Regulation of T-cell receptor D beta 1 promoter by KLF5 through reiterated GC-rich motifs.

Rearrangement of T-cell receptor (TCR) and immunoglobulin genes by a common V(D)J recombination machinery is regulated by developmentally specific chromatin changes at the target locus, a process associated with transcription. At the TCRbeta locus, the Ebeta enhancer and the Dbeta1 promoter regulate germline transcription originating near the TCR Dbeta1 gene segment. The Dbeta1 promoter contains 3 GC-rich motifs that bind a common set of nuclear proteins from pro-T-cell lines.

The leukemia-associated gene Mllt1/ENL: characterization of a murine homolog and demonstration of an essential role in embryonic development.

MLLT1 (ENL/LTG19) is one of a number of fusion gene partners with the MLL oncogene involved in 11q23 translocations in human leukemia and encodes a transcriptional regulator of unknown function. Leukemias bearing MLL translocations may be myeloid or lymphoid or bear mixed lineage properties; however, those bearing MLL/MLLT1 translocations are predominantly lymphoid, suggesting that MLLT1 may influence the leukemic phenotype. The murine homolog Mllt1 exhibits 86% amino acid sequence identity with the human gene and is broadly expressed in murine tissues and cell lines, with the exception of liver and myeloid cell lines.

Mutations and molecular variants of the NBS1 gene in non-Hodgkin lymphoma.

Non-Hodgkin lymphomas (NHLs) are characterized by chromosomal translocations that juxtapose loci encoding lymphoid antigen receptors with cellular proto-oncogenes. These translocations are thought to arise from inaccurate processing of DNA breaks created during physiologic recombination of the antigen receptor genes in lymphocytes. The inherited disorders ataxia-telangiectasia and Nijmegen breakage syndrome are caused by mutations in the ATM and NBS1 genes, respectively, and are characterized by generalized genomic instability and a high incidence of lymphoid cancers.

JAK2, complemented by a second signal from c-kit or flt-3, triggers extensive self-renewal of primary multipotential hemopoietic cells.

Defining signals that can support the self-renewal of multipotential hemopoietic progenitor cells (MHPCs) is pertinent to understanding leukemogenesis and may be relevant to developing stem cell-based therapies. Here we define a set of signals, JAK2 plus either c-kit or flt-3, which together can support extensive MHPC self-renewal. Phenotypically and functionally distinct populations of MHPCs were obtained, depending on which receptor tyrosine kinase, c-kit or flt-3, was activated.

Perturbation of B-cell development in mice overexpressing the Bcl-2 homolog A1.

Decisions about cell survival or death are central components of adaptive immunity and occur at several levels in immune system development and function. The Bcl-2 family of homologous proteins plays an important role in these decisions in lymphoid cells. Bcl-2, Bcl-xL, and A1 are differentially expressed during B- and T-cell development, and they have shared and distinct roles in regulating cell death.

Non-Hodgkin's Lymphoma: Molecular Features of B Cell Lymphoma.

The rapid increase in the incidence of the B cell non-Hodgkin's lymphomas (NHL) and improved understanding of the mechanisms involved in their development renders timely a review of the theoretical and practical aspects of molecular abnormalities in B cell NHL. In Section I, Dr. Macintyre addresses the practical aspects of the use of molecular techniques for the diagnosis and therapeutic management of patients with B cell NHL.

V(D)J rearrangement in Nijmegen breakage syndrome.

Repair of DNA double-strand breaks is essential for maintenance of genomic stability, and is specifically required for rearrangement of immunoglobulin (Ig) and T cell receptor (TCR) loci during development of the immune system. Abnormalities in these repair processes also contribute to oncogenic chromosomal rearrangements that underlie many lymphoid malignancies. Nijmegen breakage syndrome (NBS) is a rare autosomal recessive condition characterized by immunodeficiency, radiation sensitivity, and increased predisposition to lymphoid cancers bearing oncogenic Ig and TCR locus translocations.

Chimeric del20q in a case of chronic neutrophilic leukemia.

Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative disorder in which recurrent abnormalities of chromosome 20 have been reported. We report the case of a 76-year-old woman with CNL with partial deletion of the long arm of chromosome 20 in a subset of bone marrow metaphases, suggesting coexistence of a clonal stem cell disorder and normal hematopoiesis. Review of the literature suggests that such mosaicism is common in CNL, possibly accounting for the favorable prognosis observed in many patients with this disorder.

Analysis of ku80-mutant mice and cells with deficient levels of p53.

Absence of Ku80 results in increased sensitivity to ionizing radiation, defective lymphocyte development, early onset of an age-related phenotype, and premature replicative senescence. Here we investigate the role of p53 on the phenotype of ku80-mutant mice and cells. Reducing levels of p53 increased the cancer incidence for ku80(-/-) mice.

Regulation of lymphoid homeostasis by IL-2 receptor signals in vivo.

High-affinity IL-2R signals are required for peripheral lymphoid homeostasis in vivo. We found that CD25 was required for regulation of peripheral T cells in mice bearing either the DO11.10 MHC class II-restricted TCR transgene or an Iabeta-null mutation, suggesting that MHC class I- and class II-dependent T cell subsets are regulated independently by IL-2R signals.

Genetic pathway to recurrent chromosome translocations in murine lymphoma involves V(D)J recombinase.

Chromosome translocations involving antigen receptor loci are a genetic hallmark of non-Hodgkin's lymphomas in humans. Most commonly, these translocations result in juxtaposition of the immunoglobulin heavy-chain (IgH) locus with one of several cellular proto-oncogenes, leading to deregulated oncogene expression. The V(D)J recombinase, which mediates physiologic rearrangements of antigen receptor genes, may play a mechanistic role in some lymphoma translocations, although evidence is indirect.

Promoter element for transcription of unrearranged T-cell receptor beta-chain gene in pro-T cells.

The hallmark of T- and B-lymphocyte development is the rearrangement of variable (V), diversity (D), and joining (J) segments of T-cell receptor (TCR) and immunoglobulin (Ig) genes to generate a diverse repertoire of antigen receptor specificities in the immune system. The process of V(D)J recombination is shared in the rearrangement of all seven antigen receptor genes and is controlled by changes in chromatin structure, which regulate accessibility to the recombinase apparatus in a lineage- and stage-specific manner. These chromatin changes are linked to transcription of the locus in its unrearranged (germline) configuration.

Biology of the interleukin-2 receptor.

Studies of the biology of the IL-2 receptor have played a major part in establishing several of the fundamental principles that govern our current understanding of immunology. Chief among these is the contribution made by lymphokines to regulation of the interactions among vast numbers of lymphocytes, comprising a number of functionally distinct lineages. These soluble mediators likely act locally, within the context of the microanatomic organization of the primary and secondary lymphoid organs, where, in combination with signals generated by direct membrane-membrane interactions, a wide spectrum of cell fate decisions is influenced.

T cell growth cytokines cause the superinduction of molecules mediating antigen-induced T lymphocyte death.

TCR stimulation of T lymphocytes that are activated and cycling in the presence of IL-2 leads to programmed cell death. We now show that this effect is at least partly attributable to the ability of IL-2 to dramatically increase the expression of mRNAs encoding ligands and receptors that mediate apoptosis. We also found that cyclosporin was not able to fully inhibit the TCR induction of death molecule mRNAs or TCR-induced apoptosis, although it could completely turn off IL-2 expression.

Functional responses and apoptosis of CD25 (IL-2R alpha)-deficient T cells expressing a transgenic antigen receptor.

IL-2 was initially defined as a T lymphocyte growth factor, but recent studies have provided evidence that it may also play a role in regulating T cell differentiation, apoptosis, and tolerance. To examine the contribution of IL-2 to these processes, we have bred a class II-restricted TCR transgene into mice deficient in the alpha-chain of the IL-2R, CD25. We show that in response to Ag, T cells from these mice are unable to use IL-2 and, as a result, are less efficient at traversing the cell cycle, and proliferate less than wild-type cells.

Developmental regulation of V(D)J recombination and lymphocyte differentiation.

Recent insights into the mechanism of V(D)J recombination have clarified the direct role of the products of the recombination-activating genes Rag-1 and Rag-2 in site-specific DNA cleavage at recombination signal sequences and have identified components of the general DNA double-strand break repair pathway that participate in the rejoining of the Rag-1 and Rag-2-cut receptor gene segments. The V(D)J reaction is restricted to particular antigen receptor loci in a lineage-specific and stage-specific manner. This specificity appears to involve cis-regulatory elements, some of which also regulate transcription of the germline antigen receptor loci.

Genomic organization and chromosomal localization of the mouse Bp3 gene, a member of the CD38/ADP-ribosyl cyclase family.

The mouse Bp3 antigen is a variably glycosylated phosphatidylinositol-linked cell surface glycoprotein expressed on early B and T lineage cells, myeloid cells, intestinal epithelial cells, and a discrete population of reticular cells in peripheral lymphoid tissues. The deduced amino acid sequence of Bp3 cDNA shares significant similarity to human and mouse CD38 and molluscan ADP-ribosyl cyclase, enzymes that generate the calcium mobilizing agent cyclic ADP-ribose from NAD. In this study, we cloned and characterized the Bp3 gene.

Methods of stem cell mobilization.

The rapid rescue of hematopoiesis following transplantation of peripheral blood stem cells (PBSC) has facilitated expanded application of high-dose chemotherapy regimens for several malignancies. A variety of regimens have been described to enhance the circulation of PBSC, including the use of hematopoietic growth factors, either alone or following myelosuppressive chemotherapy. Such improvements of PBSC mobilization can increase the number of hematopoietic progenitors for transplantation and reduce the number of leukapheresis procedures required.

Increased T-cell apoptosis and terminal B-cell differentiation induced by inactivation of the Ets-1 proto-oncogene.

The Ets-1 proto-oncogene is a member of a transcription factor family characterized by homology to the v-ets oncogene. In adult mice, Ets-1 is expressed predominantly in lymphoid cells where it has been implicated in regulating transcription of lymphocyte-specific genes. Following T-cell activation, the specific DNA binding activity of Ets-1 is inactivated by transient phosphorylation, suggesting a function in the transition from the resting to activated state.

Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment.

Interleukin-2 receptor alpha chain (IL-2R alpha) expression occurs at specific stages of early T and B lymphocyte development and is induced upon activation of mature lymphocytes. Young mice that lack IL-2R alpha have phenotypically normal development of T and B cells. However, as adults, these mice develop massive enlargement of peripheral lymphoid organs associated with polyclonal T and B cell expansion, which, for T cells, is correlated with impaired activation-induced cell death in vivo.

Association between cervical inflammation and cervical shedding of human immunodeficiency virus DNA.

A cross-sectional study was conducted among prostitutes in Nairobi, Kenya, to determine the prevalence and correlates of cervical human immunodeficiency virus (HIV) DNA. Ninety-two HIV-seropositive prostitutes were evaluated during 137 clinic visits. Cervical HIV DNA was detected by polymerase chain reaction assay in 36 (39%) women at initial visits and in 40 (44%) women at any visit.

Detection of HIV DNA in cervical and vaginal secretions. Prevalence and correlates among women in Nairobi, Kenya.

Objective: Factors that influence heterosexual transmission of the human immunodeficiency virus (HIV), including sexually transmitted diseases, contraceptive practices, sexual practices, HIV-related immunosuppression, and presence of cervical ectopy and the penile foreskin, have been identified through cross-sectional and prospective cohort epidemiological studies. To more directly characterize factors that influence infectivity, we conducted a study of HIV shedding from the genital tract in women.

Design: Ninety-seven HIV-seropositive women attending a sexually transmitted disease clinic in Nairobi, Kenya, completed a questionnaire and underwent a physical examination and an evaluation for sexually transmitted diseases.

Human immunodeficiency virus infection among high-risk seronegative prostitutes in Nairobi.

To determine the frequency and duration of antibody-negative human immunodeficiency virus (HIV) infection among heterosexually exposed African women, 56 HIV-seronegative female prostitutes in Nairobi were studied. Polymerase chain reaction (PCR) was used to detect HIV DNA in peripheral blood at enrollment, and women were followed prospectively with serologic testing to determine HIV seroincidence. Six women (11%) were infected with HIV by PCR criteria at enrollment.

Simian immunodeficiency virus is restricted to a subset of blood CD4+ lymphocytes that includes memory cells.

HIV and the related simian immunodeficiency virus (SIV), which causes AIDS in macaques, infect only a small percentage of CD4+ lymphocytes at any point during the disease. We have identified three distinct cellular phenotypes within the CD4+ subpopulation in macaques, based on cell surface expression of CD44 and CD45R, which putatively represent successive stages of postthymic proliferation and functional maturation. Two of these subsets, CD44hi CD45R+, which contained virtually all circulating cells in cycle, and CD44hi CD45R-, which was noncycling and has been linked to immunologic memory, were selectively depleted in SIV-infected animals at an asymptomatic stage of disease.