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

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

We studied the adhesion of primitive and committed progenitors from chronic myelogenous leukemia (CML) and normal bone marrow to stroma and to several extracellular matrix components. In contrast to benign primitive progenitors from CML or normal bone marrow, Ph1-positive primitive progenitors from CML bone marrow fail to adhere to normal stromal layers and to fibronectin and its proteolytic fragments, but do adhere to collagen type IV, an extracellular matrix component of basement membranes. Similarly, multilineage colony-forming unit (CFU-MIX) progenitors from CML bone marrow do not adhere to fibronectin or its adhesion promoting fragments but adhere to collagen type IV. Unlike committed progenitors from normal bone marrow, CML single-lineage burst-forming units-erythroid and granulocyte/macrophage colony-forming units fail to adhere to fibronectin or its components but do adhere to both collagen type IV and laminin. Evaluation of adhesion receptor expression demonstrates that fibronectin receptors (alpha 4, alpha 5, and beta 1) are equally present on progenitors from normal and CML bone marrow. However, a fraction of CML progenitors express alpha 2 and alpha 6 receptors, associated with laminin and collagens, whereas these receptors are absent from normal progenitors. These observations indicate that the premature release of malignant Ph1-positive progenitors into the circulation may be caused by loss of adhesive interactions with stroma and/or fibronectin and acquisition of adhesive interactions with basement membrane components. Further study of the altered function of cell-surface adhesion receptors characteristic of the malignant clone in CML may lead to a better understanding of the mechanisms underlying both abnormal expansion and abnormal circulation of malignant progenitors in CML.
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PMID:Mechanisms underlying abnormal trafficking of malignant progenitors in chronic myelogenous leukemia. Decreased adhesion to stroma and fibronectin but increased adhesion to the basement membrane components laminin and collagen type IV. 138 71

The SCL (tal-1, TCL5) gene is a member of the basic domain, helix-loop-helix (bHLH) class of putative transcription factors. We found that (i) the SCL promoter for exon Ia contains a potential recognition site for GATA-binding transcription factors, (ii) SCL mRNA is expressed in all erythroid tissues and cell lines examined, and (iii) SCL mRNA increases upon induced differentiation of murine erythroleukemia (MEL) cells, and inferred that SCL may play a physiologic role in erythroid differentiation. We used gel shift and transfection assays to demonstrate that the GATA motif in the SCL promoter binds GATA-1 (and GATA-2), and also mediates transcriptional transactivation. To identify a role for SCL in erythroid differentiation, we generated stable transfectants of MEL and K562 (a human chronic myelogenous leukemia cell line that can differentiate along the erythroid pathway) cells overexpressing wild-type, antisense or mutant SCL cDNA. Increasing the level of SCL expression in two independent MEL lines (F4-6 and C19, a 745 derivative) and K562 cells increased the rate of spontaneous (i.e. in the absence of inducer) erythroid differentiation. Conversely, induced differentiation was inhibited in MEL transfectants expressing either antisense SCL cDNA or a mutant SCL lacking the basic domain. Our experiments suggest that the SCL gene can be a target for the erythroid transcription factor GATA-1 and that the SCL gene product serves as a positive regulator of erythroid differentiation.
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PMID:The SCL gene product: a positive regulator of erythroid differentiation. 139 92

Patients with chronic myelogenous leukemia (CML) have been treated with interferon (IFN) alpha-2b alone or in combination with IFN gamma. In order to predict clinical response to IFN, bone marrow samples from 15 CML patients were incubated with serial dilutions of IFN alpha-2b to obtain the IC50 values for erythroid burst forming units (BFU-E) and granulocyte-macrophage colony forming units (CFU-GM). A dose-dependent inhibition of at least one lineage was observed in all but one sample. An inhibitory effect of greater than 50% was reached for BFU-E in 8/14 patients and for CFU-GM in 10/14 patients. All three patients with no response (NR) to IFN treatment had IFN-sensitive BFU-E and CFU-GM. In four patients with hematologic remission (HR) or partial hematologic remission (PHR), BFU-E or CFU-GM were affected very little by the inhibitory effect of IFN. These observations suggest no predictive value for pretesting IFN sensitivity in vitro. The in vivo effect of IFN on the hemopoietic progenitor cells BFU-E and CFU-GM was evaluated in patients treated with either IFN alpha-2b alone (n = 11), or in combination with low dose IFN gamma (n = 10). All patients were newly diagnosed and not pretreated. After a median treatment duration of 11 months (range 3-25) a significant decrease in BFU-E and CFU-GM was observed in both groups of patients. We conclude that in vitro colony growth reflects the therapeutic efficacy of IFN.
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PMID:Clonogenic assay is not predictive but reflects therapeutic efficacy of interferons in the treatment of chronic myelogenous leukemia. 145 16

Expression of the normally cryptic blood group antigen Tn has occasionally been reported in hematologic disease, but the true frequency of this change is not known. A mouse monoclonal antibody (FBT3) and immunohistochemistry were used to examine expression of the Tn antigen. Expression was not detected in 35 normal bone marrow aspirates examined, but it was detected in 5 of 725 abnormal bone marrow aspirates, including 2 (3.6%) of 55 cases of de novo acute nonlymphocytic leukemia and 2 cases that terminated in acute nonlymphocytic leukemia. In two patients, one with acute myeloblastic leukemia and the other in blast transformation of chronic myeloid leukemia, the Tn antigen was expressed on 2 percent of blast cells. In one case of non-Hodgkin's lymphoma, 4 percent of normal myeloid cells expressed the antigen. In the other two cases, one of acute myelomonocytic leukemia and the other of myelodysplasia, only 2 to 8 percent of myeloid and erythroid cells initially were Tn positive. Subsequent serial immunohistochemical studies of bone marrow aspirates and peripheral blood in these two cases showed increasing numbers of Tn-positive erythroid and myeloid cells 8 to 12 months before polyagglutination was detected serologically. Tn-positive cells increased to > 90 percent in the terminal phase in both cases of both diseases. The results suggest that Tn expression in these two patients may have conferred a growth advantage to the cells and could be related to disease progression.
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PMID:Expression of the Tn antigen in myelodysplasia, lymphoma, and leukemia. 147 Dec 47

Twenty-eight allogeneic BMT patients (16 with acute leukemia, 12 with chronic myeloid leukemia) were included in a single center, prospective, randomized, controlled trial to assess the value of recombinant human erythropoietin (rh-Epo) in this setting. rh-Epo was administered through a central venous catheter as a single bolus injection (days 0-7: 100 U/kg/d; days 7-30: 150 U/kg/d). No secondary effects to rh-Epo treatment were detected. An earlier appearance of reticulocytes and a diminished need of red blood cells (RBCs) transfusions were observed in patients who were treated with rh-Epo (4 units vs 12 units; p < 0.05). The time to unsupported platelets above 25 x 10(9)/l was less in patients treated with rh-Epo than in control patients (19 days vs 31; p < 0.05), and they received significantly fewer platelet transfusions (36 units vs 138.5; p < 0.05). Our results show that rh-Epo treatment is capable of accelerating the erythroid reconstitution and decreasing the need for RBC transfusions. A beneficial effect on platelet reconstitution is also suggested, but further studies are necessary to confirm this point.
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PMID:Erythropoietin treatment in allogeneic BMT accelerates erythroid reconstitution: results of a prospective controlled randomized trial. 149 Feb 3

The multistep nature of human cancers is well illustrated by chronic myelogenous leukemia (CML), a clonal hematologic malignancy with two distinct phases: chronic and acute. Transition between these phases is characterized by unregulated growth and loss of differentiation of myeloid cells and their progenitors. We recently reported that loss of normal p53 expression correlates with transition from the chronic to acute phase in at least 25% of cases of CML. However, the precise relationship between this loss and biologic features of acute-phase CML is uncertain. To study this question, we artificially expressed normal p53 in K562, an erythroid acute-phase CML cell line lacking normal p53 expression. Biological effects were assessed by determining several growth parameters and by measuring synthesis of hemoglobin, a feature of mature erythroid cells. K562 cells expressing normal p53 had an increased proportion of cells in G1 versus S + G2, a longer doubling time and a lower growth saturation density than control K562 cells or K562 cells with antisense p53. Cells with normal p53 also expressed up to 50-fold more hemoglobin than controls. These data are consistent with the notion that loss of p53 expression may be responsible for many of the features of acute-phase CML cells. The data also demonstrate direct involvement of p53 in differentiation processes.
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PMID:Expression of the normal p53 gene induces differentiation of K562 cells. 150 93

Experiments were undertaken to investigate the molecular basis of primitive hematopoietic progenitor cell regulation in both the long-term culture system and in methylcellulose, particularly with a view to characterizing factors either able or unable to influence the behaviour of primitive leukemic cells from patients with chronic myeloid leukemia (CML). Long-term cultures of CML cells with or without irradiated normal marrow feeder layers were initiated from peripheral blood cells of CML patients with high white blood cell counts. Three weeks later the effect of exogenously added transforming growth factor-beta 1 (TGF-beta 1) on progenitor cycling status was examined. A single addition of 5 ng/ml TGF-beta 1 was able to reversibly arrest the otherwise uninterrupted turnover of primitive leukemic erythroid and granulopoietic progenitors for a period of up to 7 days both in the presence and absence of a normal adherent cell population. When TGF-beta 1 was incorporated into methylcellulose cultures, its ability to inhibit colony formation by CML progenitors showed the same differential activity on primitive cell types exhibited by normal progenitors. Dose-response curves for analogous populations of normal and leukemic cells were indistinguishable. Increasing the concentration of granulocyte-macrophage colony-stimulating factor (GM-CSF) in methylcellulose colony assays decreased the sensitivity displayed by normal clonogenic cells to TGF-beta 1 and no differences were detectable when CML cells were used in such regulator competition experiments. These findings support a general model of primitive hematopoietic cell regulation in which entry into S-phase is determined at the intracellular level by multiple convergent pathways that may deliver either positive or negative signals from activated cell surface receptors for distinct extracellular factors. The present study shows for the first time that primitive CML progenitors exposed to TGF-beta 1 in vitro can be transiently blocked in a noncycling state for several days without loss of viability and that the mechanisms responsible for the emergence and maintenance of a clonal population of CML cells in vivo do not appear to involve changes in their sensitivity to TGF-beta 1. It is thus unlikely that the heightened proliferative activity exhibited by primitive CML progenitors both in vivo and in long-term culture can be explained by an abnormality in the intracellular mechanisms normally activated by TGF-beta 1 receptor-ligand binding. We suggest that primitive CML cells are either defective in their ability to see (or activate) endogenously produced TGF-beta 1, or are defective in their responsiveness to another, undefined, regulator.
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PMID:Granulocyte-macrophage colony-stimulating factor modulation of the inhibitory effect of transforming growth factor-beta on normal and leukemic human hematopoietic progenitor cells. 151 2

The chimeric bcr-abl gene formed by the Philadelphia translocation is thought to initiate chronic myeloid leukemia. Engraftment of mice with bone marrow cells infected with a bcr-abl retrovirus has been shown to elicit multiple hematopoietic disorders, including a clonal but nontransplantable hyperproliferation of erythroid and/or mast cells. Culture of spleen and bone marrow cells from such mice usually yielded mast cell lines, even when erythroid disease dominated the primary animal. The mast cells, which carried the same proviral insert as the primary disease, generally grew slowly and were neither transplantable nor clonogenic in agar until they had been cultured for several months. Unexpectedly, several bcr-abl-induced lines switched in vitro from mast cell to megakaryocytic and/or erythroid character, and one became myeloid. The dramatic phenotypic shifts seem likely to involve changes occurring within progenitor cells maintaining the clone, rather than mutation of mature mast cells. The variant lines exhibited substantial spontaneous differentiation, despite being readily transplantable and therefore fully transformed. The production of hematopoietic growth factors by the mast cell lines and their phenotypic variants may implicate an autocrine loop in their evolution. These novel bcr-abl cell lines should aid in the study of genetic events in the progression from chronic to acute leukemia and facilitate analysis of hematopoietic lineage commitment.
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PMID:bcr-abl-Induced cell lines can switch from mast cell to erythroid or myeloid differentiation in vitro. 153 51

The tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) inhibits the entry into DNA synthesis of murine spleen colony-forming units (CFU-S) and protects these cells during chemotherapy. This synthetic peptide also inhibits the growth of normal human marrow progenitors granulocyte-macrophage colony-forming units (CFU-GM) and erythroid burst-forming units (BFU-E) and decreases their percentage in DNA synthesis at nanomolar concentration. In view of its clinical application as a marrow protector, we have investigated its effects on malignant cells. Studies were carried out on HL-60 cells and on fresh leukemic cells from patients with either chronic myeloid leukemia (CML) or acute myeloid leukemia (AML). Results showed that AcSDKP, whatever the doses used, did not modify the proliferation of both HL-60 cells and AML cells even when enhanced by stimulating factors such as interleukin 3 or granulocyte-macrophage colony-stimulating factor (GM-CSF). In addition, no change in the number and the percentage in S-phase of both HL-60 clonogenic cells and CML progenitors was observed. Our data clearly demonstrate that the tetrapeptide AcSDKP was ineffective on leukemic cells and therefore by acting selectively on normal progenitors represents a potent therapeutical agent for the protection of normal bone marrow progenitors during chemotherapy.
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PMID:The tetrapeptide AcSDKP, an inhibitor of the cell-cycle status for normal human hematopoietic progenitors, has no effect on leukemic cells. 154 96


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