA can antagonize cytotoxic chemotherapy and radiation, so use of 13-cis-RA in neuroblastoma is limited to maintenance after completion of cytotoxic chemotherapy and radiation. A limitation on the antitumor benefit of ATRA in APL is the marked decrease in drug levels that occurs during therapy as a result of induction of drug metabolism, resulting in a shorter drug half-life and decreased plasma levels. Although early studies sought to overcome the pharmacologic limitations of ATRA therapy in APL, the demonstration that ATO is active against APL in RA-refractory patients has led to a focus on studies employing ATO. Use of 13-cis-RA in neuroblastoma has avoided the decreased plasma levels seen with ATRA. It is likely that recurrent disease seen during or after 13-cis-RA therapy in neuroblastoma is due to tumor cell resistance to retinoid-mediated differentiation induction. Studies in neuroblastoma cell lines resistant to 13-cis-RA and ATRA have shown that they can be sensitive, and in some cases collaterally hypersensitive, to the cytotoxic retinoid fenretinide. Fenretinide induces tumor cell cytotoxicity rather than differentiation, acts independently from RA receptors, and in initial phase I trials has been well tolerated. Clinical trials of fenretinide, alone and in combination with ceramide modulators, are in development.

Antineoplastic Agents↗
PubMed1995

Acute promyelocytic leukemia.

Significant advances have occurred in the diagnosis, treatment, and long-term outcome of patients with acute promyelocytic leukemia (APL). The purpose of this review is to describe the molecular genetics of this disease, the use of all-trans retinoic acid (ATRA) in clinical trials of APL, and the clinical and basic research questions for future investigation. Findings of clinical studies in mainland China using ATRA as induction therapy for patients with APL concurrent with laboratory characterization of the molecular changes in APL have led to worldwide clinical trials of ATRA in the treatment of patients with APL. Major advances in understanding the molecular biology and genetics of APL have occurred over the past 5 years. These findings have been translated into novel treatment strategies using all-trans retinoic acid as a differentiation agent in the induction phase of therapy resulting in improved long-term outcome, reduced morbidity, and lower costs for patients with APL. Advanced molecular techniques are being employed for diagnosis and for monitoring of patient response to treatment.

Child↗
PubMed1994

Multiple congenital anomalies in a man with (X;6) translocation.

X;autosome translocations in humans, often associated with congenital anomalies or with gonadal dysgenesis syndromes, are informative for the study of X-linked gene expression and of the phenomenon of X chromosome inactivation. When such translocations occur in association with multiple congenital anomaly (MCA) syndromes, the observed phenotypes are not always attributable solely to disruption of specific genes, if X-inactivation spreads onto the translocated autosome, rendering some distal genes inactive. We report on a man with multiple congenital anomalies and a maternally inherited (X;6)(p22.1;p25) translocation. He has abnormalities not described in the Klinefelter or 6p deletion syndromes. His unique findings constitute a recognizable syndrome, which is likely caused by disomy for a region of Xp in conjunction with a partial 6p deletion.

Abnormalities, Multiple↗
PubMed1992

Structure, chromosomal assignment, and expression of the gene for proteinase-3. The Wegener's granulomatosis autoantigen.

Proteinase-3 (PR-3) is a neutral serine proteinase present in the azurophil granules of human polymorphonuclear leukocytes. It degrades a variety of extracellular matrix proteins including elastin in vitro and causes emphysema when administered by tracheal insufflation to hamsters. It is identical to the target autoantigen (c-ANCA) associated with Wegener's granulomatosis and to myeloblastin, a serine proteinase first identified in HL-60 leukemia cells. In this study, the gene encoding PR-3 was cloned and sequenced. The gene spans approximately 6.5 kilobase pairs and consists of five exons and four introns. The genomic organization of PR-3 is similar to that of the other serine proteinases expressed in hemopoietic cells. Each residue of the catalytic triad of PR-3 is located on a separate exon, and the positions of the residues within the exons are similar to those in human leukocyte elastase and cathepsin G. The phase and placement of the introns in the PR-3 gene are also similar to those in human leukocyte elastase and cathepsin G. The 400-base pair (bp) 5'-flanking sequence of the PR-3 gene contains a TATA box at position 379. There is no CAAT box promoter element. The 3'-untranslated region is 200 bp, extending from a TGA stop codon to the site of polyadenylation 10 bp after the canonical AATAAA signal. Amplification of PR-3 from a human/hamster hybrid cell line localizes the gene to human chromosome 19. Evidence from Northern analysis suggests that PR-3 expression is primarily confined to the promyelocytic/myelocytic stage of bone marrow development.

Amino Acid Sequence↗
PubMed1991

Cellular myosin heavy chain in human leukocytes: isolation of 5' cDNA clones, characterization of the protein, chromosomal localization, and upregulation during myeloid differentiation.

We have isolated 5' cDNA clones encoding a member of the cellular myosin heavy chain gene family from human leukocytes. The predicted amino acid sequence shows 93% identity to a chicken cellular myosin heavy chain, 76% to chicken smooth muscle, and 40% to human sarcomeric myosin heavy chain. The mRNA is expressed as a 7.4- to 7.9-kb doublet in many nonmuscle cells, and is upregulated in myeloid cell lines on induction from a proliferating to a differentiated state. Antisera raised against a peptide made from the predicted amino acid sequence specifically reacts with a 224-Kd polypeptide in leukocyte cell lines, and the protein is also upregulated during the induction of monocytic and granulocytic differentiation in these cells. The gene for this cellular myosin heavy chain maps to chromosome 22, bands q12.3-q13.1, demonstrating that it is not located in the previously described sarcomeric gene clusters on chromosomes 14 and 17. This cellular myosin heavy chain may be a major contractile protein responsible for movement in myeloid cell lines because no mRNA for sarcomeric myosin heavy chain is detected in these cells.

Amino Acid Sequence↗
PubMed1991

Hepsin, a cell membrane-associated protease. Characterization, tissue distribution, and gene localization.

Hepsin, a putative membrane-bound serine protease, was originally identified as a human liver cDNA clone (Leytus, S.P., Loeb, K.R., Hagen, F.S., Kurachi, K., and Davie, E.W. (1988) Biochemistry 27, 1067-1074). In the present study the human hepsin gene was localized to chromosome 19 at q11-13.2. The messenger RNA of hepsin is 1.85 kilobases in size and present in most tissues, with the highest level in liver. Hepsin is synthesized as a single polypeptide chain, and its mature form of 51 kDa was found in various mammalian cells including HepG2 cells and baby hamster kidney cells. It is present in the plasma-membrane in a molecular orientation of type II membrane-associated proteins, with its catalytic subunit (carboxyl-terminal half) at the cell surface, and its amino terminus facing the cytosol. Hepsin is found neither in cytosol nor in culture media. The results obtained suggest that hepsin has an important role(s) in cell growth and function.

Amino Acid Sequence↗
PubMed1991

t(16;21)(p11.2;q22): a recurrent primary rearrangement in ANLL.

We have identified three patients with acute nonlymphocytic leukemia (ANLL), subtypes M2, M4, and M7, who had a t(16;21)(p11.2;q22) in the affected cells. There are six previously reported cases of ANLL with the same t(16;21). The t(6;21) should therefore be included as another primary rearrangement in ANLL. Follow-up of these cases, though still limited, suggests a poor prognosis, as most patients have achieved a clinical remission but only for a short duration.

Adult↗
PubMed1991

Localization of the gene encoding insulin-degrading enzyme to human chromosome 10, bands q23----q25.

Insulin-degrading enzyme (IDE) is a cytosolic proteinase involved in the cellular processing of insulin. Using somatic cell hybrid analysis and in situ chromosomal hybridization, we have localized the gene encoding IDE to human chromosome 10, bands q23----q25. The murine Ide gene was previously mapped to Chromosome 19; together, these results suggest that the IDE gene is a member of a conserved syntenic group on human chromosome 10, bands q23----q25 and mouse Chromosome 19.

Animals↗
PubMed1990

Genomic organization of the selectin family of leukocyte adhesion molecules on human and mouse chromosome 1.

A structurally and functionally related group of genes, lymph node homing receptor (LHR), granule membrane protein 140 (GMP-140), and endothelial leukocyte adhesion molecule 1 (ELAM-1) are shown to constitute a gene cluster on mouse and human chromosome 1. In situ hybridization mapped GMP-140 to human chromosome 1 bands 21-24 consistent with chromosomal localization of LHR. Gene linkage analysis in the mouse indicated that these genes and serum coagulation factor V (FV) all map to a region of distal mouse chromosome 1 that is syntenic with human chromosome 1, with no crossovers identified between these four genes in 428 meiotic events. Moreover, long range restriction site mapping demonstrated that these genes map to within 300 kb in both the human and mouse genomes. These data suggest that LHR, ELAM-1, and GMP-140 comprise an adhesion protein family, the selectins, that arose by multiple gene duplication events before divergence of mouse and human. Furthermore, the location of these genes on mouse and human chromosome 1 is consistent with a close evolutionary relationship to the complement receptor-related genes, which also are positioned on the same chromosomes in both species and with which these genes share a region of sequence homology. These data characterize the organization of a genomic region that may be critical for intercellular communication within the immune system.

Animals↗
PubMed1990

Cloning and characterization of the t(15;17) translocation breakpoint region in acute promyelocytic leukemia.

A reciprocal chromosomal translocation, t(15;17)(q22;q11.2-12), is characteristic of acute promyelocytic leukemia (APL) of French-American-British (FAB) subtype M3, and is not associated with any other human malignancy. The non-random pattern of the APL translocations suggests that specific genes on chromosomes 15 and 17 are somehow altered or deregulated as a consequence of the rearrangement. Translocation breakpoints in APL patients provide physical landmarks that suggest an approach to isolating the APL gene(s). Genetic and physical maps constructed for the APL breakpoint region on chromosome 17 have indicated that two fully-linked DNA markers, defining loci for THRA1 and D17S80, map to opposite sides of an APL breakpoint yet reside on a common 350-kb Clal fragment. Cosmid-walking experiments to clone this APL breakpoint have revealed a 38-kilobase deletion on chromosome 17. Studies in additional APL patients have shown that the breakpoint region on chromosome 17 spans at least 80 kilobases.

Chromosome Walking↗
PubMed1990

Chromosomal localization of the human hexabrachion (tenascin) gene and evidence for recent reduplication within the gene.

Using analysis of rodent-human somatic cell hybrids as well as in situ hybridization of hexabrachion cDNA probes to normal human metaphase chromosomes, we have localized the human hexabrachion gene to chromosome 9, bands q32-q34. We also put forward the hypothesis that there has been a recent reduplication of a small segment of the human hexabrachion gene. We support this hypothesis by comparison of codon usage in this segment of the gene to codon usage in the remainder of the gene. This hypothesis is also supported by comparison of the sequence of human hexabrachion to that of the chicken hexabrachion. In addition, the latter comparison shows that the reduplication most likely occurred after the divergence of mammalian and avian species.

Amino Acid Sequence↗
PubMed1990

A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin.

A secreted inhibitor of angiogenesis that is controlled by a tumor suppressor gene in hamster cells has been found to be similar to a fragment of the platelet and matrix protein thrombospondin. The two proteins were biochemically similar and immunologically crossreactive and could substitute for one another in two functional assays. Human thrombospondin inhibited neovascularization in vivo and endothelial cell migration in vitro, as does the hamster protein, gp140. gp140 sensitized smooth muscle cells to stimulation by epidermal growth factor, as does human thrombospondin. The thrombospondin gene has been localized on human chromosome 15. These results demonstrate a function for the ubiquitous adhesive glycoprotein thrombospondin that is likely to be important in the normal physiological down-regulation of neovascularization. In addition, they raise the possibility that thrombospondin may be one of a number of target molecules through which a tumor suppressor gene could act to restrain tumor growth.

Amino Acid Sequence↗
PubMed1990

Structure and chromosomal localization of the gene for the oligodendrocyte-myelin glycoprotein.

Utilizing a cDNA clone encoding the oligodendrocyte-myelin glycoprotein (OMgp) to screen a human genomic DNA library, we have obtained a clone that contains the OMgp gene. The genomic clone was restriction mapped and the OMgp gene and its 5' and 3' flanking regions were sequenced. A single intron is found in the 5' untranslated region of the gene, while the coding region is uninterrupted by an intron. This placement of a single intron in the OMgp gene is identical to that of the gene for the alpha-chain of platelet glycoprotein Ib, which, along with OMgp, belongs to a family of proteins sharing two distinct structural domains: an NH2-terminal cysteine-rich domain and an adjacent domain of tandem leucine-rich repeats. Hence, it is possible that this family of proteins is not only related in terms of primary structure, but also through similar gene structure. Sequence comparison of the 5' and 3' flanking regions did not reveal striking similarities to other DNA sequences, and no obvious promoter elements were noted. By hybridization of the genomic clone to metaphase cells, we have localized the human OMgp gene to chromosome 17 bands q11-12, a region to which the neurofibromatosis type 1 gene has been previously mapped.

Amino Acid Sequence↗
PubMed1989

Interleukin-4 and interleukin-5 map to human chromosome 5 in a region encoding growth factors and receptors and are deleted in myeloid leukemias with a del(5q).

Interleukin-4 (IL-4) is a potent mediator of growth and differentiation of cells of several hematopoietic lineages. Interleukin-5 (IL-5) is a lineage-specific hematopoietic growth factor that stimulates the production of eosinophils and eosinophil colonies from normal human bone marrow cells. By using somatic cell hybrids and in situ chromosomal hybridization, we localized the IL-4 and IL-5 genes to human chromosome 5 at bands q23-31, a chromosomal region that is frequently deleted [del(5q)] in patients with myeloid disorders. By in situ hybridization, the IL-4 and IL-5 genes were found to be deleted in the 5q- chromosome of four patients with refractory anemia (RA) or therapy-related acute nonlymphocytic leukemia (t-ANLL), who had a del(5q). Thus a small segment of chromosome 5 contains IL-4, IL-5, IL-3, and GM-CSF as well as other genes such as CD14 and EGR1. Our findings that each of these genes was deleted in the 5q- chromosome suggest that loss of function of one or more of these genes may play an important role in the pathogenesis of hematologic disorders associated with a del(5q).

Chromosome Deletion↗
PubMed1989

Interstitial deletion of chromosome 5, del(5q), in a newborn with Down syndrome and an unusual hematologic disorder.

A newborn with Down syndrome was noted on the 1st day of life to have an elevated white blood cell count of 79,900/mm3 with 62% lymphoblasts and a platelet count of 61,000/mm3, consistent with either transient myeloproliferative disorder of Down syndrome (TMD) or acute leukemia. Karyotype analysis of a bone marrow aspirate revealed that 20% of the cells had a 47,XY, +21 karyotype, and 80% had a 47,XY, +21, del(5)(q13q31) complement. Cytochemical and immunophenotyping of the peripheral blasts were consistent with the presence of an acute undifferentiated precursor blast clone. Results of clonogenic assays of hematopoietic progenitors from this patient's bone marrow were similar to those of patients with TMD. This patient's hematologic abnormalities resolved spontaneously without treatment by week 10 of life. This is the first report of an interstitial deletion of 5q associated with a hematologic abnormality present in an infant at birth.

Adult↗
PubMed1988

Translocation and rearrangement of myeloperoxidase gene in acute promyelocytic leukemia.

Acute promyelocytic leukemia (subtype M3) is characterized by malignant promyelocytes exhibiting an abundance of abnormally large or aberrant primary granules. Myeloperoxidase (MPO) activity of these azurophilic granules, as assessed by cytochemical staining, is unusually intense. In addition, M3 is universally associated with a chromosomal translocation, t(15;17)(q22;q11.2). In this report, the MPO gene was localized to human chromosome 17 (q12-q21), the region of the breakpoint on chromosome 17 in the t(15;17), by somatic cell hybrid analysis and in situ chromosomal hybridization. By means of MPO complementary DNA clones for in situ hybridization and Southern blot analysis, the effect of this specific translocation on the MPO gene was examined. In all cases of M3 examined, MPO is translocated to chromosome 15. Genomic blot analyses indicate rearrangement of MPO in leukemia cells of two of four cases examined. These findings suggest that MPO may be pivotal in the pathogenesis of acute promyelocytic leukemia.

Bone Marrow↗