Mark Blick

Association of the epstein-barr virus with lymphoepithelioma of the thymus

A 30‐year‐old woman with the histologic diagnosis of lymphoepithelioma of the thymus is reported on. Investigation of Epstein‐Barr serology showed evidence of infection, and Southern blot analysis showed the presence of the viral genome in the tumor specimen. The patient achieved complete remission after treatment with combination chemotherapy, autologous bone marrow transplant, and radiotherapy. These findings suggest that lymphoepithelioma of the thymus may have a viral pathogenesis similar to that of nasopharyngeal carcinoma.

Rearrangement in the Breakpoint Cluster Region and the Clinical Course in Philadelphia-Negative Chronic Myelogenous Leukemia

We have followed one patient with Philadelphia (Ph)-negative chronic myelogenous leukemia and identified an additional four patients from the literature who showed the rearrangement in the breakpoint cluster region (bcr) on chromosome 22 characteristic of Ph-positive chronic myelogenous leukemia. The clinical course of these five patients was similar to that of Ph-positive patients, with easily controlled leukocyte counts, a prolonged benign phase, and prolonged survival. Furthermore, we have shown, for the first time, that bcr rearrangement in Ph-negative chronic myelogenous leukemia can result in expression of the aberrant 210-kilodalton bcr-abl fusion protein, which has been strongly implicated in Ph-positive leukemogenesis. Research data pertaining to possible cytogenetic mechanisms leading to production of p210bcr-abl in the absence of the Ph chromosome are reviewed. Molecular analysis provides an important tool for classifying and predicting prognosis of some patients with Ph-negative chronic myelogenous leukemia.

Molecular characteristics of chronic myelogenous leukemia in blast crisis

We have studied the expression of c-abl and c-myc in leukemic cells of patients in all clinical phases of chronic myelogenous leukemia. We demonstrate that an aberrant 8-Kb c-abl related transcript is present in the RNA of the leukemic cell from all patients with Ph+ CML and that the loss of both normal chromosome #9 is associated with the loss of the normal c-abl related transcripts. This represents direct evidence that the normal c-abl related transcripts derive from the normal c-abl gene locus on the normal chromosome #9, while the aberrant c-abl related transcript in Ph+ CML derives from the hybrid bcr-abl gene formed as a result of the t(9;22). We further demonstrate that trisomy 8 in some instances is associated with enhanced expression of the c-myc oncogene.

Effect of differentiation-inducing agents on oncogene expression in a chronic myelogenous leukemia cell line

K562 is a Philadelphia (Ph) chromosome‐positive chronic myelogenous leukemia (CML) blast crisis cell line representing a pluripotent precursor cell. At the molecular level, K562 cells express high levels of the aberrant bcr‐abl product, p210bcr‐abl, believed to be critical to the pathogenesis of CML. The authors demonstrate that exposure of K562 cells to hemin causes a state of partial, reversible erythroid maturation, accompanied by a marked decrease in p210bcr‐abl. The change in bcr‐abl expression may be mediated at the translational level since steady state amounts and enzymatic activity of the bcr‐abl protein are reduced whereas bcr‐abl mRNA levels are unaltered. The decrease in p210bcr‐abl phosphokinase enzymatic activity can be detected within 2 hours after addition of hemin to the culture media, indicating that changes in expression of this oncogene probably occur before or concurrent with differentiation. No change in bcr‐abl protein occurred in a CML cell line (KBM‐5) which did not undergo differentiation after exposure to hemin, consistent with a direct relationship between altered p210bcr‐abl expression and hemin‐induced erythroid differentiation. Importantly, the marked diminuition in bcr‐abl protein was not associated with a disruption in K562 growth rates, indicating that the proliferative capacity of these cells may be independent of the bcr‐abl product. In contrast to hemin, cytosine arabinoside (Ara‐C) caused terminal erythroid differentiation of K562 cells, characterized by irreversible hemoglobin accumulation and cytostasis; and no change in bcr‐abl protein expression was observed. The distinct effects of Ara‐C and hemin could reflect the existence of pleiotropic differentiation pathways. Both Ara‐C and hemin‐exposed cells showed a decrease in c‐myc and c‐myb transcripts, suggesting that altered levels of these proto‐oncogenes may be associated with erythroid maturation, regardless of the rate of cell division. K562 cells provide a useful model for analyzing the interaction between oncogene expression and CML cell growth and differentiation.

Expression ofabl and other oncogenes is independent of metastatic potential in Abelson virus-transformed malignant murine large cell lymphoma

The role of oncogene expression in tumor metastasis was examined using the Abelson leukemia virus-transformed murine large cell lymphoma RAW117. Cell sublines of low and high metastatic potential expressed equallyabl oncogene-coded mRNA and its phosphoprotein product p160, and the capacity of p160 to become autophosphorylated withγ-[32P]ATP was the same among low and high metastatic cells. The expression of other oncogene-coded mRNAs (fos, myc, myb), if present, was also similar in low and high metastatic RAW117 cells. Although oncogene expression is thought to be important in initiating, and in some cases maintaining, the transformed phenotype, its expression in RAW117 lymphoma cells appears to be unrelated to metastatic phenotype.

The c-abl, bcr and cλ genes are amplified in a cell line but not in the uncultured cells from a patient with chronic myelogenous leukemia

Structural alterations of the oncogenes in human tumors are reported to result from a variety of mechanisms: point mutations, chromosomal translocations and gene amplifications. In over 90% of the cases of chronic myelogenous leukemia (CML), the c-abl oncogene is translocated from chromosome 9 to chromosome 22, and forms in part the Philadelphia (Ph1) chromosome. We have molecularly analysed a double Ph1-positive (Ph1+) cell line, KBM-5 that was established from a patient with CML in the blast-transformed phase (CML-BP). We report that the c-abl, bcr, and C lambda genes are amplified approximately eight-fold in the cell line but not in the fresh uncultured cells from which KBM-5 was derived.

Rearrangement and enhanced expression of c-myc oncogene in fresh tumor cells obtained from a patient with acute lymphoblastic leukemia

Both enhanced and altered expressions of cellular oncogenes have recently been implicated in specific forms of human malignancy (for review: [2, 8]). The fact that certain human tumors have characteristic chromosomal translocations has led to the hypothesis that specific cellular oncogenes may be activated in these genetic recombinations. In a number of human undifferentiated B-cell lymphoma (UBL) cell lines carrying the t(8:14) translocation it has been shown that the human c-myc gene is located on the region of chromosome 8 (8q24), which is translocated to the immunoglobulin heavy-chain (IHC) locus on chromosome 14 [7, 24]. We report here the molecular cloning of the recombination site between c-myc and IHC in fresh uncultured cells obtained from a patient with rapidly progressive and fatal acute lymphoblastic leukemia. The translocation was associated with an enhanced c-myc expression in the tumor cells of this patient.