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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The v-abl transforming protein P160v-abl and the P210c-abl gene product of the translocated c-abl gene in Philadelphia chromosome-positive chronic myelogenous leukemia cells have tyrosine-specific protein kinase activity. Under similar assay conditions the normal c-abl gene products, murine P150c-abl and human P145c-abl, lacked detectable kinase activity. Reaction conditions were modified to identify conditions which would permit the detection of c-abl tyrosine kinase activity. It was found that the Formalin-fixed Staphylococcus aureus formerly used for immunoprecipitation inhibits in vitro abl kinase activity. In addition, the sodium dodecyl sulfate and deoxycholate detergents formerly used in the cell lysis buffer were found to decrease recovered abl kinase activity. The discovery of assay conditions for c-abl kinase activity now makes it possible to compare P150c-abl and P145c-abl kinase activity with the altered abl proteins P160v-abl and P210c-abl. Although all of the abl proteins have in vitro tyrosine kinase activity, they differ in the way they utilize themselves as substrates in vitro. Comparison of in vitro and in vivo tyrosine phosphorylation sites of the abl proteins suggests that they function differently in vivo. The development of c-abl kinase assay conditions should be useful in elucidating c-abl function.
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PMID:Detection of c-abl tyrosine kinase activity in vitro permits direct comparison of normal and altered abl gene products. 387 12

The v-abl protein of Abelson murine leukemia virus is a tyrosine-specific kinase. Its normal cellular homolog, murine c-abl, does not possess detectable tyrosine kinase activity in vitro. Previously, we have detected tyrosine kinase activity in vitro for an altered c-abl gene product (c-abl P210) in the K562 human chronic myelogenous leukemia cell line. The expression of this variant c-abl gene product correlates with chromosomal translocation and amplification of the c-abl gene in K562 cells. Like v-abl, c-abl P210 is a fusion protein containing non-abl sequences near the amino terminus of c-abl. We compared the in vitro tyrosine kinase activity of c-abl P210 with that of wild-type murine v-abl. The remarkable similarities of these two proteins with respect to cis-acting autophosphorylation, trans-acting phosphorylation of exogenous substrates, and kinase inhibition, using site-directed abl-specific antisera, suggested that c-abl P210 could function similarly to v-abl in vivo. In addition, c-abl P210 possessed an associated serine kinase activity in immunoprecipitates. The serine kinase activity was not inhibited by site-directed, abl-specific antisera that inhibit the tyrosine kinase activity, suggesting that the serine kinase activity is not an intrinsic property of c-abl P210. Thus, the activation of the c-abl gene in a human leukemia cell line may have functional consequences analogous to activation of the c-abl gene in Abelson murine leukemia virus.
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PMID:Activation of the c-abl oncogene by viral transduction or chromosomal translocation generates altered c-abl proteins with similar in vitro kinase properties. 403 28

The transforming gene of the Abelson murine leukaemia virus, v-abl, contains two open reading frames (orf). The 5' orf encodes a tyrosine-specific protein kinase while the 3' orf has the capacity to code for an 18,000 Mr protein. However, no 3' orf product has yet been identified. Using probes capable of distinguishing between the 5' and 3' orfs of v-abl, we have examined the abl-related transcripts present in human haematopoietic cells and leukaemia-derived cell lines, including the chronic myeloid leukaemia-derived cell line K562. Our results indicate that transcripts of 6 kb, 7 kb and 8 kb (kilobase, 10(3) base-pairs) show strong homology to v-abl 5' protein kinase-encoding orf sequences, but are devoid of any sequences from the v-abl 3' orf. In addition, transcripts of 5 kb, 3 kb, 1.6 kb and 1.4 kb, reacting with both 5' orf and 3' orf probes, were observed. The latter species, with coding sequences from both the tyrosine kinase and the putative 18,000 Mr protein, must be transcribed from the human c-abl gene as this is apparently the only human gene containing sequences homologous to the v-abl 3' orf. The 6 kb, 7 kb and 8 kb transcripts may arise either from the c-abl gene through differential splicing, or from one of the three other regions of the human genome with sequences homologous to the 5' orf of v-abl. Examination of genomic DNA from the K562 cell line revealed that the amplification of abl-related sequences, which is presumed to result in the elevated levels of the 8 kb transcript found in this cell line, does not involve sequences homologous to the v-abl 3' orf. This lends credence to the idea that the 8 kb transcript may derive from an abl-related gene other than c-abl. While the significance of the 3' orf of v-abl remains unknown, the data presented strongly suggest the existence of at least two distinct abl-related proteins in human haematopoietic cells.
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PMID:Two families of abl-related transcripts in human haematopoietic cells differing in their homology to v-abl. 608 79

The pattern of protein kinase activity in leukemic cells from patients with chronic myelocytic leukemia, acute myeloblastic leukemia, acute monocytic leukemia, chronic lymphocytic leukemia, and acute lymphoblastic leukemia was studied and compared with normal peripheral blood granulocytes and lymphocytes. Our data showed that: (a) histone kinase activity was slightly lower in leukemic cells than in normal cells, whereas casein kinase activity was 2- to 3-fold higher in leukemic cells; (b) cyclic adenosine 3':5'-monophosphate stimulated 1.4- to 1.6-fold histone kinase activity of both normal and leukemic cells, whereas it did not stimulate casein kinase activity; (c) the ratio of histone kinase activities to casein kinase activities correlated directly with the maturation of the white blood cells; and (d) histone and casein kinase activities of extracts from normal and leukemic cells behaved similarly on chromatography on phosphocellulose and casein/Sepharose 4B. These results suggest that the increase in casein kinase activity is not due to the appearance of a new type of casein kinase but to an increase of the casein kinases 1 and 2 present in normal cells.
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PMID:Cyclic adenosine 3':5'-monophosphate-dependent and -independent protein kinases in human leukemic cells. 629 19

Human hairy cell leukemia (HCL) cells in culture showed a marked increase in both [1-14C]acetate and [14C]choline incorporation into phosphatidylcholine (PC) when treated with a 10 nM concentration of 12-O-tetradecanoylphorbol 13-acetate (TPA) for 3 h. Dramatic morphological changes occurred and synthesis of most phospholipids was stimulated. However, the most dramatic increase was seen in the [14C]acetate labeling of both long- and short-chain fatty acid-containing sphingomyelins (from 200-425% of control levels), sphingomyelin being especially enriched in HCL cells. Negligible incorporation of [14C]choline into sphingomyelin was observed and phospholipase inhibitor (U10029A) studies indicated that PC was the major source of sphingomyelin choline. These changes were most clearly seen by autoradiography of two-dimensional thin-layer chromatography plates. Chronic myelogenous leukemia (CML) blasts, which did not respond morphologically to TPA, showed no increased phospholipid synthesis under the same conditions and increases in sphingomyelin synthesis were modest. Other non-TPA-responding leukemic cells were similarly refractive. However, one out of four acute monomyelocytic leukemic (AMMoL) cells studied responded morphologically in a manner identical to HCL cells and exhibited the same dramatic increase in sphingomyelin synthesis. Data are presented which suggest that TPA may also stimulate PC phospholipase C activity in addition to activating the calcium-dependent protein kinase by mimicking diacylglycerol.
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PMID:Phorbol ester tumor promoters specifically stimulate choline phospholipid metabolism in human leukemic cells. 659 31

BCR is an interesting signaling protein, whose cellular function is currently unknown. Its biochemical properties include serine kinase activity, SH2-binding activity, and a GTPase-activating activity. The SH2-binding activity is particularly interesting because it may link BCR to signaling pathways involving SH2-containing molecules. Since tyrosine phosphorylation of BCR has been detected in CML-derived cell lines and since tyrosine-phosphorylated BCR shows increased affinity toward certain SH2 domains, it seems particularly important to further characterize this activity. This chapter described a simple purification scheme for partial purification of BCR, which can be used to assess in vitro kinase and SH2-binding activities.
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PMID:Characterization of breakpoint cluster region kinase and SH2-binding activities. 747 25

This review attempts to provide current information on the role played by the p53 gene in normal and leukemic hematopoiesis with particular emphasis on chronic myeloid leukemia. On the basis of the currently available data we can argue that p53 acts as a negative regulator of proliferation of myeloid mature cells and CD34+ progenitors, and its action is mediated through changes in cell cycle kinetics, mainly before the S phase. The p53-dependent pathway is also regulated by several proteins, including p16, p21, p27 (cyclin-dependent kinase [CDK] inhibitors), and a few oncogenes (bcl-2, bax, MDM-2). Although there is some information about the changes in the p53 gene seen in various types of leukemia, the functions and biological importance of these changes in the pathogenesis of leukemia are still largely elusive. During the past several years, accumulated evidence suggests that changes in the p53 gene are commonly associated with blast crisis of chronic myeloid leukemia (CML) but rarely with chronic phase, and they are represented by rearrangements, deletions and point mutations. As for most of the tumors, the majority of point mutations occur between exons 4 and 8 (hot regions). In patients with CML in blastic crisis the most frequent mechanism of p53 inactivation is complete deletion of one allele in association with a point mutation in the remaining allele.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of p53 in leukemogenesis of chronic myeloid leukemia. 754 4

The cyclin-dependent kinase inhibitors known as p15, p16 and p18 have been suggested as candidates for tumour suppressor genes. We examined these genes for their alterations in 46 myeloid leukaemias and 15 myeloid leukaemia cell lines. p16 mRNA expression was studied in 41 myeloid leukaemias. The p15 and p16 genes were either deleted or mutated in myeloid leukaemia lines at a high frequency [6/15 (40%) for p15; 8/15 (53%) for p16] but alterations in primary myeloid leukaemias are much less frequent [2/46 (4%) for p15; 3/46 (6%) for p16]. Alterations of p18 were not found in any of the samples. 13 primary myeloid leukaemia samples had negligible levels of p16 mRNA. In summary, the deletions of p15 and p16 genes identified in the myeloid leukaemia cell lines probably occurred during their in vitro immortalization. Alterations of the p16 or p15 gene only occurred in primary acute myeloid leukaemia samples that were of mixed myeloid/lymphoid lineage (CD19/CD20-positive acute myeloid leukaemia [AML], CD2/CD19-positive AML, and lymphoid blastic crisis of chronic myeloid leukaemia). Further studies are required to determine if the absence of mRNA expression results from inactivation of the p16 gene.
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PMID:Structural integrity of the cyclin-dependent kinase inhibitor genes, p15, p16 and p18 in myeloid leukaemias. 757 21

Treatment of acute promyelocytic leukemia (APL) blasts with cyclic adenosine monophosphate (cAMP) analogs, in combination with all-trans retinoic acid (ATRA), results in the upregulation of the expression of leukocyte alkaline phosphatase (LAP), a marker for the differentiation of the granulocyte. The synergistic interaction between the cyclic nucleotide analogs and the retinoid is not unique to APL cells, as it is observed also in the peripheral granulocytes of chronic myelogenous leukemia (CML) patients. The molecular mechanisms underlying LAP induction were studied in NB4, an immortalized APL cell line. Induction of LAP enzymatic activity is dependent on the time of exposure and on the concentrations of dibutyryl-cAMP or 8-bromo-cAMP and ATRA, two factors that influence the kinetics of appearance of detectable levels of the enzyme. Augmentation of LAP levels by ATRA and cAMP is the result of both transcriptional and early posttranscriptional events and requires de novo protein synthesis. LAP induction correlates with augmentation in the levels of the type I catalytic subunit of cAMP-dependent protein kinase transcript and with granulocytic differentiation. The transcriptional component of the process leading to increased LAP gene expression was reproduced in its main features by transient transfection experiments performed in COS-7 cells using the normal retinoic acid receptor type alpha (RAR-alpha) or the APL-specific aberrant form (PML-RAR) and the upstream promoter of the liver/bone/kidney (L/B/K)-type alkaline phosphatase gene. The promoter is upregulated by treatment with ATRA, and this upregulation is further increased by cAMP analogs.
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PMID:All-trans retinoic acid and cyclic adenosine monophosphate cooperate in the expression of leukocyte alkaline phosphatase in acute promyelocytic leukemia cells. 778 Jan 46

CML is an excellent target for development of selective treatment because of its highly consistent genetic abnormality t(9;22) and unique fusion gene product, p210bcr/abl, although it is not yet clear what form of specific therapy might be effective. Several components of p210bcr/abl are thought to be essential for its transforming activity: These include the constitutive tyrosine kinase activity of abl and the ability of the first exon for bcr both to specifically bind to abl's SH2 binding domain and possibly also to function as a novel type of serine kinase. Relatively little is yet known about what specific abnormalities in the regulatory pathways are caused by the altered tyrosine kinase activity of p210bcr/abl and other bcr/abl oncoproteins, but whatever its precise mode of action proves to be, p210bcr/abl presumably somehow changes the normal pattern of phosphorylation of key regulatory proteins in the signaling pathways so that the genes which normally direct the orderly sequence of proliferation and maturation of the myeloid progenitors are not properly regulated. The end results of this 'disregulation' are that there is asynchronous or discordant maturation; relative to comparable normal progenitors, a higher proportion of CML progenitors exhibit earlier cytoplasmic and delayed nuclear maturation. The leukemic progenitors do not proliferate more rapidly than comparable normal progenitors or have increased ultimate proliferative potential, but they go through one or more additional divisions during passage through the later maturation compartments and also live longer, resulting in overexpansion of the leukemic population. It is important to recognize the close linkage between maturation and proliferation in designing experiments to correlate the molecular and biological abnormalities and in seeking novel therapies to selectively affect the leukemic progenitors.
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PMID:Integration of molecular and biological abnormalities in quest for selective treatment of chronic myelogenous leukemia (CML). 812 37


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