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Biomedical subjects

P Leder

Publications and source records attributed to P Leder.

At least 199 records · Page 11Linked to original sources
PubMed1983

Regulation of the humoral immune response: from immunoglobulin genes to regulatory T cell networks.

Leukemic lymphocytes were used in studies to define the rearrangements of immunoglobulin genes and the networks of immunoregulatory T cells that are important to the control of immunoglobulin synthesis in humans. Leukemic B cells displayed rearrangements of their expressed mu and k or lambda genes. Surprisingly, the k constant region genes were deleted or rearranged in all lambda-expressing B lymphocytes examined. Most non-T, non-B lymphocytic leukemias had immunoglobulin gene rearrangements, which indicates that these cells were committed to B cell development at the immunoglobulin gene level. The pattern of immunoglobulin gene rearrangements in the B cell precursor and B cell leukemias suggests an ordered hierarchy of somatic rearrangements with mu genes preceding light chains and k light chain genes preceding lambda. Some of the leukemic T cells studied were homogeneous populations of cells that retained immunoregulatory functions with many Sézary T leukemic cells functioning as helper cells in their interactions with B lymphocytes. In contrast, malignant cells from patients with the adult T leukemia of Japan frequently functioned as suppressor cells. In contrast to normal unactivated T cells or other leukemic T cells, the leukemic T cells from all adult T cell leukemia patients studied had an activated receptor for T cell growth factor. The malignant cells of a patient with an acute T cell leukemia functioned as prosuppressor cells. Under the influence of normal T cells or their secreted inducer products, these leukemic cells matured both functionally and in terms of cell surface antigens into suppressor effector cells.

Adult↗
PubMed1983

Cell-specific regulation of the c-myc gene by lymphocyte mitogens and platelet-derived growth factor.

We show that c-myc is an inducible gene that is regulated by specific growth signals in a cell-cycle-dependent manner. Specifically, agents that initiate the first phase of a proliferative response in lymphocytes (lipopolysaccharide or Concanavalin A) and fibroblasts (platelet-derived growth factor) induce c-myc mRNA. Within one to three hr after the addition of these mitogens to the appropriate cells, c-myc mRNA concentration is increased between 10- and 40-fold. This induction of c-myc mRNA occurs in the presence of cycloheximide and, therefore, does not require the synthesis of new protein species. Consequently, the induction of c-myc mRNA is not secondary to growth. In addition, c-myc mRNA is "superinduced" by the combination of cycloheximide and mitogen, a finding consistent with a model that a labile protein may regulate c-myc levels in these cells. Further, this work suggests a regulatory linkage between the function of two oncogenes--c-myc and c-sis--the latter being the putative structural gene for PDGF.

Animals↗
PubMed1983

The human c-myc oncogene: structural consequences of translocation into the IgH locus in Burkitt lymphoma.

We have determined the sequence of the normal human c-myc gene and compared it to portions of a c-myc gene that has been translocated into the immunoglobulin heavy chain locus in a Burkitt lymphoma cell. The normal c-myc gene is encoded in three discrete exons divided by two large intervening sequences. Its mRNA is transcribed from two active promoters located about 150 nucleotides from one another. Each promoter initiates transcription of a long (approximately 550 bp) untranslatable leader sequence encoding the entire first exon. This exon and additional 5' flanking sequences are tightly conserved between mouse and man. In the Burkitt cell BL22, the rearranged c-myc gene retains both promoters and is unchanged in its amino acid coding domains. Translocation of this gene joins it to the immunoglobulin heavy chain switch region at a point approximately 1000 bp 5' to the dual c-myc promoters. These genes are joined in opposite transcriptional orientation. The structure of the translocated gene and the nature of its linkage to the immunoglobulin locus and the presence of two c-myc promoters and consequently two long leader sequences raise novel possibilities for the activation of an oncogene.

Amino Acid Sequence↗
PubMed1983

Immunoglobulin gene rearrangement and cell surface antigen expression in acute lymphocytic leukemias of T cell and B cell precursor origins.

We have explored the relationship among immunoglobulin gene rearrangement, cytoplasmic immunoglobulin production, and cell surface antigen expression within 37 cases of acute lymphocytic leukemia. All 12 cases of the T cell type had germ-line kappa and lambda genes and 11 of 12 had germ-line heavy chain genes. In contrast, all 25 cases of the "non-T, non-B" classification, which lacked both definitive T cell markers and surface immunoglobulin, had rearranged immunoglobulin genes, indicating that they represent precursor cells already committed to the B cell lineage at the gene level. 14 had rearranged heavy chain genes, yet retained germ-line light chain genes, whereas 11 cases had both heavy and light chain gene reorganizations. All patterns of immunoglobulin gene rearrangement predicted by a model that proceeds from heavy chain gene recombination to light chain genes were observed. Despite the uniform presence of rearranged immunoglobulin genes, only five cases produced cytoplasmic mu-chain, one exceptional case produced gamma-chain, and another produced only lambda-chain. The cases of B cell precursor type that do not produce immunoglobulin may represent cells that frequently possess ineffectively rearranged immunoglobulin genes. Included in this group may be a set of cells trapped within the B cell precursor series because their ineffective rearrangements have eliminated certain gene subsegments necessary for the assemblage of an effective heavy chain gene. All seven cases of the non-T, non-B subgroup that bore HLA-DR but lacked CALLA (the common acute lymphocytic leukemia-associated antigen) represented the earliest recognizable stage of B cell precursors with rearranged heavy chain genes but germ-line light chain genes. Correlations here suggest that cells entering B cell development express HLA-DR and rearrange heavy chain genes before the expression of a B cell-associated antigen recognized by the antibody BA-1, the antigen CALLA, and any subsequent light chain gene rearrangements.

B-Lymphocytes↗
PubMed1982

Localization of human variable and constant region immunoglobulin heavy chain genes on subtelomeric band q32 of chromosome 14.

Analysis of a group of human/rodent somatic cell hybrids with nucleic acid probes prepared from cloned human variable region (VH), junctional (JH), and constant region (C epsilon) heavy chain immunoglobulin genes indicates that all of these IgH genes are localized on the subtelomeric (q32) band of chromosome 14. Somatic cell hybrids were isolated in selective medium after fusing human fibroblasts with hprt- Chinese hamster cells. The human parental cells contained two translocation chromosomes representing a reciprocal translocation between chromosomes X and 14. Only those hybrid cell lines retaining a complete human autosome 14 or the X/14 translocation chromosome (i.e. containing band 14q32) retained the human IgH genes. Retention of these genes did not correlate with the presence of the other translocation chromosome, 14/X. These results indicate that all human IgH genes (VH, JH, and CH) map to the same chromosomal band (14q32) which is commonly involved in reciprocal translocations with human chromosome 8 (8q24) in B-cell neoplasms.

Animals↗
PubMed1982

Normal human B cells display ordered light chain gene rearrangements and deletions.

Human kappa-producing B cell lines and leukemias retain their excluded lambda light chain genes in the germ line configuration, whereas transformed lambda-producing B cells uniformly rearrange or delete their kappa genes (12). Whether the unexpected lambda gene recombinations within malignant lambda-producing B cells reflect a normal developmental process or are secondary to transformation and specific chromosomal translocations was uncertain. To resolve this issue, we purified circulating lambda-bearing B cells from a normal individual to 97% purity by using a series of negative selection steps and a final positive selection on a cell sorter. Over 95% of the collective kappa genes in these lambda B cells were no longer in their germ line form, with the majority (60%) deleted and the remainder present but in a rearranged state. The chromosomal loss of the germ line kappa genes included the joining (J kappa) segments as well as the constant (C kappa) region, yet the particular variable (V kappa) gene family studied was spared. In addition, the incidence of kappa gene deletions was higher in long-term than in freshly transformed lambda B cell lines. This implies that the deletion of aberrantly rearranged kappa genes may occur as a second event. Such a mechanism would serve to eliminate aberrant transcripts and light chain fragments that might interfere with the synthesis and assembly of effective immunoglobulin molecules. Thus, despite the nearly equal usage of kappa and lambda light chain genes in man, there appears to be a sequential order to their expression during normal B cell ontogeny in which kappa gene rearrangements precede those of lambda.

B-Lymphocytes↗
PubMed1982

Chromosomal location of human kappa and lambda immunoglobulin light chain constant region genes.

The chromosomal location of human constant region light chain immunoglobulin (Ig) genes has been determined by analyzing a group of human fibroblast/rodent somatic cell hybrids with nucleic acid probes prepared from cloned human kappa and lambda constant region genes. Human chromosomes in each cell line were identified by isoenzyme analysis. The DNA from hybrid cells was digested with restriction endonucleases, size fractionated by gel electrophoresis, transferred to nitrocellulose or DBM paper, and hybridized with (32)P-labeled nucleic acid probes. The C(kappa) gene was assigned to human chromosome 2 and the C(lambda) genes to chromosome 22, based upon analysis of these hybrid cell lines, and these assignments were confirmed by analysis of subclones. A group of previously unassigned loci can be mapped to chromosome 2 by virtue of their close linkage to C(kappa). The lambda and kappa light chain and heavy chain Ig genes have now been assigned to all three human chromosomes that are involved in translocations with chromosome 8 in human B cell neoplasms. These techniques and probes provide a means to study the detailed arrangement of human Ig genes and their pseudogenes.

Animals↗
PubMed1982

Evolution of human immunoglobulin kappa J region genes.

Immunoglobulin kappa chain variable region genes are assembled from two discontinuous DNA segments, a V and a J gene. The J region genes, in addition to encoding amino acid positions 96-108 of the kappa polypeptide chain, also provide sequences required for both DNA and RNA splicing reactions. For purposes of evolutionary comparison and to establish the complexity of the kappa J region locus in man, we have determined an approximately 3000 basepair nucleotide sequence in a cloned human DNA fragment that encodes the germline distinct J region segments. Significant blocks of homology have been tightly maintained between this region and an analogous segment of the mouse genome. In particular, the short sequences, GGTTTTTGT and CACTGTG, thought to be involved in V-J recombination, are the most highly conserved regions (97% homology). In addition, from heteroduplex data and computer analysis of the nucleotide sequences, it is clear that the mouse J3 sequence, a pseudogene, is not present in the human cluster. This can be explained by a duplication event in the mouse J region gene cluster that may have been the result of unequal crossing over between homologous chromosomes.

Animals↗
PubMed1982

The sequence of a mouse embryonic beta-globin gene. Evolution of the gene and its signal region.

We have determined the nucleotide sequence of an embryonic beta-globin gene of the Balb/c mouse. It possesses structural features typical of known expressed beta-globins, including 5'-untranslated region, potential capping site, initiation and terminator codons, poly(A) addition signal, splicing signals, and intervening sequences. There is a striking 15-base homology between the putative RNA polymerase binding site of this gene and the corresponding region of a human embryonic beta-gene which may be important in the control of expression during embryonic development. The sequence of the gene predicts the sequence of the entire y2 protein, which has not previously been available. As expected from evolutionary considerations, it is more homologous to human embryonic beta-globin than to mouse adult beta-globin.

Animals↗
PubMed1982

Duplication and deletion in the human immunoglobulin epsilon genes.

The human IgE gene encodes a polypeptide chain that is involved in allergic reactions and in the immune response to parasitic disease in man. We have cloned three chromosomal regions corresponding to this sequence and find that two of them derive from curiously duplicated gene segments that also encode IgA constant-region genes. One of the IgE sequences corresponds to the active gene, and its structure defines a complete amino acid sequence of the human IgE constant region. The other cloned segment is a pseudogene from which the first two IgE coding domains have been deleted and replaced by a switch-like sequence that also occurs close to the normal IgE gene. The third IgE segment remains unlinked to the other heavy-chain genes. Evidently, the epsilon-alpha locus has been the site of several complicated genetic rearrangements during recent evolutionary time.

Amino Acid Sequence↗
PubMed1982

A processed human immunoglobulin epsilon gene has moved to chromosome 9.

Processed genes--genes that resemble processed RNA transcripts rather than interrupted genomic sequences--have been identified as dispersed members of several gene families. Here we describe a processed gene that is one of the three human IgE-like sequences present in the human genome. The processed IgE gene has precisely lost its three intervening sequences, thereby fusing its four coding domains. The homology of the gene to its functional counterpart ends in an adenine-rich tail followed by an 11-base-pair sequence that is directly repeated 150 base pairs 5' to its first coding domain. In addition, the processed gene is located on human chromosome 9 rather than on chromosome 14, the site of the active immunoglobulin locus. The structure and evident mobility of this sequence support the concept that sequences can move about in the genome via RNA intermediates and that processed genes are a prominent feature of genomic structure.

Animals↗