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 human chronic myelogenous leukemia cell line K562 expresses a structurally altered c-abl protein with tyrosine kinase activity. Erythroid differentiation of K562 cells was induced by tyrosine kinase inhibitors, but not by other kinase inhibitors. Treatment of K562 cells with 5'd(TACTGGCCGCTG-AAGGGC)3', complementary to the second exon (codons 2 to 7) of c-abl mRNA, inhibited cell growth and induced benzidine-positive cells in a dose-dependent manner. However, exposure to the sense oligomer did not induce erythroid differentiation of the cells. These results suggest that inhibition of abl tyrosine kinase activity is closely related to induction of erythroid differentiation of K562 cells. A multidrug-resistant subline (K562R) was induced to undergo erythroid differentiation by tyrosine kinase inhibitors such as genistein or herbimycin A as effectively as the parent K562 cells were. Therefore, tyrosine kinase inhibitors might be useful as cancer chemotherapeutic agents against some multidrug-resistant leukemias having abnormally high activity of oncogene tyrosine kinase(s).
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PMID:Inhibition of abl oncogene tyrosine kinase induces erythroid differentiation of human myelogenous leukemia K562 cells. 212 38

Acute megakaryoblastic leukemia (AMkL) is a newly defined acute leukemia in which the differentiation of proliferating blasts is arrested at the megakaryocytic precursor stage. In order to clarify whether a target cell of leukemic transformation in AMkL is a cell committed to megakaryocytic lineage, or a multipotential stem cell, we examined AMkL patients with regard to: a) the presence of myelodyplastic features in residual erythroid and granulocytic cells, b) coexistence of myeloperoxidase (MPO)-positive blasts with megakaryoblasts, and c) the presence of the same chromosomal abnormality in erythroid and granuloid colony-forming cells as seen in megakaryoblasts. Regarding the former two items, results were compared with those from megakaryoblastic crisis of chronic myelocytic leukemia (CML-MkBC) and transient myeloproliferative disorder in Down syndrome (DS-TMD), which are thought to be multipotential stem cell disorders. Among 18 patients with AMkL, three, all complicating myelofibrosis, had marked myelodysplastic changes of erythroid series and/or granulocytic series. In 4 out of 7 patients with CML-MkBC, 5 out of 8 patients with DS-TMD, and 7 out of 18 patients with AMkL, MPO-positive blasts, even though rare, were observed in addition to PPO-positive blasts. All except one of these patients with AMkL also showed complicating myelofibrosis. In one case of AMkL with myelofibrosis, chromosomal analysis of cultured cells of individual colonies revealed that all the analysable metaphases from both CFU-GM and BFU-E had the same chromosomal abnormality as megakaryoblasts. This study has clarified that a considerable proportion of AMkL cases, particularly those with complicating myelofibrosis or showing acute myelofibrosis, arise against the background of a multipotential stem cell disorder, even if blasts are exclusively megakaryocytic in phenotype.
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PMID:Target cell of leukemic transformation in acute megakaryoblastic leukemia. 216 21

A novel erythroid cell line, RM10, was established from a long-term bone marrow culture of a patient with chronic myelogenous leukemia (CML). RM10 cells were positive for periodic acid Schiff (PAS), but negative for peroxidase and dual esterase. RM10 cells had la, pre B (CD10), myeloid (CD13, CD14, CD33) and erythroid (glycophorin A) markers, but had no other lymphoid, megakaryocytic, or mesenchymal cell markers. RM10 cells spontaneously synthesized hemoglobin, which was markedly enhanced with hemin. Isoelectric focusing of the cell lysates and northern blot analysis of the total cellular RNA revealed hemoglobin synthesis in the cells. Using 125I-labeled recombinant human erythropoietin (Epo), two classes of Epo receptors were demonstrated in the RM10 cells. However, Epo did affect neither growth nor erythroid differentiation of the cells. RM10 cells rapidly differentiated to monocytic cells in the presence of 12-0-tetradecanoylphorbol-13-acetate, and simultaneously expressed glycoprotein IIb/IIIa. RM10 cells had Philadelphia chromosome (Ph), and expressed p210bcr-abl using immunoprecipitation with anti-c-abl and anti-phosphotyrosine antibodies. These results indicate that the RM10 cells have the characteristics of multipotential hemopoietic cells originating from Ph-positive CML and that high affinity Epo receptor class is not a sufficient condition for Epo responsiveness.
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PMID:A novel CD10-positive erythroid cell line, RM10, established from a patient with chronic myelogenous leukemia. 216 10

The authors established a new hemopoietic cell line (JK-1) from a patient with chronic myelogenous leukemia in erythroid crisis. This JK-1 line predominantly consists of immature cells, but a small number of mature erythroblasts and red cells can be consistently seen without any specific differentiation inducer. The JK-1 cells grow in suspension culture supplemented with human plasma and carry double Philadelphia chromosomes. Hemoglobin staining with benzidine was positive for about 20% of cells and the type of the hemoglobin was for the most part HbF. Surface-marker analysis revealed JK-1 cells positive for glycophorin A, EP-1, and HAE9. The proportion of mature cells was elevated by the addition of delta-aminolevulinic acid. Erythropoietin (EPO) enhanced the growth of JK-1 cells either in the suspension or in methylcellulose semisolid culture. The total number of EPO receptors was 940 per cell, of which 220 sites had an affinity higher than the other 720 sites. This is the first report of an established human erythroid cell line which spontaneously undergoes terminal differentiation.
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PMID:Establishment of an erythroid cell line (JK-1) that spontaneously differentiates to red cells. 216 92

An increasing amount of data provides strong evidence for the complex multifactorial control of primary hemopoietic functions. Here we present a new multicellular functional unit, the Hematon, isolated from the light-density floating fraction of normal human bone marrow (BM) aspirates. The Hematon is organized in a compact, three-dimensional spheroid complex from central adipocytes, fibroblastoid cells, and resident macrophages that compartmentalize myeloid, erythroid, and megakaryocyte progenitor cells and their progenies. The Hematon fraction is more than twofold more abundant in progenitor cells when compared to the mononuclear cell (MNC) fraction as gauged by cytological techniques and by analysis of granulocyte-macrophage colony-forming unit (GM-CFU) populations. Individual Hematons may produce, within 2-3 weeks, up to 50,000 hemopoietic cells of different cell lineages in organotypic microcultures. Recombinant human hematopoietic growth factors interleukin 3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and macrophage colony-stimulating factor (M-CSF) significantly stimulated the endogenous cell production of some but not all of the individually treated Hematons, indicating the heterogeneity of factor-responsive cells within the Hematon population. Comparative observations of 184 BM aspirates support the hypothesis that the presence of Hematons in a BM aspirate correlates positively with homeostatic blood cell production, because the Hematon was present in normal BM (31/40) and it was rare among patients with myelodysplastic syndromes (15/53), acute myeloblastic leukemia (7/39), and chronic myelocytic leukemia (5/52). We suggest that the Hematon represents a unifying model around which the variability of fundamental BM functions and dysfunctions can be explored.
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PMID:Hematon, a multicellular functional unit in normal human bone marrow: structural organization, hemopoietic activity, and its relationship to myelodysplasia and myeloid leukemias. 218 30

CML cell line, KU-812-F, originally established from a patient with Philadelphia-chromosome-positive chronic myelocytic leukemia has maintained the ability to differentiate into both granuloid (basophilic) and erythroid lineages. The expression of P210bcr/abl in KU-812-F cells during differentiation was studied by immunoblotting and immunoprecipitation. Immunoblotting with anti-phosphotyrosine sera revealed the down-regulation of P210bcr/abl in both granuloid and erythroid lineages. Immunoprecipitation with anti-abl antibodies of 35S-methionine-labelled cells revealed a reduced rate of synthesis of P210bcr/abl protein. Cytotoxic agents that caused growth inhibition of the cells did not alter the expression of P210bcr/abl. These results indicate that the down regulation of P210bcr/abl protein is a lineage non-specific event accompanied by differentiation.
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PMID:Lineage non-specific down regulation of P210bcr/abl in the CML cell line, KU-812-F, during differentiation. 223 52

Tyrosine phosphorylation is important in the transmission of growth and differentiation signals; known tyrosine kinases include several oncoproteins and growth factor receptors. Interestingly, some differentiated cell types, such as erythrocytes and platelets contain high amounts of phosphotyrosine. We analyzed tyrosine kinases expressed in the K-562 chronic myelogenous leukemia cell line, which has a bipotential erythroid and megakaryoblastoid differentiation capacity. Analysis of 359 polymerase chain reaction-amplified cDNA clones led to the identification of 14 different tyrosine kinase-related sequences (JTK1-14). Two of the clones (JTK2 and JTK4) represent unusual members of the fibroblast growth factor receptor gene family, and the clones JTK5, JTK11, and JTK14 may also belong to the family of receptor tyrosine kinases but lack a close relationship to any known tyrosine kinase. Each of these different genes has its own characteristic expression pattern in K-562 cells and several other human tumor cell lines. In addition, the JTK11 and JTK14 mRNAs are induced during the megakaryoblastoid differentiation of K-562 cells. These tyrosine kinases may have a role in the differentiation of megakaryoblasts or in the physiology of platelets.
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PMID:Putative tyrosine kinases expressed in K-562 human leukemia cells. 224 64

Chronic myelogenous leukemia (CML) is characterized by two distinct phases--chronic and acute. Features of the chronic phase include proliferation and accumulation of mature myeloid cells and their progenitors; differentiation is seemingly intact. In contrast, the acute phase is characterized by impaired differentiation. Acute phase is heterogeneous--granulocytes, lymphocytes, megakaryocytes, and erythroid cells are involved singly or in combination. The t(9;22) translocation, which results in the Ph1 chromosome, is the hallmark of chronic phase CML. Transition to acute phase is often accompanied by additional chromosome abnormalities. Here we suggest that these additional abnormalities determine the phenotype of acute phase CML.
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PMID:Do chromosome abnormalities determine the type of acute leukemia that develops in CML? 229 2

Fourteen children with a primary myelodysplastic syndrome (MDS) were seen at this center over a 10-year period. Six of the patients, including two pairs of siblings, had a monosomy 7 population in their bone marrow. Seven patients had the clinical and laboratory features of "juvenile chronic myeloid leukemia." Three patients could be considered to have either the monosomy 7 syndrome or "juvenile chronic myeloid leukemia," indicating that these two entities are not mutually exclusive. All patients fulfilled the French-American-British (FAB) criteria for a myelodysplastic syndrome. Clonal chromosomal abnormalities were detected in 13 of the 14 patients, and consistently involved either monosomy 7, multiple abnormalities, and/or multiple clones. Hematopoietic progenitor assays of blood and marrow samples obtained from most patients showed abnormal progenitor frequencies, or differentiation patterns in culture (or both), often affecting the erythroid as well as the granulopoietic lineages. In particular, granulopoietic progenitors from four to six patients in the "juvenile chronic myeloid leukemia" category generated predominantly abnormal appearing macrophage colonies. Clinical outcomes were poor with rapid transformation to acute myeloid leukemia in most patients. All treated patients responded poorly to conventional chemotherapy, although in two cases remission was achieved with intensive therapy and allogeneic bone marrow transplantation. Childhood myelodysplasia includes a group of diseases that are clinically heterogeneous, and current terminology is confused and inconsistent. Until a better understanding of the biologic and molecular basis of these diseases is obtained, it is proposed that the use of the FAB categories developed for adult MDS might help to improve diagnostic precision and therapeutic comparisons.
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PMID:Childhood myelodysplasia: suggested classification as myelodysplastic syndromes based on laboratory and clinical findings. 230 81

The possible presence of tumor cells in remission bone marrow (BM) is one of the major problems for the success of autologous BM transplantation (ABMT), because the reinfusion of viable malignant cells may result in relapse. In this study we attempted the purging of the malignant cells by the use of VP-16-213 (VP-16) and nitrogen mustard (NM) either alone or in combination. Four cell lines from various hematological malignancies were utilized: SK-DHL-2 was established from a B-cell diffuse histiocytic lymphoma; RAJI was from an Epstein-Barr virus (EBV)-infected B-cell lymphoma cell line; K-562 were from a chronic myelogenous leukemia (CML) blastic crisis; and HL-60, derived from a human promyelocytic leukemia, were used in exponential growth phase. Four logs of tumor cell-elimination were observed after 1-h incubation of RAJI cells with 25 micrograms/ml of VP-16. K-562 and SK-DHL-2 cells showed a greater than 4 logs reduction after 1-h exposure to 75 micrograms/ml of VP-16, and HL-60 cell line growth was inhibited by 3.2 logs. Under the same conditions (i.e., the treatment with 75 micrograms/ml), we observed a mean recovery of 2.7% of BM granulocyte-macrophage colonies (granulocyte-macrophage colony-forming units, CFU-GM), 3.2% of erythroid (erythroid burst-forming units, BFU-E), and 2.5% of pluripotent (granulocyte erythrocyte macrophage megakaryocyte colony-forming units, CFU-GEMM) progenitors, respectively. More than 3 logs reduction of leukemia and lymphoma cell lines were reached following 1-h treatment with 1 micrograms/ml of NM. After exposure to the same concentration of the drug we obtained 2.5% CFU-GM, 1.2% BFU-E, and 2% CFU-GEMM recovery. A drug mixture containing constant doses of VP-16 (10 and 20 micrograms/ml) and NM (1 micrograms/ml) reduced HL-60 and SK-DHL-2 cell growth to undetectable levels (i.e., 4 and 5 logs elimination) in the presence of an excess of irradiated BM cells, whereas it did not further affect the recovery of the BM precursors as compared to the single drugs used alone. These results suggest that the combination of these two drugs at the selected dose level could provide a better therapeutic index (i.e., higher tumor cell killing coupled with no additional cytotoxic effect on normal BM cells) than the same chemotherapeutic agent used alone and that this mixture may be useful for the "ex vivo" treatment of BM grafts.
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PMID:In vitro cytotoxicity of VP-16-213 and nitrogen mustard: agonistic on tumor cells but not on normal human bone marrow progenitors. 239 48


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