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)

alpha-Interferon (IFN-alpha) is important in the management of chronic myelogenous leukemia (CML). The P210bcr/abl fusion protein, with enhanced tyrosine kinase activity, is implicated in the pathogenesis and progression of the disease. To elucidate the inhibitory mechanism of IFN-alpha on CML cell proliferation, we studied the effect of IFN-alpha on P210bcr/abl in K-562 cells. The phosphorylated level of P210bcr/abl was not altered by treatment with IFN-alpha alone despite its inhibiting cell proliferation. However, when K-562 cells were treated with either a low (5 x 10(2) U/ml) or high (10(4) U/ml) concentration of IFN-alpha in the presence of hemin, P210bcr/abl protein activity decreased through reduction of in vivo phosphorylation, but not through inhibition of de novo protein synthesis. Furthermore, hemoglobin content was increased by IFN-alpha at both low and high concentrations in tandem with hemin-induced erythroid differentiation and the change in P210bcr/abl. These results demonstrate that IFN-alpha synergises hemin-mediated erythroid differentiation as it reduces the in vivo tyrosine phosphorylation of P210bcr/abl in K-562 cells.
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PMID:Alpha-interferon reduces in vivo phosphorylation of P210bcr/abl protein during hemin-induced erythroid differentiation of K-562 cells. 199 6

More than 95% of patients with chronic myelogenous leukemia (CML) contain an abnormal chromosome termed the Philadelphia chromosome (Ph1). Ph1 and the resulting BCR-ABL fused genes are markers for this type of leukemia. The product of the fused BCR-ABL genes is a protein of about 2000 amino acids termed P210 BCR-ABL. Although the BCR-ABL protein can be routinely detected in blood cells from blast crisis CML patients by assaying for its activated tyrosine kinase activity, detection of P210 BCR-ABL in early stage CML patients (chronic phase) has not yet been possible (S. A. Maxwell et al., Cancer Res., 47: 1731, 1987). A procedure involving Western blotting with an anti-ABL monoclonal antibody was developed that allows detection of P210 BCR-ABL and P145 ABL in cells from chronic phase and blast crisis CML patients, but as expected only P145 ABL was found in normal white blood cells. Most chronic phase patients also contained one to two ABL proteins with a molecular weight of about 190,000. Interestingly, the ratio of BCR-ABL to ABL proteins increased in four blast crisis patients compared to 18 chronic phase patients. Also, one chronic phase patient analyzed on three separate occasions lacked P210 BCR-ABL and exhibited only the Mr 190,000 form. This assay should also be useful in other leukemias that express altered forms of the ABL protein.
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PMID:Detection of BCR-ABL proteins in blood cells of benign phase chronic myelogenous leukemia patients. 203 43

Chronic myeloid leukaemia (CML) is an excellent model for the study of molecular rearrangements caused by a cytogenetic anomaly associated with a disease. The formation of a Philadelphia chromosome by translocation between chromosomes 9 and 22 provokes the breaking and migration of a cellular oncogen (ABL), located in the 9q34 region, towards chromosome 22 and the 22q11 region where the PHL gene is situated. This gene is broken in the bcr area the rearrangements of which are specific to CML. The ABL and PHL genes fragments fuse together, creating a new hybrid gene which is transcribed into an 8.5 kilobase messenger RNA specific to CML. This RNA is translated into a 210 kilodalton protein whose abnormally high tyrosine kinase activity seems to contribute to the development of the disease. Genetic engineering techniques improve our understanding of CML molecular mechanisms and can be very useful to clinicians as they permit the diagnosis of CML in some cases devoid of chromosomal markers, and the detection of a possible relapse in marrow-grafted patients with a much greater sensitivity (one in 100,000 cells) than that of cytogenetics.
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PMID:[Chronic myeloid leukemia: from cytogenetics to molecular biology]. 209 36

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

In the great majority of patients with chronic myelogenous leukemia (CML) the reciprocal translocation between chromosomes 9 and 22, t(9;22)(q34;q11), resulting in the Philadelphia (Ph) chromosome produces fusion DNA sequences consisting of the 5' part of the major breakpoint cluster region-1 (M-BCR-1) and the ABL protooncogene which encodes for the P210BCR-ABL phosphoprotein with tyrosine kinase activity implicated in the pathogenesis of CML. Molecular analysis was performed on 25 patients with Ph-positive CML using 2 breakpoint cluster region (bcr) probes within the M-BCR-1 DNA sequences, and two of them did not contain either detectable rearranged DNA homologous to the 5' side bcr probe or ABL-related fusion mRNA. The chromosomal in situ hybridization technique revealed that these two Ph-positive CML cases did not carry DNAs homologous to the 5' bcr or ABL probes on the Ph chromosome. Furthermore, one of the two Ph-positive CML cases did not show either rearranged DNA or regions homologous to the 3' bcr probe on a 9q+ chromosome, while the other CML case showed a rearrangement detected by the 3' bcr probe and transposition of the 3' bcr homologous to the 9q+ chromosome. Thus, the possibility is raised that the BCR/ABL fusion DNA has been deleted in rare CML cases, and that the deletion possibly occurred in a stepwise manner following the formation of the Ph chromosome at any stage of the disease.
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PMID:Philadelphia chromosome-positive chronic myelogenous leukemia with deleted fusion of BCR and ABL genes. 215 92

The effects of 1 alpha, 25-dihydroxyvitamin D3 (VD3) on proliferation, differentiation, and macromolecular synthesis in the new Philadelphia chromosome-positive chronic myelogenous leukemia cell line, RWLeu-4, were investigated. Binding of [3H]VD3 was saturable, with approximately 2000-3000 sites/cell, and half-maximal binding occurring at 0.21-0.33 nM. Treatment of RWLeu-4 cells with VD3 induced 24R-hydroxylase activity, a marker of vitamin D3 responsiveness in many tissues. Exposure of RWLeu-4 cells to VD3 also inhibited proliferation and DNA synthesis with a 50% effective dose of 3.5-10 nM within 72 h; in addition, protein and RNA synthesis were inhibited by VD3 treatment. Exposure of RWLeu-4 cells to 5 nM VD3 for 72 h caused 50% of the cells to differentiate into macrophage/monocyte type cells as judged by nitroblue tetrazolium staining and adherence to plastic. Progressive expression of cell surface maturation-specific antigens of the monocyte/macrophage lineage was induced by treatment of RWLeu-4 cells with VD3 for 24 to 72 h at doses that inhibited cellular proliferation. c-myc RNA, which is constitutively expressed in RWLeu-4 cells, increased after 0.5 h of treatment with 50 nM VD3 and then rapidly decreased to barely detectable levels after 4 h of treatment. Finally, the in vitro tyrosine kinase activity associated with the p210bcr-abl oncogene product was decreased approximately 50% by VD3 treatment. Because of the presence of a functional receptor-effector system for VD3 and multiple biological responses to the hormone, these cells provide a unique model system with which to probe the specific effects of VD3 on cell growth and differentiation in chronic myelogenous leukemia.
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PMID:Effects of 1 alpha, 25-dihydroxyvitamin D3 on the human chronic myelogenous leukemia cell line RWLeu-4. 215 72

Until recently, T cells were believed not to be involved in chronic myeloid leukemia. We describe an example of CML in T lymphoblastic crisis with massive generalized lymphadenopathy in which the blasts were CD2(+), CD5(+), and CD7(+), variably CD1(+) and CD3(+), and both responded to and could be induced to produce the T cell growth factor, interleukin-2. Additionally, the blasts were shown to contain the CML-related tyrosine kinase P210bcr-abl rather than the smaller kinase associated with Ph1(+) ALL. Finally, the participation of the T lymphoid lineage in the CML clone was proven by the presence of the same BCR rearrangement in blasts as in granulocytes, suggesting the existence of a bone marrow progenitor common to the T cell and myeloid lineages.
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PMID:Chronic myeloid leukemia arising in a progenitor common to T cells and myeloid cells. 216 6

CML has provided a model for the genetic basis of human neoplasia. Since 1960 with the discovery of the Ph chromosome, study of this disease has provided a conceptual basis for viewing cancer as a clonal disorder occurring at the stem cell level and associated with intrinsic genetic defects which contribute to abnormal growth regulation. Although several oncogenes have been identified through the study of tumor-producing retroviruses in animals, discovery of the BCR/ABL translocation, the altered 8.5 kb BCR/ABL transcript, and the hybrid BCR/ABL P210 protein with enhanced tyrosine kinase activity has provided one of the first examples of a human neoplasm in which structural alterations in a normal cellular gene might lead to malignant transformation. However, it is likely that P210 is necessary but not sufficient for the full spectrum of malignant behavior observed in this disease. Investigation of the molecular events that are associated with the additional cytogenetic abnormalities of blast phase will most likely reveal alterations of other important growth regulatory genes which contribute to the multistep nature of malignant transformation in CML.
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PMID:Chronic myelogenous leukemia as a model for the genetic basis of cancer. 218 95

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

The presence of Philadelphia chromosome t(9:22) is a hallmark of 95% of clinical cases of chronic myelogenous leukemia (CML) as well as 20% of adult acute lymphoblastic leukemia (ALL) and 5% of acute myeloid leukemia (AML). The product of t(9;22) is a fusion protein BCR-ABL. The fusion proteins of CML, ALL and AML have increased tyrosine kinase activity and show a transforming potential in vitro and in animal models. The shorter p190 protein is associated almost only with ALL and AML, while the protein p210 is present in both chronic phase and blast crisis of CML and also in 50% of Philadelphia-positive (Ph1+) ALL. In CML the transition from chronic phase to blast crisis is usually accompanied by additional genetic events, e.g. additional chromosomal abnormalities, and oncogene activation(s). The detailed understanding of molecular basis of CML, and Ph1+ ALL and AML provides highly sensitive molecular and serological methods to complement classical cytogenetics. The advantages and limitations of these techniques are described and discussed below.
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PMID:Molecular pathology of chronic myelogenous leukemia. 224 53


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