We report on investigations aimed at detecting mutated RAS genes in a variety of preleukemic disorders (1,5,6). Moreover, in all cases investigated thus far, the mutations turned out to be specific for the tumor cells and were not found in normal cells of the respective patient. Activation of RAS genes has been detected in a variety of different neoplasias with variable frequencies. By far, the highest incidence (25-50%) has been reported in acute myelocytic leukemia (AML) (6-8).To gain further information on the biological significance of RAS mutations in leukemogenesis, we investigated the occurrence of RAS gene mutations in AML compared to a broad spectrum of other preleukemic and leukemic disorders involving the myeloid lineage. For this purpose we used, in addition to DNA transfection analyses (tumorigenicity assay), a dot-blot screening procedure based on a combination of in vitro amplification of RAS-specific sequences and hybridization to mutation-specific oligonucleotide probes (9)(10)(11)
The clinical course of 141 unselected patients (64 m, 77 f, median age 59) with polycythemia vera (PV), treated during the period 1967 to 1986 was analyzed to study prognostic factors and the correlation between treatment strategies and complication rates. Therapy was performed according to a prospectively defined treatment protocol. Primary control of the disease was achieved by phlebotomy. Marrow suppression by radioactive phosphorus or low dose busulphan was used only as a second-line therapy or to lower high platelet counts. The clinical course of the patients was characterized by a low rate of acute leukemia (4%) and a high rate of thromboembolic complications (40%). Myelofibrosis developed in 17 patients (12%). Median survival of the patents was 9.4 years. The prognostic influence of several parameters at the time of diagnosis was tested: age, sex, spleen size, percentage of blood blasts + promyelocytes, leucocyte count, platelet count, hemoglobin, hematocrit, reticulocyte count and the values of the lactate-dehydrogenase (LDH) and the alkaline neutrophil phosphatase (ANP) all had no significant influence on the length of survival. The prognosis of PV patients with atypical disease presentation at diagnosis was not different from patients with typical disease.
Of 661 patients with Philadelphia chromosome (Ph)-positive, nonblastic chronic granulocytic leukemia, 58 had cytogenetic abnormalities in addition to the Ph at the time of diagnosis. Twenty patients had reduplication of the Ph in one or more metaphases. Twenty-one patients with a single Ph exhibited hyperdiploidy in one or more metaphases. Eleven patients had two or more hypodiploid metaphases as their only numerical abnormality. The remaining six patients had a variety of abnormalities. Many patients had more than one type of abnormality. Survival of patients in the different subgroups was similar, but these 58 patients had a shorter course than the 603 patients without additional cytogenetic abnormalities (P less than .02). Survival curves for the two populations did not diverge until the 2-year point, after which the annual death rate among patients with additional cytogenetic abnormalities was approximately 40% higher than that of patients without such abnormalities. The two populations had similar relative risk values according to a hazard ratio formula previously described by the International CGL Prognosis Study Group. Thus, they would have been expected to have essentially identical survival curves. We conclude that the presence of additional cytogenetic abnormalities at the time of diagnosis constitutes an independently significant prognostic feature with an unusually delayed influence on survival.
Two permanent cell lines, designated LU‐65 and SK‐Luci‐6, were established from large‐cell anaplastic lung cancers of two patients. Both cell lines grew as solid tumors in nude mice. The histologic pattern of the tumors in the nude mouse resembled that of the primary lung cancers in that the xeno‐transplanted tissues showed no distinctive features indicative of cell type, a finding consistent with origin from a large‐cell anaplastic lung cancer. Cells from both lines formed clones in semisolid agar. Flow cytometric analysis of SK‐Luci‐6 showed a hypertriploid stemline with a very high RNA‐index. Line LU‐65 had a hyperdiploid stemline evolving into a hypertriploid stemline with a high RNA‐index. Chromosome analysis showed aneuploidy with abnormalities and marker chromosomes in both tumor cell lines. The isoenzyme pattern of LU‐65 and SK‐Luci‐6 indicated that they were of human origin and distinct from HeLa cells or another common contaminating line. Both cell lines released biologically active agents that could have caused the neutrophilia and hypercalcemia seen in the patients.
Spleen cells from mice immunized with the human lung cancer line SK-LC-3 were fused with mouse NS-1 myeloma cells. One of the hybrid clones produced a monoclonal IgM antibody (designated F-3), detected with antimouse Ig-MHA and hemagglutination assays. This antibody was completely absorbed by O red cells and completely inhibited by low concentrations of H(O) glycoproteins and hog mucin (A + H). Bombay (Oh) red cells completely failed to absorb F-3 activity even after treatment with neuraminidase. A1, A2, A1B, A2B, and B red cells and A- and B-glycoproteins were less effective in absorbing or inhibiting F-3 activity. Other glycoproteins (including those having Lea or blood group precursor structures) showed little or no inhibitory activity. Serum from nude mice carrying F-3 hybridoma agglutinated O and A2 red cells at a titer of 1:40,000 and 1:640, respectively. A1, A1B, A2B, and B red cells were agglutinated with titers of 1:80 or less. Monoclonal antibody F-3 is, therefore, highly specific for H(O) blood group determinants.
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