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A Peled

Publications and source records attributed to A Peled.

At least 19 recordsLinked to original sources
PubMed1995

Augmented DNA-binding activity of p53 protein encoded by a carboxyl-terminal alternatively spliced mRNA is blocked by p53 protein encoded by the regularly spliced form.

DNA-binding activity of the wild-type p53 is central to its function in vivo. However, recombinant or in vitro translated wild-type p53 proteins, unless modified, are poor DNA binders. The fact that the in vitro produced protein gains DNA-binding activity upon modification at the C terminus raises the possibility that similar mechanisms may exist in the cell. Data presented here show that a C-terminal alternatively spliced wild-type p53 (ASp53) mRNA expressed by bacteria or transcribed in vitro codes for a p53 protein that efficiently binds DNA. Our results support the conclusion that the augmented DNA binding activity of an ASp53 protein is probably due to attenuation of the negative effect residing at the C terminus of the wild-type p53 protein encoded by the regularly spliced mRNA (RSp53) rather than acquisition of additional functionality by the alternatively spliced C' terminus. In addition, we found that ASp53 forms a complex with the non-DNA-binding RSp53, which in turn blocks the DNA-binding activity of ASp53. Interaction between these two wild-type p53 proteins may underline a mechanism that controls the activity of the wild-type p53 protein in the cell.

Alternative Splicing↗
PubMed1995

The effects of passive anti-viral immunotherapy in AKR mice: II. Susceptibility to B cell lymphomagenesis.

Prevention of high frequency spontaneous T cell lymphoma development in AKR mice by mAb 18-5 treatment was shown to involve inhibition of the recombinant Class I MCF virus formation and elimination of the early occurring potential lymphoma cells (PLCs). A low B cell lymphoma incidence (16% at a mean latency of 540 days) and a low level of PLCs (yielding 12% B cell lymphoma development following lymphoid cell transfer) was observed in mAb 18-5 treated mice (in contrast to a high PLC level in thymectomized AKR mice that could be experimentally triggered to progress to overt CD5+ B cell lymphomas). Administration of anti CD8 mAb or IL-4 to 12-month-old mAb 18-5 pre-treated mice only slightly increased B cell lymphoma incidence (up to 30-40%). Exposure to split-dose irradiation resulted in 26% B cell lymphomas at a 250 day mean latency. The phenotypes of the B lymphomas developing in mAb 18-5 treated mice were: B220+ (14.8+, 6B2+), 6C3+, Mac2+, CD5-. Most lymphomas expressed l-a and surface IgM, pointing to their mature B cell characteristics. Moreover, in some of the lymphomas, high levels of IgM production and secretion were determined. A comparison of the morphological characteristics (based on light and ultrastructure microscopy) of CD5+ and CD5- B cell lymphomas developing in AKR mice indicated marked differences. Analysis of the IgH locus of representative CD5- B lymphomas showed an identical pattern of IgH rearrangement in some tumors (similar to previous findings among CD5+ lymphomas). The virological analysis of the CD5- B cell lymphomas (similar to those observed in the CD5+ B cell lymphomas of AKR origin) showed that their development did not require formation of the pathogenic MCF recombinant viruses. The differences observed between the CD5+ and CD5- B cell lymphomas developing in AKR mice (following prevention of spontaneous T cell lymphomagenesis) may be due to their origin of different B cell precursors or from B cells at different levels of differentiation.

Animals↗
PubMed1995

Role of cytokines in termination of the B cell lymphoma dormant state in AKR mice.

The high incidence of spontaneous T cell lymphomas in AKR mice (affected by sustained viremia) can be greatly reduced by experimental manipulations including thymus removal at young age or by genetic manipulation changing the Fv-1 allele that controls replication and spread of viruses (establishing the congenic AKR.Fv-1b mice). Although T cell lymphomagenesis is prevented, all these mice were shown to carry endogenous ecotropic provirus-induced potential lymphoma cells (PLCs) in a dormant state. The termination of the dormant state, leading to a high incidence of CD5+ IgM+ B cell lymphomas, was triggered by interference with T cell functions (optimal effect observed following in vivo administration of anti-CD8 moAb), administration of T cell growth factors or by injecting the MCF-247 recombinant virus isolate (from AKR origin) that affects T cell functions. The assumption that the PLC dormant state is maintained through specific immunological mechanisms (involving T cells or antibodies recognizing PLCs) could not be substantiated experimentally. The results of the present studies suggest that T cells provide immunoregulatory signals or factors that contribute to the maintenance of the B cell lymphoma arrest and/or proliferation. Analysis of cytokine levels produced by splenocytes taken from mice during PLC dormancy or its breakdown indicated reduced levels of IL-2 and IL-4 and marked elevation of IL-1 and IL-6 associated with the termination of the dormant state. The effect of IL-1 and IL-6 on terminating the dormant state was demonstrated by injecting these cytokines into PLC carriers, thymectomized 12-month-old AKR mice, yielding 80-85% CD5+ IgM+ B cell lymphomas. The role of IL-6 on B cell lymphoma proliferation was also indicated in MCF-247 mediated termination of dormancy, by inhibiting significantly its effect via in vivo administration of anti IL-6 moAbs.

Aging↗
PubMed1995

The effects of passive antiviral immunotherapy in AKR mice: I. The susceptibility of AKR mice to spontaneous and induced T cell lymphomagenesis.

The AKR inbred mouse strain displays a high incidence of spontaneous T cell lymphomas that arise predominantly in the thymus of 6 to 12-month-old mice. Heterogenous nonacute transforming retroviruses are associated with the etiology of the disease: the endogenous ecotropic viruses (inherited in AKR mice at two non-linked chromosomal loci, Akv-1 and Akv-2), the xenotropic virus and recombinant viruses. Prevention of spontaneous T cell lymphomagenesis in AKR mice by passive anti-viral immunotherapy was accomplished by suppressing endogenous ecotropic virus release. Treatment with monoclonal antibody Hy-72 reacting only with Akv1 type ecotropic viruses, or with mAb 18-5 with specificity for both ecotropic and MCF recombinant virus envelope glycoprotein (administered from birth for 10 days) inhibited similarly T cell lymphoma development. A reduced thymus cellularity observed in these mAb treated mice coincided with reduced level of earliest intrathymic low CD4 precursor population in their thymus. The role of endogenous viruses (MuLV) and presence of potential lymphoma cells (PLCs) (identified among bone marrow cells of untreated AKR mice) in enhanced T cell lymphomagenesis in AKR mice, triggered by different leukemogenic agents, was evaluated. Intrathymic injection of the radiation leukemia virus variant A-RadLV or administration of methylnitrosourea resulted in a high lymphoma incidence within a short latent period of 80-100 days irrespective of the presence or absence of MuLV or PLCs in these treated mice. Thus, a direct action of these agents on thymocytes seems to occur. The high susceptibility of untreated AKR mice to radiation induced T cell lymphomagenesis was not affected by pretreatment with mAb Hy-72; in contrast to markedly reduced sensitivity following pretreatment with mAb 18-5 (15 vs 100%). The mAb 18-5 induced resistance to radiation lymphomagenesis seems to be related to defects in the bone marrow stem cell pool as well as in the thymus microenvironment of mAb 18-5 treated mice. Thus, different developmental pathways are involved in enhanced T cell lymphomagenesis in AKR mice.

Animals↗
PubMed1994

Myeloblastic cell line expresses osteoclastic properties following coculture with marrow stromal adipocytes.

Osteoclasts are derived from hemopoietic precursors in the marrow. Their differentiation pathway is still undefined, but an important role was observed for the marrow microenvironment in the regulation of osteoclastogenesis. Various marrow stromal cell subtypes were used to study their possible role in the formation of osteoclasts from myeloblast (M1) cells. Interactions between M1 cells and the 14F1.1 endothelial-adipocyte stromal cell line were demonstrated in a coculture model. M1 cells attached to the adherent layer of 14F1.1 cells and formed distinct foci reminiscente of "cobblestone areas." Following these interactions, M1 cells developed specific enzymatic activities and became multinucleated. Both mononuclear and multinuclear M1 cells became positive to tartrate-resistant acid phosphatase (TRaP) and ATPase, a feature characteristic of osteoclasts, and were also responsive to calcitonin. Furthermore, they attached to mineralized bone particles and their membrane changed into a ruffled border at the zone of interaction with the bone matrix. We thus demonstrated that marrow endothelial-adipocytes may play a role in regulating the differentiation of myeloblasts into osteoclasts.

Acid Phosphatase↗
PubMed1993

Lymphomagenesis in AKR.Fv-1b congenic mice.

In the AKR.Fv-1b congenic strain the Fv-1n allele of the AKR/J mice was substituted with the Fv-1b allele, thereby limiting viral replication and spread of the endogenous N-tropic murine leukemia virus. As a result of this genetic change AKR.Fv-1b mice develop a low spontaneous incidence (7%) of T-cell lymphomas and about 28% of Ly-1+ B-cell lymphomas are observed in old mice. Characteristic changes in thymus subpopulations of AKR/J mice (related to the formation of the dual tropic mink cell focus inducing (MCF) type virus in the thymus) were not observed in the thymus of AKR.Fv-1b mice. In contrast to the low susceptibility to spontaneous T-cell lymphoma development, these mice were highly sensitive to fractionated irradiation or to radiation leukemia virus (a mixture of N- and B-tropic viruses) induced T-cell lymphoma. Potential lymphoma cells (that would ultimately develop into Ly-1+ B-cell lymphomas) were demonstrated in bone marrow and spleens of 16-24-month-old mice. Analysis of the Ly-1+ IgM+ B-cell population in spleens of 18-month-old mice revealed a significant increase in this population (35% versus 2% in young spleens). The spontaneous Ly-1+ B-cell lymphoma incidence could be enhanced (up to 77%) by in vivo administration of anti-CD8 monoclonal antibody or IL-4 to 18-month-old mice. Virological analysis of T/B-cell lymphomas for class I MCF viruses indicated that Class I MCF development was tightly correlated with T-lymphoma development (except radiation induced tumors that showed no MCF provirus involvement). In contrast, Ly-1+ B-cell lymphoma development was independent of Class I MCF pathogenic virus involvement.

AKR murine leukemia virus↗
PubMed1993

Analysis of Ly-1+ B-cell populations and IgH rearrangements in "normal" spleens and in lymphomas of AKR/J and AKR Fv-1b mice.

AKR mice are highly susceptible to development of spontaneous T-cell lymphoma. Thymus removal at the age of 1-3 months greatly reduces T-cell lymphoma. Lymphomas that have the characteristics of T- and/or B-cells occur sporadically in peripheral lymphoid tissues of old thymectomized AKR/J mice. These thymectomized mice were shown to carry dormant potential lymphoma cells. Transplantation of lymphoid cells from 8-12-month-old AKR/J mice, thymectomized at the age of 6 to 8 weeks, into intact or thymectomized young recipients yielded 80-100% Ly-1+ pre-B or B-cell lymphomas. In the AKR-Fv-1b congenic strain the Fv-1n allele of AKR/J mice was substituted with the Fv-1b allele, thereby limiting viral replication and spread of the endogenous N-tropic murine leukemia virus. As a result of this restriction in virus spread, AKR-Fv-1b mice develop a low spontaneous incidence (7%) of T-cell lymphomas and about 28% of Ly-1+ B-cell lymphomas at old age. In spleens of 15-18-month-old thymectomized AKR/J mice and intact AKR-Fv-1b mice, 30-60% of the B-cells were of the Ly-1+ B type. Analysis of the IgH locus in these normal old spleens and Ly-1+ B lymphomas indicated mono- or oligoclonality. One particular IgH rearrangement was identified in many individual old spleens and tumors. A second specific IgH rearrangement was found in some tumors. Possible mechanisms involved in the expansion of Ly-1+ clones and their progression into tumors are discussed.

Age Factors↗
PubMed1993

Mixed phenotype murine leukemias.

Cell lines were derived from eight individual leukemias induced by X-rays in NFS mice. First typed as null cells (surface immunoglobulin negative, Thy-1 negative), they turned out to have a mixed phenotype with myeloid cytochemical markers, pre-B surface antigens and molecular markers of pro-B lymphocytes. They represent murine models for mixed phenotype (pro-pre-B-myeloid) leukemias.

Animals↗
PubMed1992

Termination of the B cell lymphoma dormant state in thymectomized AKR mice.

AKR mice are highly susceptible to spontaneous T cell lymphomagenesis and thymus removal at the age of 1 to 3 mo greatly reduces its development. Twelve-mo-old AKR mice thymectomized at young age were shown previously to carry potential lymphoma cells that could be triggered to develop into B cell lymphomas (80 to 100%) after removal from their host "restrictive" environment into young histocompatible hosts. Additional attempts were made to terminate the potential lymphoma cell dormant state in 12-mo-old thymectomized AKR mice. Replenishment of some deficiencies caused by thymectomy at a young age, including a s.c. syngeneic thymus graft or a single injection of the dual tropic recombinant virus isolates DTV-71 or MCF-247 into 12-mo-old thymectomized AKR mice resulted in Ly-1+ pre-B or B cell lymphoma development in 80 to 98% of these treated mice. In vivo elimination of T cell subsets by administration of cyclosporin A or by mAb expressed on Th cells (anti-CD4) or cytotoxic T cells (anti-CD8) stimulated the progression of dormant potential lymphoma cells towards B cell lymphoma development. The most striking results were observed after administration of anti-CD8 mAb: 90 to 100% of these treated mice developed Ly-1+ B cell lymphomas within 80 days. The effect of rIL-2 on dormant PLC was also tested. Administration of rIL-2 to 12-mo-old thymectomized mice terminated tumor dormancy in 94% of the treated mice within 66 days. Tests of the resulting B lymphomas for dual tropic recombinant virus/mink cell focus-inducing virus infection indicated that the breakdown of tumor dormancy did not result from development of pathogenic class I mink cell focus-inducing viruses. These results suggest that T cell subsets and/or their products are involved in the proliferation arrest of potential lymphoma cells present in thymectomized AKR mice.

Animals↗
PubMed1992

Thy-1 antigen-mediated adhesion of mouse lymphoid cells to stromal cells of haemopoietic origin.

Thy-1 antigen is one of the widespread cell surface antigens. The antigen is expressed in the cells of a wide variety of different tissues and species and its pattern varies considerably during development and among species. Although the Thy-1 is one of the members of Ig-superfamily its function(s) remain unknown. Here we show that monoclonal antibodies to mouse Thy-1.2 antigen prevent adhesion of Thy-1.2-positive mouse T-leukemic cells 127 to monolayers of two mouse bone marrow stromal cell lines (14F1.1 and MBA-15). The same antibodies do not prevent adhesion of cell 127 to monolayers of two other mouse bone marrow stromal cell lines (MBA-2.1 and MBA-1.1.1) and to a wide spectrum of different normal and tumor mouse cell lines. A characteristic of the cell line 14F1.1 is the ability to support growth of mouse haemopoietic stem-cells. This data suggest that cells of stromal lines 14F1.1 and MBA-15 contain on their surface a specific ligand for the Thy-1 molecule. Cell-cell interaction via this ligand and the molecule on the cell surface may be an important step for development of certain lineages of cells.

Animals↗
PubMed1992

Absence of negative growth regulation in three new murine radiation-induced myeloid leukemia cell lines with deletion of chromosome 2.

Murine radiation-induced acute myeloid leukemia (RI-AML) may be considered as the experimental counterpart of human secondary leukemia. Three new myelomonocytic cell lines derived from RI-AML and carrying a partially deleted chromosome 2 are described. The RI-AML cells responded with increased proliferation after being incubated with the hemopoietic growth factors rG-CSF, rGM-CSF and IL-3. Increased proliferation of the same extent without any effect in differentiation, was also demonstrated in the RI-AML cells after incubation with IL-6 and with mouse lung conditioned medium (CM) and Krebs ascites tumor cells CM which induce differentiation in normal and most leukemic myeloid cells. Down-regulation of the c-myc gene and induction of (2'-5') oligo-adenylate synthetase (reflecting autocrine interferon secretion), two essential mechanisms operating during arrest of growth and concomitant differentiation, were demonstrated to be absent in RI-AML cells. In contrast, the M1 cells responded to the above differentiating factors with growth arrest and differentiation and with appropriate c-myc down-regulation and synthetase induction. The genetic basis for the distinct RI-AML cells' behavior may be connected with the loss or structural and/or functional abnormalities of DNA sequences located in the deleted part of chromosome 2 or in the respective allele. The presently described new RI-AML cell lines may be used for studies concerning myeloid leukemogenesis in general and secondary leukemia in particular.

2',5'-Oligoadenylate Synthetase↗
PubMed1992

Initiation and promotion in radiation-induced myeloid leukemia.

Acute myelomonocytic leukemia develops in 10-30% of irradiated (300 rad) SJL/J mice, after a lag period of around one year. Additional treatment with dexamethasone shortly after irradiation increased leukemia incidence up to 50%. Experiments were conducted in order to demonstrate the existence of preleukemic cells in irradiated mice and to explore the possible role of dexamethasone, cyclophosphamide, and different hemopoietic growth factors on their promotion to overt leukemia. Transplantation of bone marrow cells from mice exposed to 300 rad plus dexamethasone into appropriate recipients, performed 4-5 months after leukemogenic treatment, resulted in acute myeloid leukemia (AML) development of donor origin in 70% of the recipients. Transfer of fractionated preleukemic bone marrow showed that the highest AML incidence developed in the recipients of fractions enriched in early hemopoietic precursors. The promoting effect of dexamethasone on preleukemic cells was confirmed by demonstrating its similar coleukemogenic effect whether administered within several hours or 130 days after radiation. Treatment with cyclophosphamide shortly after radiation could not replace the dexamethasone effect but was found to be complementary to the coleukemogenic effect of dexamethasone. Early administration of hemopoietic growth factors (starting 14 days after radiation and dexamethasone) showed that colony-stimulating factor (CSF) 1 increased the AML incidence (75%) and reduced its latency. Treatment with recombinant granulocyte-CSF (rG-CSF) had a reduced effect and recombinant granulocyte-macrophage CSF (rGM-CSF) had no promoting effect. However, administration of different factors several months after the leukemogenic treatment revealed that rGM-CSF increased AML incidence (75%) and shortened its latency, whereas rG-CSF and CSF-1 had no effect. In contrast, the late administration of recombinant interleukin 6 reduced AML incidence significantly (23%). The present results indicate that murine radiation induced AML is a multiphase process involving radiation induced preleukemia that can be promoted by different treatments.

Animals↗
PubMed1991

Involvement of wild-type p53 in pre-B-cell differentiation in vitro.

Wild-type p53 protein is a growth modulator whose inactivation has been found to be a key event in malignant transformation. Reconstitution of wild-type p53 in the p53-nonproducer, Abelson murine leukemia virus-transformed pre-B-cell line L12 gave rise to stably growing clones. Wild-type p53-producer derived cell lines exhibit an altered cell cycle, however. More cells with an extended G0/G1 phase were found than in the p53-nonproducer parental cell line. Furthermore, when injected into syngeneic mice, these cells induced a lower incidence of tumors and these tumors were less aggressive. Analysis of immunoglobulin expression revealed that wild-type p53 induced the expression of cytoplasmic immunoglobulin mu heavy chain. In addition, these derived cells lines exhibited increased levels of a B-cell-specific surface marker, B220. These results suggest that wild-type p53 may function as a cell differentiation factor that can induce development of pre-B cells into a more advanced stage in the pathway of B-cell maturation. In these pre-B cells, wild-type p53 may induce cell differentiation without terminal growth arrest of the cell population.

Abelson murine leukemia virus↗
PubMed1991

Expression of alpha-smooth muscle actin in murine bone marrow stromal cells.

Human fibrotic bone marrow (BM) stroma has been shown to contain alpha-smooth muscle actin (alpha-SMA)-positive cells. These closely resemble myofibroblasts that were described in other fibrotic tissues. We studied the expression of alpha-SMA in a series of murine BM-derived stromal cell lines to investigate the cellular origin and functional significance of myofibroblast-like cells in hematopoietic tissues. Although these cell lines differed in their biologic properties, most of them expressed alpha-SMA under certain conditions. Cells expressing alpha-SMA constituted a minor population in post-confluent, growth-arrested cultures. However, the incidence of cells expressing alpha-SMA increased significantly when cultures were transferred to nonconfluent conditions. A similar increase in alpha-SMA-positive cells occurred after a strip of cells was scraped away from the confluent cell layer; the cells of the affected area acquired alpha-SMA-positive contractile phenotype. The relationship between alpha-SMA expression and hematopoietic activity was studied using a cloned cell line of BM origin (14F1.1). The ability of these endothelial-adipocyte cells to support hematopoiesis in vitro was maximal under confluent conditions, whereas their expression of alpha-SMA under such conditions was residual. Moreover, in long-term BM cultures supported by confluent 14F1.1 cells, stromal areas associated with proliferating hematopoietic precursors, known as "cobblestone areas," were devoid of alpha-SMA-positive cells. These observations suggest that the expression of alpha-SMA is reversible and inversely related to hematopoietic activity.

Actins↗
PubMed1991

Prevention of spontaneous AKR T cell lymphomagenesis by 24-666, a virus isolated from an AKR B cell lymphoma.

Injection of a nonlymphomagenic ecotropic virus 24-666 isolated from a B cell lymphoma of AKR origin into young AKR mice (1-60 days old) inhibited spontaneous T cell lymphoma development. The reduction in T cell lymphoma incidence (16/106-15%) was accompanied with the appearance of B cell lymphomas (16/106-34%) in older mice (500 days mean latency). Infection of newborn to 60-day-old AKR mice with 24-666 prevented changes in thymus subpopulations and expression of MuLV-related cell surface antigens, normally observed in the thymus of 5- to 6-month-old AKR mice prior to lymphoma development. Thymuses of 24-666-infected 9- to 12-month-old mice lacked recombinant dual tropic virus (DTV) expression and retained the thymus pattern of 2-month-old AKR mice. At 12 months after 24-666 administration a striking decrease in Thy1.1 level and in the CD4+ CD8+ population and an increase in CD4- CD8- cells and in mu+ B cells, predominantly Ly1+, were observed. The presence of B cells in these thymuses was also reflected in the high response of thymocytes to LPS blastogenesis accompanied by a decreased response to PHA. Although T cell lymphoma development was markedly reduced by 24-666 administration, the establishment of potential lymphoma cells (PLC) was not affected. Transfer of lymphoid cells from 12-month-old grossly normal 24-666-infected mice to the appropriate recipients resulted in a high incidence (64-80%) of B cell lymphoma development. Thus, 24-666 seems to act through interference with the establishment of DTV in the thymus, thereby preventing PLC promotion to overt T cell lymphomas. Lack of the favorable microenvironment for PLC development in the T cell pathway enables PLC development in the B cell pathway in older mice.

Aging↗
PubMed1991

Prevention of spontaneous AKR T cell lymphomagenesis by elimination of potential lymphoma cells with antibody to specific gp 71 determinants.

AKR mice, highly susceptible to spontaneous T cell lymphomagenesis, were protected from developing the disease by a course of daily treatment with antibody 18-5 to gp 71 determinants (administered from birth to 10 days). Potential lymphoma cells (PLC) identified among bone marrow cells of untreated AKR mice since birth (using the transplantation bioassay method) were eliminated following treatment with antibody 18-5. Namely, transplantation of bone marrow cells and thymocytes of 250-day-old untreated AKR mice into (AKR/J x DBA/2)F1 and/or AKR recipients yielded 86-93% T cell lymphoma of AKR origin at a short mean latent period of 38-42 days. In contrast, transfer of lymphoid cells from 18-5-treated mice at a matching age caused only 7-13% T cell lymphoma of AKR origin. The accelerating effect of MCF 247 on lymphoma development in untreated AKR mice was not effective in 18-5-treated mice, probably due to lack of PLC that are promoted by MCF 247 to overt T cell lymphoma. The characteristic changes in thymus subpopulations preceding lymphoma development and coinciding with PLC identification in the thymus of untreated mice was prevented by 18-5. It is suggested that prevention of lymphoma development in AKR mice by passive antiviral immunotherapy involves elimination of PLC representing the initial tumorigenic phase in AKR lymphomagenesis.

Aging↗
PubMed1991

Involvement of wild-type p53 protein in the cell cycle requires nuclear localization.

Transfection of wild-type p53 into a pre-B, p53 nonproducer cell line yielded the generation of stable clones. Although constitutively expressing the growth-suppressor wild-type p53 protein, these cells proliferate continuously in vitro. However, expression of wild-type p53 in these cells altered their cell cycle pattern and reduced their growth in vivo. When the same parental cells were transfected with a plasmid coding for a wild-type p53 lacking nuclear localization signals, a wild-type cytoplasmic p53 protein was expressed. Expression of this cytoplasmic p53 product did not exert any changes in the growth of the parental cells, suggesting that wild-type p53 affects the cell cycle only when localized in the nuclear cell compartment.

Animals↗