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Biomedical subjects

W S Alexander

Publications and source records attributed to W S Alexander.

At least 73 records · Page 4Linked to original sources
PubMed1989

Oncogene cooperation in lymphocyte transformation: malignant conversion of E mu-myc transgenic pre-B cells in vitro is enhanced by v-H-ras or v-raf but not v-abl.

Although transgenic mice bearing a c-myc gene controlled by the immunoglobulin heavy-chain enhancer (E mu) eventually develop B-lymphoid tumors, B-lineage cells from preneoplastic bone marrow express the transgene but do not grow autonomously or produce tumors in mice. To determine whether other oncogenes can cooperate with myc to transform B-lineage cells, we compared the in vitro growth and tumorigenicity of normal and E mu-myc bone marrow cells infected with retroviruses bearing the v-H-ras, v-raf, or v-abl oncogene. The v-H-ras and v-raf viruses both generated a rapid polyclonal expansion of E mu-myc pre-B bone marrow cells in liquid culture and 10- to 100-fold more pre-B lymphoid colonies than normal in soft agar. The infected transgenic cells were autonomous, cloned efficiently in agar, and grew as tumors in nude mice. While many pre-B cells from normal marrow could also be induced to proliferate by the v-raf virus, these cells required a stromal feeder layer, did not clone in agar, and were not malignant. Most normal cells stimulated to grow by v-H-ras also cloned poorly in agar, and only rare cells were tumorigenic. With the v-abl virus, no more cells were transformed from E mu-myc than normal marrow and the proportion of tumorigenic pre-B clones was not elevated. These results suggest that both v-H-ras and v-raf, but apparently not v-abl, collaborate with constitutive myc expression to promote autonomous proliferation and tumorigenicity of pre-B lymphoid cells.

Animals↗
PubMed1989

The transgenic window on lymphoid malignancy.

Transgenic mice bearing an oncogene targetted for expression in a specific tissue can reveal how that oncogene influences differentiation and help to delineate the pathways to malignancy. To explore lymphoid neoplasia, we have made strains of transgenic mice bearing different oncogenes driven by the immunoglobulin heavy chain enhancer (E mu), which promotes expression within lymphocytes and certain myeloid cells. The prototype E mu-myc mice succumb to pre-B and B cell lymphomas, following a preneoplastic phase in which cycling pre-B cells are overproduced. The similar fate of E mu-N-myc mice suggests that N-myc and myc have overlapping functions. Surprisingly, E mu-N-ras mice develop T lymphomas and macrophage tumours but no B lineage tumours; thus the ability of ras to initiate tumorigenesis may be lineage specific. Similarly, the high predisposition of E mu-v-abl mice to develop plasmacytomas may indicate that v-abl is oncogenic only at certain stages of B cell maturation. The bcl-2 gene promotes cell survival rather than proliferation, and E mu-bcl-2 mice produce copious resting B lymphocytes. The random onset and monoclonality of tumours in the transgenic strains argues for spontaneous genetic alterations that cooperate with the trans-oncogene. Indeed, most plasmacytomas of E mu-v-abl mice bear spontaneous myc rearrangements. Moreover, a minority of E mu-myc B lymphomas exhibit ras mutation, and the tumorigenesis can be reconstructed by crossing E mu-myc and E mu-ras mice, or by retroviral delivery of v-ras or v-raf, either in vitro or in vivo. To access novel cooperating oncogenes, we are using a retrovirus lacking an oncogene as an insertional mutagen. This approach should be applicable to any trans-oncogenic strain and help to delineate the genetic events that trigger malignant clones.

Animals↗
PubMed1989

Lymphomagenesis in E mu-myc transgenic mice can involve ras mutations.

Transgenic mice bearing c-myc driven by the immunoglobulin heavy chain enhancer (E mu) initially exhibit a preneoplastic lymphoproliferative syndrome from which clonal pre-B or B lymphomas develop at random. To investigate whether this transition involves the activation of oncogenes capable of transforming fibroblasts, we transfected DNA from 14 E mu-myc lymphomas into NIH3T3 cells and tested the tumorigenicity of the transfectants in nude mice. By this assay and subsequent direct analysis of the lymphoma mRNA by cDNA cloning or the polymerase chain reaction, two independent E mu-myc lymphomas were shown to contain an N-ras or a K-ras oncogene mutated at codon 61. When incorporated into a recombinant retrovirus, the mutant N-ras allele could collaborate with myc to transform preneoplastic E mu-myc bone marrow pre-B cells. These results indicate that spontaneous mutation of ras genes is one pathway to lymphomagenesis in E mu-myc mice but that many of the lymphomas arise in response to changes that do not register in fibroblasts.

Animals↗
PubMed1988

Hemopoietic lineage switch: v-raf oncogene converts Emu-myc transgenic B cells into macrophages.

Hemopoietic lineage commitment can be breached by concomitant expression of the c-myc and v-raf oncogenes. Switching to the myeloid lineage occurred frequently when B lineage cells, from either lymphomas or preleukemia bone marrow cells of Emu-myc transgenic mice, were infected with a retrovirus bearing v-raf. Cloned pre-B and B cell lines changed into either mature or immature macrophages as assessed by morphology, adherence, phagocytic activity, surface markers, and lysozyme production, but retained clonotypic immunoglobulin gene rearrangements. Although expression of the Emu-myc transgene was reduced or abolished in the more differentiated lines, the lines remained tumorigenic. The converted lines produced the myeloid growth factor GM-CSF, and most had karyotypic alterations. These results suggest that constitutive myc plus raf expression can provoke genetic reprogramming in lymphocytes.

Animals↗
PubMed1987

Immunologic competence of B cells subjected to constitutive c-myc oncogene expression in immunoglobulin heavy chain enhancer myc transgenic mice.

B cell activation is associated with a marked transient rise in expression of the c-myc proto-onco-gene. A unique opportunity to examine the effects of constitutive c-myc expression upon B cell function is provided by transgenic mice in which the c-myc oncogene is regulated by the enhancer (E mu) from the immunoglobulin locus (E mu-myc mice). We have examined the immunologic competence of B cells from E mu-myc mice both in vitro and in vivo. Upon stimulation, many E mu-myc B cells can proliferate to form clones most of which contain antibody-forming cells. However, the frequency of responsive B cells from E mu-myc donors is only about 30% that of B cells from normal littermates. Thus, enforced myc expression is not sufficient to block the differentiation of all B cells, but a much larger fraction of the immunoglobulin-bearing cells from E mu-myc mice are incompetent. Upon immunization, E mu-myc mice mounted specific antibody responses, although some responses were delayed. Isotype switching can occur, since we observed hemolytic plaques of both IgM and IgG type and detected specific antibody of both classes in the serum. Moreover, the serum from nonimmunized E mu-myc mice contained normal levels of both IgM and IgG. Thus constitutive expression of the c-myc gene appears to retard B cell differentiation, but does not grossly impair immunologic function in the intact animal.

Animals↗
PubMed1987

Expression of the c-myc oncogene under control of an immunoglobulin enhancer in E mu-myc transgenic mice.

Transgenic mice bearing a cellular myc oncogene coupled to the immunoglobulin heavy-chain enhancer (E mu) exhibit perturbed B-lymphocyte development and succumb to B lymphoid tumors. To investigate how the enhancer has affected myc expression, we analyzed the structure and abundance of myc transcripts in tissues of prelymphomatous mice and in the lymphomas. Expression of the E mu-myc transgene appeared to be confined largely to B lymphoid cells, being dominant in bone marrow, spleen, and lymph nodes, with no detectable expression in T cells or other hematopoietic lineages examined. The myc transcripts initiated very predominantly at the normal myc promoters, although use of the more upstream myc promoter was accentuated and an enhancer-associated promoter may be used infrequently. The level of E mu-myc transcripts in the preneoplastic lymphoid tissues and in the E mu-myc tumors was not markedly higher than myc RNA levels in proliferating normal lymphocytes. Thus, enforced expression of structurally normal myc transcripts at only a modestly elevated level has profound biological consequences. The absence of detectable endogenous c-myc RNA in any tumor, or in preneoplastic bone marrow, supports a negative feedback model for normal c-myc regulation.

Animals↗
PubMed1985

Gliomatosis cerebri--report of a case.

An unusual case of gliomatosis cerebri in a 37 yr-old man is reported. He presented with a variable clinical picture. Mental changes, brain stem signs, cerebellar signs and rise in intracranial pressure were the constant findings. The postmortem findings are described and the available literature is reviewed.

Adult↗
PubMed1982

Wernickes encephalopathy with central pontine myelinolysis presenting with hypothermia.

A male alcoholic who presented with hypothermia and confusion was diagnosed as suffering from Wernicke's encephalopathy. He showed in addition signs of bulbar damage with cranial nerve signs, weakness of all limbs and absent oculo-vestibular responses. His course was complicated by recurrent episodes of aspiration pneumonia with death resulting from this cause. Neuropathological findings included typical features of Wernicke's encephalopathy as well as central pontine myelinolysis.

Adult↗
PubMed1979

Granulomatous angiitis of the CNS.

A 25-year-old man had granulomatous angiitis of the CNS. The disease began with symptoms of an upper respiratory tract infection; it had a relentless course, simulating viral encephalitis, with the patient dying some six months after the onset of symptoms. The lesions were confined to small intracranial arteries and veins, predominantly about the cerebellum. An unusual feature was the occurrence of a small (2 mm) aneurysm on a leptomeningeal artery deep in a cerebellar sulcus. There is a need for pooling data and pathological material by an international body to enable detailed expert analysis of large numbers of cases of cerebral angiitis that do not now constitute a homogeneous group.

Adult↗