摘要:

AbstractBy genetically manipulating hematopoietic cells of the myeloid lineage, including both normal cells and differentiation inducible leukemic cell lines, evidence was obtained to indicate that myeloid differentiation primary response (MyD) genes and proto‐oncogenes, which are known to control cell growth, function as positive and negative regulators of terminal hematopoietic cell differentiation, which is associated with inhibition of cell growth, and, ultimately programmed cell death (apoptosis). Interferon regulatory factor‐1 (IRF‐1), an MyD gene induced by Interleukin 6 (IL‐6) or Leukemia Inhibitory factor (LIF), plays a role in growth inhibition associated with terminal differentiation. Leucine zipper transcription factors of thefos/junfamily, also identified as MyD genes, function as positive regulators of hematopoietic cell differentiation, increasing the propensity of myeloblastic leukemia cells to be induced for differentiation in vitro, and reducing the aggressiveness of their leukemic phenotype in vivo. The zinc finger transcription factor EGR‐1, an MyD gene specifically induced upon macrophage differentiation, was shown to be essential for and to restrict differentiation along the macrophage lineage. Finally, evidence has been accumulating to indicate that the novel MyD genes—MyD116, MyD118 and gadd45 (a member in the MyD118 gene family)—play a role in growth arrest and apoptosis of hematopoietic cells, as well as other cell types. The proto‐oncogenes c‐mycand c‐myb, known to regulate cellular growth, were shown to function as negative regulators of terminal differentiation. Both c‐mycand c‐mybare normally expressed in proliferating myeloblasts and suppressed following induction of differentiation. Deregulated and continuous expression of c‐mycwas shown to block terminal myeloid differentiation at an intermediate stage in the progression from immature blasts to mature macrophages, whereas deregulated and continuous expression of c‐mybblocked the terminal differentiation program at the immature myeloblast stage. By manipulatingmycfunction in conditional (differentiation inducible) mutant myeloblastic leukemia cell lines, expressing a chimeric mycer transgene, it was shown that there is a window during myeloid differentiation, after the addition of the differentiation inducer, when the terminal differentiation program switches from being dependent on c‐mycsuppression to becoming c‐mycsuppression independent, and where activation of c‐mychas no apparent effect on mature macrophages. These myeloblastic leukemia cell lines provide a powerful tool to increase our understanding of the role of c‐mycin normal hematopoiesis and in leukemogenesis, while also providing a strategy to clonemyctarget genes. The ongoing molecular‐genetic dissection of terminal myeloid differentiation, growth arrest and apoptosis will continue to impart information on how these biological processes are normally controlled, as well as how a perturbation of these controls can play a role in leukemogenesis. Following through with this research, including the analysis of interactions between positive and negative differentiation regulators and their target genes, a regulatory network of molecular interactions should emerge, contributing to a greater understanding of the genetic events involved in the pathogenesis of different leukemias, ultimately aiding in diag

ISSN:1066-5099    

DOI:10.1002/stem.5530120402

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractSevere thrombocytopenia and clinical bleeding remain major clinical problems in leukemic patients undergoing remission induction and those receiving high dose chemotherapy. Prophylactic platelet transfusions have made a major impact on hemorrhagic deaths over the last 20 years. The effectiveness of platelet transfusions is influenced by a number of clinical factors including the status of the spleen, prior bone marrow transplantation, the presence of disseminated intravascular coagulation and the presence of HLA antibodies. Optimal platelet transfusion therapy requires that transfusions be monitored routinely by post‐transfusion counts and that a refractory group be clearly defined. The cytokine granulocyte colony stimulating factor (G‐CSF) has not had a clinically significant impact on thrombocytopenia. Granulocyte‐macrophage colony stimulating factor (GM‐CSF) also probably has little clinical relevance, although in a randomized study, thrombocytopenia was worse in GM‐CSF‐treated patients. Interleukin‐3 (IL‐3) can increase platelet count and has the potential to protect against thrombocytopenia in patients receiving chemotherapy. This hypothesis is currently being tested in on‐goin

ISSN:1066-5099    

DOI:10.1002/stem.5530120403

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe generation of drug resistant bone marrow may facilitate the development of aggressive chemotherapeutic regimens that might otherwise be lethal due to marrow toxicity. With the availability of technology that permits in vitro manipulation of human marrow and peripheral blood stem cells, it is now possible to introduce genes that confer drug resistance to these hematopoietic progenitors. Animal models and in vitro work with human progenitors using drug resistance genes are reviewed.

ISSN:1066-5099    

DOI:10.1002/stem.5530120404

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe multifunctional cytokine interleukin 6 (IL‐6) is a potent promoter of megakaryocytic maturation in vitro. In vivo, IL‐6 has similar effects on the maturation of megakaryocytes, as shown by enhancing size, ploidy and platelet production. IL‐6 is capable of augmenting the platelet count in both normal animals and those with reduced megakaryocyte mass; ongoing clinical trials suggest a similar thrombocytopoietic effect in man. Moreover, IL‐6 alters platelet function, rendering them more sensitive to activation by thrombin and platelet activating factor. Finally, IL‐6 promotes increases in plasma fibrinogen and von Willebrand factor, and a decrease in free protein S concentration. These modifications of the platelet and coagulant phases of the clotting mechanism may result in an overall prohemostatic tendency, which may prove beneficial for the amelioration of bleeding propensity following chemotherapy. However, additional investigation will be required to determine if IL‐6‐mediated alterations of hemostasis may lead to patholog

ISSN:1066-5099    

DOI:10.1002/stem.5530120405

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractEvaluation of minimal residual disease (MRD) in different forms of acute leukemias is an expanding field of experimental hematology. Several strategies and techniques, including cytomorphology, immunophenotype and karyotype, have been applied to evaluate MRD, but molecular biology has provided more sensitive and accurate tools to detect the neoplastic clones.This concise review summarizes some of the technical aspects and pitfalls associated with different molecular approaches such as the analysis of clonospecific DNA sequences in lymphoid malignancies and the demonstration of chimeric genomic products generated by chromosomal translocations. The feasibility, specificity and clinical relevance of all these studies will be briefly discussed.

ISSN:1066-5099    

DOI:10.1002/stem.5530120406

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe systemic treatment of soft tissue sarcomas is difficult due to the limited availability of active cytotoxic drugs. Combinations of cytotoxic drugs at standard doses do increase toxicity but do not improve response rates or survival. All combinations are limited by myelosuppression, mainly leukocytopenia. For at least two of the four active drugs (doxorubicin and ifosfamide) studies have shown a clear dose‐response relationship. Recent studies have focused on increasing dose‐intensity by increasing dosages or shortening treatment intervals, which is only possible by the use of hematological growth factors. This review will focus on the latter conc

ISSN:1066-5099    

DOI:10.1002/stem.5530120407

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe expression of c‐kitligand and interleukin 6 (IL‐6) genes in mouse bone marrow‐derived stromal cell lines was examined using quantitative polymerase chain reaction (PCR) analysis based on the design of an internal DNA control. The stromal cells studied included the 14F1.1 endothelial‐adipocytes that support long‐term hemopoiesis and two additional cell lines (MBA‐1, MBA‐13) which do not have this function. All the cell lines expressed c‐kitligand gene constitutively, and this expression was not increased by lectins. On the other hand, the expression of the IL‐6 gene was markedly induced in all the lines by lipopolysaccharide (LPS) and by phorbol 12‐myristate 13 acetate (PMA).The constitutive expression of c‐kitligand in 14F1.1 cells was the lowest among the three cell lines studied and could be increased by stimulation with IL‐4. Thus, we observed some quantitative differences among the cell lines in their expression of cytokine genes. However, the unique capacity of 14F1.1 cells to support in vitro hemopoiesis cannot thus far be explained solely on the basis of the ability of these cells to secrete cytokines which are not produced by other stromal cell lines. c‐kitligand may be necessary, but its presence alone is not sufficient for 14F1.1 cells to supp

ISSN:1066-5099    

DOI:10.1002/stem.5530120408

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractProduction of human granulocyte colony stimulating factor (G‐CSF) by stromal cells was studied in vitro. Induction of G‐CSF by interleukin 1 (IL‐1) and lipopolysaccharide (LPS) was compared using enzyme immunoassay in various kinds of stromal cells. Primary human bone marrow stromal cells, a human bone marrow‐derived stromal cell line (KM‐102), and peripheral blood monocytes secreted small amounts of G‐CSF without stimulation, while vascular endothelial cells and skin fibroblasts secreted G‐CSF only when induced by IL‐1 or LPS. The production of G‐CSF by monocytes was stimulated predominantly by LPS, whereas that by KM‐102 cells, endothelial cells, and fibroblasts was induced by IL‐1 but much less so by LPS. IL‐1 and LPS stimulated similar levels of G‐CSF production by primary bone marrow stromal cells which consisted of various types of cells. In situ hybridization for G‐CSF mRNA showed that only a small proportion of primary bone marrow stromal cells expressed a large amount of G‐CSF mRNA upon stimulation. The positive cells were round or oval in shape, while most of the spindle‐shaped stromal cells were negative for specific grains. Although further characterization of positive cells is needed, the results suggest that bone marrow stromal cells are heterogeneous in terms of thei

ISSN:1066-5099    

DOI:10.1002/stem.5530120409

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractAlthough clinical trials are being used to evaluate economic outcomes of new agents, there are methodological problems. Decisions based on these analyses may lead to inefficient use of medical resources.Randomized clinical trials provide important information on the efficacy of new pharmaceutical agents for cancer patients. Policy makers are likely to require both economic and clinical data in order to approve pharmaceuticals for widespread use. Clinical trials provide an opportunity to evaluate economic outcomes for new agents. However, the interpretation of economic analyses of clinical trials raises issues related to perspective of the investigators, study design, collection of data on resource utilization, and generalizability of data to other settings. In this paper, we review these issues and illustrate problems associated with analyses of economic data from a recent phase III trial of hematopoietic growth factors.Clinical results were similar in both Paris and New York in this phase III trial. However, economic results differed markedly between the hospital in Paris and the hospital in New York. While significant savings in terms of fewer days in the hospital and fewer laboratory tests and radiographs for the granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) patients were noted at the New York hospital, resource savings were not identified at the hospital in France.Caution must be used when reimbursement policies are based on economic analyses of clinical trials. Policy decisions must be based on studies that are carefully conducted, analyzed, and interpreted from both a clinical and an economic perspe

ISSN:1066-5099    

DOI:10.1002/stem.5530120410

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe effect of recombinant human stem cell factor (SCF) on the response of human fetal bone marrow progenitor cells to irradiation was studied using immunodeficient mice with human fetal bone grafts (SCID/Hu mice). SCID/Hu mice were treated with three intraperitoneal injections of 500 m̈g/kg SCF at 20 h before, two h before, and four h after 100 cGy total body irradiation. Fourteen days following irradiation, the fetal bone grafts were harvested and studied. Most of the isolated bone marrow cells were human, as determined by flow cytometry. Colony forming assays were performed on the bone marrow to determine the survival of erythroid (BFU‐E) and myeloid (CFU‐GM) precursor cells. A statistically significant increase in BFU‐E and CFU‐GM survival after irradiation was observed for bone marrow maintained in the SCF treated mice when compared to bone marrow from mice not treated with SCF. The enhancement in colony forming unit survival after irradiation ranged from 4.3‐fold for BFU‐E (p= 0.05) to 13.1‐fold for CFU‐GM (p= 0.002). These findings suggest that SCF may be of potential clinical value for the prevention of radiation‐induce

ISSN:1066-5099    

DOI:10.1002/stem.5530120411

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY