The bcr-abl oncogene, present in 95% of patients with chronic myelogenous leukemia (CML), has been implicated as the cause of this disease. A compound, designed to inhibit the Abl protein tyrosine kinase, was evaluated for its effects on cells containing the Bcr-Abl fusion protein. Cellular proliferation and tumor formation by Bcr-Abl-expressing cells were specifically inhibited by this compound. In colony-forming assays of peripheral blood or bone marrow from patients with CML, there was a 92-98% decrease in the number of bcr-abl colonies formed but no inhibition of normal colony formation. This compound may be useful in the treatment of bcr-abl-positive leukemias.
Mechanisms of thrombocytopenia were studied in 38 patients with mild to moderately severe chronic autoimmune thrombocytopenia (AITP). 5"Cr and "'In-labeled autologous platelet turnover studies and in vitro analysis of committed megakaryocyte progenitors (CFU-Meg) were used as independent measures of platelet production. Autologous "'In-labeled platelet localization studies were performed to assess platelet clearance.Although there was no increase in the frequency of marrow CFUMeg, a specific increase in the CFU-Meg [3HJTdR suicide rate was seen which was inversely correlated with the platelet count (P < 0.001). Platelet turnover studies showed significant numbers of patients had inappropriate thrombopoietic responses to their reduced platelet counts. Platelet-associated antibody levels correlated inversely with platelet turnover suggesting that antiplatelet antibody impairs platelet production. The circulating platelet count was best predicted by an index relating platelet production (i.e., turnover) to the spleen-liver platelet clearance that correlated directly with platelet survival (P < 0.001).In summary, both depressed platelet production and increased platelet clearance by the liver and spleen contribute to the thrombocytopenia of AITP.
Through the use of long single-sequence oligonucleotide probes, the complete gene for human granulocyte-macrophage colony-stimulating factor (hGM-CSF) has been cloned from a human genomic library. The gene is 2.5 kilobases in length, contains three introns, and is present as a single copy in the human genome. When subcloned into the mammalian expression vector pD3, the gene directs the synthesis of authentic hGM-CSF. In addition to its stimulation of in vitro granulopoiesis and monopoiesis, recombinant hGM-CSF stimulates in vitro erythropoiesis and megakaryopoiesis.
Antibody L4F3 is a murine monoclonal antibody that recognizes an antigen expressed on in vitro colony-forming cells, including virtually all CFU-GM, CFU-Meg, BFU-E, and CFU-Mix. In the present study we examined whether cells that do not express the L4F3 antigen include precursors of hematopoietic colony-forming cells. Colony-forming cells were depleted from marrow by treatment with L4F3 and complement. The remaining cells generated CFU-GM, BFU-E, and CFU-Mix when cultured in the presence of irradiated adherent cell layers from long-term marrow cultures. Marrow cells not expressing the L4F3 antigen, which were separated by cell-sorting techniques, were depleted of colony-forming cells but nevertheless generated CFU-GM when cultured over irradiated adherent cell layers. These data suggest that there are marrow precursors that do not express the L4F3 antigen and that give rise to colony-forming cells of multiple types. Negative selection techniques should allow the enrichment of these precursors of colony-forming cells, thereby enabling direct studies of these immature stem cells.
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