Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Erythropoietin-receptor (EpR) expression on bone marrow cells from normal individuals and from patients with chronic myeloid leukemia (CML) was examined by multiparameter flow cytometry after stepwise amplified immunostaining with biotin-labeled Ep, streptavidin-conjugated R-phycoerythrin, and biotinylated monoclonal anti-R-phycoerythrin. This approach allowed the detection of EpR-positive cells in all bone marrow samples studied. Most of the EpR-positive cells in normal bone marrow were found to be CD45-dull, CD34-negative, transferrin-receptor-positive and glycophorin-A-intermediate to -positive. This phenotype is characteristic of relatively mature erythroid precursors, ie, colony-forming units-erythroid and erythroblasts recognizable by classic staining procedures. Approximately 5% of normal EpR-positive cells displayed an intermediate expression of CD45, suggesting that these represented precursors of the CD45-dull EpR-positive cells. Some EpR-positive cells in chronic myeloid leukemia (CML) bone marrow had a phenotype similar to the major EpR-positive phenotype in normal bone marrow, ie, CD34-negative and CD45-dull. However, there was a disproportionate increase in the relative number of EpR-positive/CD45-intermediate cells in CML bone marrow. Even more striking differences between normal individuals and CML patients were observed when EpR-expression on CD34-positive marrow cells was analyzed. Very few EpR-positive cells were found in the CD34-positive fraction of normal bone marrow, whereas a significant fraction of the CD34-positive marrow cells from five of five CML patients expressed readily detectable EpR. These findings suggest that control of EpR expression is perturbed in the neoplastic clone of cells present in patients with CML. This may be related to the inadequate output of mature red blood cells typical of CML patients and may also be part of a more generalized perturbation in expression and/or functional integrity of other growth factor receptors on CML cells.
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PMID:Increased erythropoietin-receptor expression on CD34-positive bone marrow cells from patients with chronic myeloid leukemia. 137 Jun 38

The role of the KIT protooncogene in human hematopoiesis is uncertain. Therefore, we examined KIT mRNA expression in normal human bone marrow mononuclear cells (MNC) and used antisense oligodeoxynucleotides (oligomers) to disrupt KIT function. KIT mRNA was detected with certainty only in growth factor-stimulated MNC. Expression was essentially abrogated by making MNC quiescent or by inhibiting myb gene function. Oligomers blocked KIT mRNA expression in a dose-response and sequence-specific manner, thereby allowing functional examination of the KIT receptor. In experiments with either partially purified or CD34(+)-enriched MNC, neither granulocyte nor megakaryocyte colony formation was inhibited by oligomer exposure. In contrast, KIT antisense oligomers inhibited interleukin 3/erythropoietin-driven erythroid colony formation approximately 70% and "stem cell factor"/erythropoietin-driven colony formation 100%. The presence of erythroid progenitor cell subsets with differential requirements for KIT function is therefore suggested. Growth of hematopoietic colonies from chronic myeloid leukemia and polycythemia vera patients was also inhibited, while acute leukemia colony growth appeared less sensitive to KIT deprivation. These results suggest that KIT plays a predominant role in normal erythropoiesis but may be important in regulating some types of malignant hematopoietic cell growth as well. They also suggest that KIT expression is linked to cell metabolic activity and that its expression may be regulated by or coregulated with MYB.
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PMID:Role of the KIT protooncogene in normal and malignant human hematopoiesis. 137 82

Acute myelogenous leukemia (AML) is a clonal disease that is heterogeneous with respect to the pattern of differentiative expression of the leukemic progenitors. In some patients, the involved stem cells manifest pluripotent differentiative expression, whereas in others, the involved progenitors manifest differentiative expression mainly restricted to the granulocytic pathway. This is in contrast to chronic myelogenous leukemia (CML) which is a clonal disease known to arise in a pluripotent stem cell. Therefore, we tested whether these leukemias could be distinguished with respect to their involvement of immature precursors by studying colony-forming cells (CFC) and their precursors from four glucose-6-phosphate dehydrogenase (G6PD) heterozygous patients with AML and five patients with CML. CFC were separated from their precursors by FACS for expression of CD33 and CD34 followed by growth in a long-term culture (LTC) system. The vast majority of CFC express both the CD33 and CD34 antigens, but their less mature precursors, detected by their ability to give rise to CFC in LTC, express only CD34. In three of the four patients with AML, the CD33-CD34+ cells produced CFC in LTC that appeared to be predominantly or completely normal (ie, nonclonal) in origin. In the fourth patient, a significant enrichment of nonclonal progenitors was obtained in the CD33-CD34+ population, but these cells may also have included significant numbers of clonal cells. In contrast, in four of five patients with CML, cultures of both the CD33-CD34+ and CD33+CD34+ populations produced CFC in LTC that were almost entirely clonal in origin, whereas in the fifth patient a substantial number originated from nonclonal stem cells. These data indicate that granulocyte/monocyte progenitors are predominantly clonally derived in CML and AML. In CML, their precursors are also predominantly clonal, but in some cases of AML they are not. These findings may have implications for understanding the success or failure of current therapies of AML and CML.
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PMID:Differences in the frequency of normal and clonal precursors of colony-forming cells in chronic myelogenous leukemia and acute myelogenous leukemia. 137 89

Our previous studies have shown that a unique glycoprotease from Pasteurella haemolytica specifically cleaves only proteins containing sialylated O-linked glycans. The hematopoietic progenitor cell antigen, CD34, which is heavily glycosylated with both N- and O-linked glycans, is readily cleaved by this protease. In this study, we demonstrate that the epitopes detected by five of the seven CD34 monoclonal antibodies are removed by the glycoprotease. The differential sensitivity of the CD34 epitopes to cleavage with either neuraminidase and/or glycoprotease establishes three classes of epitopes: 1) (class I) those identified by MY10, B1.3C5, 12.8, and ICH3 that are differentially affected by neuraminidase and removed by the glycoprotease; 2) (class II) the epitope detected by QBEND 10 that is removed only by the glycoprotease; and 3) (class III) those identified by TUK3 and 115.2 that are not removed by either enzyme. Cleavage of the 110-kd CD34 structure by the glycoprotease generates a major cell-bound fragment of about 75 kd, identified by the class III antibodies. We have also used the enzyme to improve the rapid recovery of CD34+ cells selected by immunomagnetic affinity techniques. In a preclinical model, we separated CD34+ KG1 cells with high yield (90%-95%) and high purity (94%-98%) from sham mixtures containing 50% CD34- cells. We also separated CD34+ blast cells from a patient in megakaryoblastic crisis of chronic myelogenous leukemia. In this case, the purity and yield were 93% and 94%, respectively. Enzyme treatment had no detrimental effect on cell viability, and the treated cells showed a normal quantitative expression and distribution of CD34 antigen as assessed with class III antibodies. We conclude that the P. haemolytica glycoprotease has potential to improve the isolation, from human bone marrow, of primitive hematopoietic cells that carry the CD34 antigen.
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PMID:Differential sensitivity of CD34 epitopes to cleavage by Pasteurella haemolytica glycoprotease: implications for purification of CD34-positive progenitor cells. 137 60

The peripheral blood of chronic myeloid leukemia (CML) patients with chronic-phase disease and elevated white blood cell (WBC) counts typically contains markedly increased numbers of a variety of neoplastic pluripotent and lineage-restricted hematopoietic progenitors. These include cells detected in standard colony assays as well as their more primitive precursors. The latter are referred to as long-term culture-initiating cells (LTC-IC) because of their ability to generate clonogenic cell progeny detectable after a minimum of 5 weeks incubation on competent fibroblast feeder layers. In this study, we have investigated a number of the properties of the LTC-IC and clonogenic cells present in the blood of such CML patients with high WBC counts. This included an analysis of the light scattering properties of these progenitors, as well as their expression of CD34 and HLA-DR, Rhodamine-123 staining, and in vitro sensitivity to 4-hydroperoxycyclophosphamide. In the case of LTC-IC, the production of different types of lineage-restricted and multipotent progeny was also analyzed. Most of the circulating LTC-IC and clonogenic cells in the CML patients studied (on average approximately 70% and approximately 90%, respectively) showed features of proliferating or activated cells. This is in marked contrast to the majority of progenitors in the blood of normal individuals and most of the LTC-IC in normal marrow, all of which exhibit a phenotype expected of quiescent cells. Interestingly, a significant proportion of the circulating clonogenic cells and LTC-IC in the CML samples studied (on average approximately 10% and approximately 30%, respectively) appeared to be phenotypically similar to normal circulating progenitors, although their absolute numbers were indicative of a neoplastic origin. Both phenotypes of circulating CML clonogenic cells and LTC-IC could be obtained at approximately 10% to 20% purity by differential multiparameter sorting. These findings suggest that expansion of the Philadelphia chromosome-positive clone at the level of the earliest types of hematopoietic cells results from the activation of mechanisms that enable some, but not all, signals that block the cycling of normal stem cells to be bypassed or overcome. In addition, they provide strategies for purifying these primitive leukemic cells that should facilitate further analysis of the mechanisms underlying their abnormal proliferative behavior.
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PMID:Phenotypic heterogeneity of primitive leukemic hematopoietic cells in patients with chronic myeloid leukemia. 138 87

CD34, which was first detected in hemopoietic and lymphopoietic progenitors, is a heavily glycosylated Type I transmembrane protein that does not share any significant similarity with other transmembrane proteins. Its functions are still unknown. Several monoclonal antibodies were raised against CD34, and at least 4 different epitopes could be recognized. CD34 expression is confined to a few cell lines, to 1-4% of adult bone marrow mononuclear cells (including marrow-repopulating cells, all multipotent and committed myeloid progenitors, B and T lymphoid precursors, osteoclast precursors, and most likely the precursors for stromal cells), and to less than 1% of peripheral blood mononuclear cells. In non-lymphohemopoietic tissues its expression is confined to endothelial cells and to some cells of the skin. In malignancies, CD34 expression is not fully elucidated. Immature hemolymphopoietic malignancies (namely acute leukemias) and the blast cells of chronic myeloid leukemia are frequently positive. Chronic lymphoproliferative disorders and lymphomas are negative. Among other tumors, only vascular derived tumors are positive. Clinical applications of CD34+ cells include autologous transplantation of putative CD34+ stem cells isolated by positive selection from the bone marrow, and transplantation of autologous peripheral blood stem cells, using the proportion and number of CD34+ cells as a guideline for the harvesting procedure.
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PMID:The CD34 hemopoietic progenitor cell associated antigen: biology and clinical applications. 138 74

A new cell line designated JA-CML was derived from the peripheral blood of a patient with blastic phase CML. Sequential evolution of phenotypic and genetic markers was demonstrated during adaptation from primary to continuous culture in vitro. In the primary sample the majority of blast cells displayed the early T-cell markers, CD7, HLA-DR, and TdT, but were negative for the common ALL antigen (CALLA), CD4 and CD8. Simultaneously, unstimulated metaphase cells showed great karyotypic variation with a range of 43-46 chromosomes per cell. Clonal changes included the Ph chromosome t(9;22), loss of the Y and gain of several altered chromosomes. The cells grew slowly in suspension during the first 10 weeks of culture. During that time, cells still expressed the CD7 and HLA-DR antigens. Karyotypic analysis at ten weeks showed a pattern of 46,X,-Y,t(9;22),+8 in more than 90% of metaphases with disappearance of all other abnormal chromosomes noted in the original sample. A tetraploid subline exhibiting duplication of most chromosomes, including the Ph, comprised the remaining metaphases. Upon further cultivation in vitro, the cells transformed spontaneously over a period of several weeks, from T-lymphoid into myeloid cells. Expression of CD7 was lost, but reactivities with monoclonal antibodies to CD34, CD33 and CD13 were newly acquired. The karyotype was hypertriploid and all cells carried two copies of t(9;22) and lacked normal copies of No. 9 or Y. The cells have since maintained stable cytogenetic and phenotypic profiles. Molecular rearrangement of the breakpoint cluster region was identified in the primary blasts and the established line and T-cell receptor gene rearrangements were not found. These observations suggest that the leukemic blast arose from primitive stem cells, not irreversibly committed T cells, and that these stem cells retained the capacity to differentiate along the myeloid pathway.
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PMID:Emergence of myeloid stem cell line from T-lymphoid blastic phase of chronic myeloid leukemia in culture. 162 78

Immunologic strategies for removal of malignant cells from autologous marrow grafts by "negative selection" (i.e., "purging") requiring multiple specific monoclonal antibodies for each tumor type. "Positive selection" of marrow stem cells for grafting is a possible alternative strategy, using a monoclonal antibody which selectively recognizes lymphohematopoietic stem cells. The human hematopoietic progenitor cell antigen, CD34, is an integral cell membrane glycoprotein of approximately 115 kD, which has been molecularly cloned and sequenced. Although its function has not been determined, the glycoprotein has been characterized biochemically, including preliminary epitope mapping. Collective results from several laboratories indicate that CD34 monoclonal antibodies (My10, BI-3C5, 12.8, etc.) have the appropriate specificity to warrant testing their utility in positive selection for autologous bone marrow transplantation. First, precursors for all human hematopoietic lineages assayed (including most CFU-GM, BFU-E, CFU-MEG, CFU-EO, CFU-MIX or CFU-GEMM, pre-CFU, CFUBLAST, and terminal transferase+ B [and probably T] lymphoid precursors) are CD34+. Second, only 1.5% (mean) of low density human marrow mononuclear cells express CD34; mature human blood and marrow cells are CD34-. Endothelial cells are the only fixed tissue cells which express CD34. Third, the expression of CD34 in malignancies appears to parallel normal cellular expression: of hematopoietic malignancies, some acute leukemias and chronic myelogenous leukemia blasts are CD34+, but chronic lymphois leukemias, lymphomas, myelomas and non-hematopoietic malignancies are uniformly CD34-. Fourth, it appears feasible to isolate CD34+ cells from clinical marrow harvest samples in large scale, using either columns or immunomagnetic microspheres. Fifth, recent studies in very small numbers of non-human primates and human patients suggest that isolated CD34+ cells include the true hematopoietic stem cell, since transplantation of CD34+ cells, into myeloblated recipients results in at least short-term hematopoietic engraftment. It is anticipated that transplantation of CD34+ marrow cells may have broad applicability in clinical bone marrow transplantation.
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PMID:Positive stem cell selection--basic science. 168 54

The expression of progenitor cell associated antigen CD34 was investigated in cells from 28 patients with chronic myeloid leukemia (CML). The CD34 positivity varied from 0-26% in patients with chronic phases CML (n = 17); from 6-64% in patients with accelerated phase CML (n = 4); and from 27-97% in the patients with blastic crisis of CML (n = 8). The difference in CD34 positivity between chronic (mean 10.1 +/- 2.3%), accelerated (37.7 +/- 13.3%) and blastic (58.0 +/- 7.3%) phases of CML is statistically significant (p less than 0.05), however, the number of patients studied, especially in accelerated and blastic phases is very small. There was no difference in the CD34 positivity of the cells in the peripheral blood and in the bone marrow. CD34 positivity was higher in patients with chronic phase CML at diagnosis (untreated patients) than in those who were studied during treatment. The possible importance of serially studying CD34 positivity in patients with CML is discussed in the paper.
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PMID:Expression of hematopoietic progenitor cell associated antigen CD34 in chronic myeloid leukemia. 171 38

The interactions between haemopoietic progenitor cells and marrow stromal cells that are essential for the regulation of normal haemopoiesis are defective in chronic phase chronic myeloid leukaemia (CML). The presence of primitive progenitor cells (blast colony-forming cells, Bl-CFC) in the blood of patients with CML is reflected by their reduced capacity to bind to marrow derived stromal layers in vitro. Whereas normal bone marrow Bl-CFC bind irreversibly to cultured stromal layers (and none are found in normal blood), the Bl-CFC in CML bind transiently and then detach. The normal cell adhesion mechanism is partially sensitive to treatment with phosphatidylinositol-specific phospholipase C (Pl-PLC), indicating the participation of a phosphatidylinositol (Pl)-linked structure; however, when CML cells were treated with Pl-PLC it had no effect on progenitor binding. Two other Pl-linked structures, decay-accelerating factor (DAF) and lymphocyte function associated antigen-3 (LFA-3) were normally expressed on CD34 positive CML cells and normally susceptible to Pl-PLC treatment. The treatment of normal cells with Pl-PLC, to mimic the situation in CML, resulted in the indiscriminate and inefficient binding of Bl-CFC to stroma. Moreover, treatment of the normal cells with 5637 conditioned medium (CM), which contains haemopoietic growth factors, also reduced the binding capacity of normal Bl-CFC; 5637CM treatment did not alter the expression of DAF. It is proposed that a Pl-linked cell adhesion molecule (CAM) is deficient in CML as a consequence of the constitutive activation of ABL kinase whilst, in normal cells, CAMs attached in this manner are responsible for efficient adhesion to stroma and are regulated by growth factors.
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PMID:Deficiency of a phosphatidylinositol-anchored cell adhesion molecule influences haemopoietic progenitor binding to marrow stroma in chronic myeloid leukaemia. 171 60


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