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)

In order to ascertain the frequency and distribution of isochromosomes in neoplasia, we surveyed the cytogenetic data from 20,007 tumors with clonal chromosome aberrations reported in the literature. Tumor types for which at least 50 cases with acquired aberrations and 10 cases with isochromosomes had been reported were selected, yielding a total of 18,160 neoplasms. Of these, 1,792 cases (9.9%) displayed a total of 2,014 isochromosomes. The 9 most common isochromosomes (detected in at least 50 cases) were, in decreasing order of frequency, i(17q), i(8q), i(1q), i(12p), i(6p), i(7q), i(9q), i(5p), and i(21q). The frequency of isochromosomes varied among the different tumor types, with the highest incidence in germ cell neoplasms (60%) and the lowest in chronic myeloproliferative disorders (2.3%). Also, the spectrum of isochromosomes differed among the neoplasms. The most common isochromosomes in the different tumor types were i(11q), i(17q), and i(21q) in acute myeloid leukemia; i(9q), i(17q), and i(22q) in chronic myeloid leukemia; i(17q) in chronic myeloproliferative disorders; i(X)(q13), i(17q), and i(21q) in myelodysplastic syndromes; i(7q), i(9q), and i(17q) in acute lymphoblastic leukemia; i(1q), i(7q), i(8q), and i(17q) in chronic lymphoproliferative disorders; i(1q), i(6p), i(9p), i(17q), and i(21q) in Hodgkin's disease; i(1q), i(6p), and i(17q) in non-Hodgkin's lymphoma; i(1q), i(8q), and i(17q) in adenocarcinoma; i(1q), i(3q), i(5p), and i(8q) in squamous cell carcinoma; i(5p), i(8q), and i(11q) in transitional cell carcinoma; i(1q), i(7q), and i(17q) in Wilms' tumor; i(1q), i(12p), and i(17q) in germ cell neoplasms; i(1p), i(1q), i(6p), and i(17q) in sarcoma; i(5p), i(6p), i(7p), and i(21q) in mesothelioma; i(1q), i(6p), and i(17q) in malignant neurogenic neoplasms; i(1q), i(6p), and i(17q) in retinoblastoma; and i(1q), i(6p), and i(8q) in malignant melanoma.
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PMID:Isochromosomes in neoplasia. 752 35

A variant of the chronic myelogenous leukemia cell line, RWLeu-4, that is resistant to the antiproliferative effects of vitamin D3 was established. Although RWLeu-4 proliferation is inhibited by 1 nmol/L vitamin D3, the resistant cells (JMRD3) continue to proliferate in the presence of 100 nmol/L vitamin D3. Both cells express similar patterns of differentiation-specific antigens after treatment with vitamin D3, and both express the retinoblastoma gene product (p110Rb). Vitamin D3 treatment of the sensitive RWLeu-4 cells decreased the level of the p110Rb protein, as well as its phosphorylation. In contrast, vitamin D3 treatment of JMRD3 had no effect on p110Rb expression or phosphorylation. Both RWLeu-4 and JMRD3 express similar vitamin D3 receptors and vitamin D3-inducible enzyme activities. Differences were detected in the DNA binding characteristics of the vitamin D3 receptors as determined by electrophoretic mobility shift studies. However, sequence analysis of the DNA-binding domain and immunoblot analysis showed no differences in the receptors. We conclude that some process subsequent to vitamin D3 receptor activation is altered in JMRD3 that partially separates vitamin D3-induced inhibition of proliferation from the induction of differentiation.
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PMID:Characterization of a vitamin D3-resistant human chronic myelogenous leukemia cell line. 799 44

Oncogenes are genes associated with causation of cancer. They were originally associated with the ability of retroviruses to cause tumors in animals. These viral oncogenes (V-onc) have their cellular counterparts (C-onc) called Proto oncogenes. Function of Proto oncogenes is to maintain cellular growth and development. Activation of these proto-oncogenes can occur due to mutation which leads to uncontrolled cell growth. The Proto oncogenes can be grouped into different categories based on their protein products, i.e. protein kinases, growth factors, growth factor receptors, and DNA binding proteins. There are also genes that normally suppress malignant transformation and these are called anti oncogenes. Loss of their suppressor activity leads to unimpeded growth. Oncogene abnormalities are seen in pediatric leukemias, lymphomas, and various solid tumors. Anti oncogenes are associated with retinoblastoma (Rb gene), Wilms' tumor, rhabdomyosarcoma and neuroblastoma, etc. Identification of these abnormalities have diagnostic, prognostic and therapeutic implications. The utility of oncogenes in classification of human cancer and monitoring cancer therapy is quite clear, but the future of these for therapeutic interventions remains uncertain. Role of c-abl oncogene in chronic myeloid leukemia (CML), bcl-2, in lymphomas, N-myc in neuroblastomas and retinoblastoma (Rb) gene in retinoblastomas is well understood and used in designing proper therapeutic approaches. Since oncogenes also control normal cellular function, their use for therapy may be limited by the amount of damage to normal cells. Their maximum therapeutic benefit may be realized only when used in combination with other modalities.
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PMID:Oncogenes: present status. 824 94

Chronic myelogenous leukemia (CML) is a hematological stem cell disorder characterized by excessive proliferation of the myeloid lineage. It has a progressive course typified by the transition from the chronic phase to the accelerated phase and on to blast crisis. The hallmark of CML is the translocation between chromosomes 9 and 22 that results in the chimeric BCR-ABL gene encoding p210BCR-ABL. The oncogenic potential of this protein has been validated, and it is believed that it contributes in a critical way to the initiation of CML. However, the secondary genetic forces responsible for the transition from the chronic state to the fully blastic stage are not clear. Evidence for chromosomal instability includes the clonal evolution which characterizes advanced CML. In regard to specific genetic aberrations, sporadic reports have shown alterations in H-RAS, c-MYC, retinoblastoma, and P53 genes, as well as production of p190BCR-ABL during the progression of CML. In addition, we have recently found evidence for excessive interleukin-1 beta production, acting in an autocrine and/or paracrine manner, in the more advanced stages of the disease. Taken together, current data suggest that multiple molecular pathways lead to disease progression, and that distinct subsets of genetic alterations exist in blast crisis patients.
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PMID:CML: mechanisms of disease initiation and progression. 825 16

The retinoblastoma susceptibility gene (RB) and p53 gene are now known to be the prototypes for a class of tumor suppressor genes. Both genes act as a regulator of cell cycle transition at G1/S in many types of cell lineages. Underphosphorylated form of RB protein (Rd) acts as a growth suppressor by blocking exit from G1 through a specific binding to E2F or promoter region of certain growth-associated genes. Phosphorylation of Rb can be viewed as inactivating Rb and allowing cell cycle progression to occur. Differentiation of hematopoietic cell is accompanied with the loss of ability to phosphorylate Rb, indicating that Rb plays an important role in hematopoietic cell growth and differentiation. Abnormalities of RB gene may, therefore, predispose to the development of hematologic malignancies. DNA rearrangement was reported to be present in 1.5-12.1% of cases with primary leukemias, and the absence of RB protein was also observed in 6.3-23.2%. The abnormalities of p53 gene were also frequently observed in hematologic malignancies. DNA rearrangement of p53 was observed in 20-30% of the cases with blastic crisis of CML. Point mutation at the "hot spot" was reported in many types of leukemias, especially in cell lines established from these cases.
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PMID:[Tumor suppressor genes and their role in abnormal production of leukocytes (leukemogenesis)]. 831 27

Human chronic myelogenous leukemia-blast crisis K562 cells have been demonstrated to be relatively resistant to antileukemic drug-induced apoptosis. This has been attributed to the activity of p210bcr-abl tyrosine kinase present in the K562 cells, which is known to suppress drug-induced apoptosis. Recently, K562 cells have been shown to express the antiapoptosis Bcl-xL but not Bcl-2 proteins. To investigate the contribution of Bcl-xL toward resistance to drug-induced apoptosis, we created K562/Bcl-xS and K562/neo cells by electroporating the expression plasmids pSFFVneo-Bcl-xS and pSFFVneo, containing the bcl-xS and neomycin resistance genes, respectively, into K562 cells. K562/Bcl-xS but not K562/neo cells expressed the bcl-xS mRNA and p19Bcl-xS protein. In contrast, both cell types expressed equivalent levels of Bcl-xL, Bax, Bcl-2, Myc, retinoblastoma, p21cbor-abl, and p145abl proteins. A significant increase in the hemoglobin levels was observed in the K562/Bcl-xS compared with the K562/neo cells (P < 0.05). In addition, K562/Bcl-xS cells were significantly more sensitive than K562/neo cells to undergoing erythroid differentiation induced by low-dose 1-beta-D-arabinofuranosylcytosine (ara-C) and hexamethyl bisacetamide (P < 0.05), but not by all-trans-retinoic acid. Low-dose ara-C- or hexamethyl bisacetamide-induced differentiation was not associated with apoptosis of K562/Bcl-xS or K562/neo cells. Low-dose ara-C-induced erythroid differentiation was accompanied by conversion of the retinoblastoma protein to predominantly its underphosphorylated isoform as well as by down-regulation of Myc levels in K562/Bcl-xS and K562/neo cells. Importantly, exposure to high-dose ara-C (HIDAC; 100 microM ara-C for 4 h) caused internucleosomal DNA fragmentation and the morphological features of apoptosis in K562/Bcl-xS cells. These effects were modestly enhanced by cotreatment with HIDAC plus herbimycin A. In contrast, K562/neo cells were completely resistant to HIDAC- and herbimycin A-induced apoptosis. These results indicate that the expression of Bcl-xS induces erythroid differentiation and partially sensitizes chronic myelogenous leukemia-blast crisis-derived K562 cells to ara-C-induced differentiation and apoptosis.
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PMID:Enforced expression of Bcl-XS induces differentiation and sensitizes chronic myelogenous leukemia-blast crisis K562 cells to 1-beta-D-arabinofuranosylcytosine-mediated differentiation and apoptosis. 895 29

The molecular mechanisms responsible for progression of chronic myelogenous leukemia (CML) to blast crisis have not been well defined. Blast crisis may be partially related to inactivation of tumor suppressor genes/such as p53 or retinoblastoma (Rb) gene. There is evidence for an association of blast cell phenotypes in CML with alterations of these genes: a strong association of myeloid phenotypes with abnormalities of the p53 gene and a weaker association of lymphoid phenotypes with abnormalities of the Rb system. We found a marked decrease in Rb gene product and rearrangements of the p53 gene simultaneously in two cases of biphenotypic blast crisis of CML (myeloid and B-lymphoid). These results support the association of blast cell phenotypes with alterations in tumor suppressor genes in CML blast crisis.
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PMID:Biphenotypic blast crisis of chronic myelogenous leukemia: abnormalities of p53 and retinoblastoma genes. 925 Aug 29

The cyclin-dependent kinase inhibitors known as p15, p16, p18 and p19 have been suggested as candidates for tumor suppressor genes. The main genetic alterations are deletions (bi- or monoallelic) or 5' CpG island methylation of p15 and p16; very few cases or cell lines had p18 or p19 deletions or hypermethylation. Hypermethylation and homozygous deletions of tumor suppressor genes establish a new paradigm of inactivation by lack of expression, in contrast to the previously identified tumor suppressors which are predominantly inactivated by point mutations followed by loss of the wild-type allele. Here, the literature data on alterations of this gene family in more than 4700 primary cases of leukemia or lymphoma and some 320 continuous leukemia-lymphoma cell lines are summarized. Among hematopoietic malignancies, the highest frequencies of p15del and p16del were seen in acute lymphoblastic leukemia (ALL) (>30%) with striking rates in T-ALL (>50%), but also high rates in B cell precursor (BCP)-ALL (>20%); the rates of deletions in chronic lymphoid leukemia (CLL), multiple myeloma, acute and chronic myeloid leukemia (AML and CML), and myelodysplastic syndromes (MDS) were rather low, only some B cell and T cell lymphomas showed increased frequencies. Results are quite different with regard to the second mode of inactivation, hypermethylation of the promoter region. Here, p15 is most often inactivated, at particularly high frequencies in the disorders lacking any p15/p16 deletions: 40-80% p15met in AML, MDS and multiple myeloma. Also p15met rates in BCP- and T-ALL cases were high (c. 40%). There is controversy concerning the prognostic impact of p15 and p16 aberrations with some studies describing a significant correlation between inactivation of these genes and poor prognosis, while most others did not detect any prognostic relevance, at least in pediatric ALL; there may be a worse prognosis for adults with B or T cell lymphomas. Despite the small number of cases studied, paired sequential analyses suggested that disease progression is associated with loss of p15/p16 activity in a certain percentage of adult patients. p15del/p16del and p15met/p16met were also detected in the large panel of leukemia-lymphoma cell lines studied. In general, the results in cell lines reproduce the data seen in primary cells with the important difference that the rates of p15/p16 inactivation are clearly higher in the cultured cells compared with the freshly explanted cells. Retrovirus- or electroporation-mediated ectopic gene transfer of p16 wild-type into p16-deficient cell lines led to growth inhibition, arrest in G1 (without apoptosis) and occasionally to differentiation, suggesting that the malignant phenotype of p16-/- cell lines can, at least partially, be reversed by restoring p16 gene expression. A striking inverse correlation between the absence of p16 (due to deletion) and presence of wild-type retinoblastoma gene was observed in cell lines confirming a common growth suppressor pathway; no comparable relationship of p16 inactivation with p53 was detected. Paired analysis of cell lines and corresponding primary cell material showed that in all instances tested both populations carried the same gene configuration of p15 and p16. Thus, p15del or p16del did not occur during establishment of the cell lines or during prolonged culture. It is likely that p15 or p16 deletions already acquired in vivo provide a dramatic growth advantage for the immortalization process in vitro, thus increasing the success rate for cell line establishment which is commonly extremely difficult. In conclusion, the present review suggests an involvement of the p15 and p16 tumor suppressor genes in leukemo- and lymphomagenesis. Future studies will determine their exact role in the development and progression of hematopoietic neoplasms. These genes may represent interesting targets for new therapeutic strategies.
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PMID:Review of alterations of the cyclin-dependent kinase inhibitor INK4 family genes p15, p16, p18 and p19 in human leukemia-lymphoma cells. 963 10

Cyclin A is a cell cycle regulatory protein that functions in mitotic and S phase control in mammalian cells. However, in contrast to other G1 phase regulatory proteins, such as cyclin D, retinoblastoma protein and p16INK4A, cyclin A seems not to be commonly involved in tumorigenesis. Recently, a second human cyclin A--cyclin A1--has been identified. In contrast to cyclin A which is expressed throughout embryonic development and in adult tissue, the expression of cyclin A1 has been reported to be restricted to embryonic and germ line cells. We have confirmed the absence of cyclin A1 mRNA from normal peripheral blood leukocytes of seven healthy donors by single step reverse transcriptase-polymerase chain reaction (RT-PCR). Furthermore, we have examined the expression of cyclin A1 mRNA in 173 peripheral blood samples of 162 patients with various hematological malignancies. Cyclin A1 mRNA was detectable in 11 of 11 patients with acute myeloid leukemia, three of three patients with acute biphenotypic leukemia, eight of eight patients with myelodysplastic syndrome, 59 of 69 patients with chronic myelogenous leukemia (CML) at diagnosis, 13 of 15 patients with CML in blastic transformation, 10 of 18 patients with chronic lymphocytic leukemia, two of nine patients with essential thrombocythemia, and only two of 10 patients with acute lymphoblastic leukemia (ALL) with both cyclin A1 RT-PCR positive ALL leukemias being undifferentiated relapses. In addition, cyclin A1 mRNA was found in one of six leukapheresis products, harvested from individuals without hematological disorders. Taken together, cyclin A1 is expressed in the majority of myeloid and undifferentiated hematological malignancies as well as in normal hematopoietic progenitor cells. We conclude that cyclin A1, a protein potentially involved in G1/S phase progression of immature cells, might be necessary for proliferation of early hematopoietic progenitor cells and their leukemic counterparts being blocked at that stage of differentiation.
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PMID:Cyclin A1 is predominantly expressed in hematological malignancies with myeloid differentiation. 963 17

Therapeutic strategies for leukemia are directed to induction of differentiation and apoptosis as well as growth inhibition. One of the key antileukemic agents, 1-beta-D-arabinofuranosylcytosine (ara C), is clinically applied according to these therapeutic aims. However, the molecular effects of 0.1 microg/ml of ara C, a concentration that corresponds to the serum level in leukemic patients on a conventional dose of ara C, have not been well disclosed. Here, we addressed these issues using K562 cells which derived from a blastic crisis of chronic myeloid leukemia. DNA synthesis of treated cells was suppressed from 1-6 h. But, it recovered at 12 h and no further inhibition was observed. The number of cells was not decreased but DNA fragmentation was observed at 72 h. The number of erythroid-differentiated cells also increased to 30% at 72 h. Along with treatment, no marked alteration of mRNAs for cell cycle-regulating genes was found and the retinoblastoma gene product remained hyperphosphorylated throughout treatment. The expression of mRNAs for apoptosis-regulating genes also remained unchanged, except for slight down-regulation of Bax. c-myc protein was not found later than 48 h, and Max mRNA was downregulated. c-jun was immediately induced, followed by the fluctuated expression level along with treatment. These findings suggest that the 0.1 microg/ml ara C changed the proliferation, differentiation and death of K562 cells in a biphasic manner. In the early phase, DNA synthesis was inhibited without altering the expression of cell cycle regulating-genes. In the latter phase, cell death and erythroid- differentiation occurred in accordance with the down-regulation of c-myc.
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PMID:Biological effects of a relatively low concentration of 1-beta-D-arabinofuranosylcytosine in K562 cells: alterations of the cell cycle, erythroid-differentiation, and apoptosis. 978 59


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