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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 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

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

The Philadelphia chromosome translocation generates a chimeric oncogene, BCR/ABL, which causes chronic myelogenous leukemia (CML). In primary neutrophils from patients with CML, the major novel tyrosine-phosphorylated protein is CRKL, an SH2-SH3-SH3 linker protein which has an overall homology of 60% to CRK, the human homologue of the v-crk oncogene product. Anti-CRKL immunoprecipitates from CML cells, but not normal cells, were found to contain p210BCR/ABL and c-ABL. Several other phosphoproteins were also detected in anti-CRKL immunoprecipitates, one of which has been identified as paxillin, a 68-kDa focal adhesion protein which we have previously shown to be phosphorylated by p210BCR/ABL. Using GST-CRKL fusion proteins, the SH3 domains of CRKL were found to bind c-ABL and p210BCR/ABL, while the SH2 domain of CRKL bound to paxillin, suggesting that CRKL could physically link p210BCR/ABL to paxillin. Paxillin contains three tyrosines in Tyr-X-X-Pro (Y-X-X-P) motifs consistent with amino acid sequences predicted to be optimal for binding to the CRKL-SH2 domain (at positions Tyr-31, Tyr-118, and Tyr-181). Each of these tyrosine residues was mutated to a phenylalanine residue, and in vitro binding assays indicated that paxillin tyrosines at positions 31 and 118, but not 181, are likely to be involved in CRKL-SH2 binding. These results suggest that the p210BCR/ABL oncogene may be physically linked to the focal adhesion-associated protein paxillin in hematopoietic cells by CRKL. This interaction could contribute to the known adhesive defects of CML cells.
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PMID:CRKL links p210BCR/ABL with paxillin in chronic myelogenous leukemia cells. 749 40

The chimeric BCR/ABL protein is characteristic of Philadelphia (Ph)+ leukemia because it is the direct product of the Ph translocation and it has been shown to play a causal role in the genesis of leukemia. The BCR/ABL protein exhibits a deregulated tyrosine-kinase activity capable of phosphorylating different cellular substrates in vivo and in vitro. CRKL, an adaptor protein consisting of SH2 and SH3 domains in the absence of a catalytic domain, is one potential in vivo substrate of BCR/ABL. Previous experiments have shown that CRKL is phosphorylated on tyrosine in the chronic myelogenous leukemia (CML) cell line K562 and that CRKL is a substrate for ABL and for BCR/ABL in COS-1 cells. In the current study, we show that in peripheral blood cells a direct correlation exists between the presence of BCR/ABL and the phosphorylation status of CRKL. In Ph- peripheral blood cells, CRKL is present only in the nonphosphorylated form. In contrast, all BCR/ABL+ CML and acute lymphoblastic leukemia patient samples examined showed clear tyrosine-phosphorylation of CRKL. This result strongly suggests that CRKL is a biologically significant substrate for BCR/ABL and is likely to play a major role in the development of Ph+ leukemia.
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PMID:Tyrosine phosphorylation of CRKL in Philadelphia+ leukemia. 752 85

Chronic myelogenous leukemia (CML) is characterized by the presence of the Philadelphia (Ph) chromosome in clonally derived hematopoietic precursors and their progeny. The Ph chromosome arises from a translocation that deregulates the c-ABL protein tyrosine kinase, giving it transforming potential and increased kinase activity. We observed a unique 39-kD tyrosine phosphoprotein (pp39), previously reported in blastic CML cell lines, in neutrophils from 50 cases of chronic phase CML. This protein was prominently and constitutively tyrosine-phosphorylated in CML neutrophils and was not phosphorylated in normal neutrophils. Stimulation of normal neutrophils with cytokines and agonists did not induce tyrosine phosphorylation of proteins migrating in the region of pp39, and the phosphorylation state of pp39 in CML neutrophils was not affected by kinase inhibitors known to downregulate the ABL kinase. The pp39 was not phosphorylated in hematopoietic cells from healthy donors or from patients with Ph chromosome-negative myeloproliferative disorders. Using micro amino acid sequencing of purified preparations of pp39, we identified pp39 as CRKL protein, which is consistent with recent immunologic studies in the blastic K562 cell line. Immunoblotting with anti-CRKL antibodies showed the presence of CRKL protein in CML cells and cell lines as well as in antiphosphotyrosine immunoprecipitates from CML cells. Our results suggest that pp39 CRKL in CML neutrophils may be stably tyrosine-phosphorylated by the BCR/ABL kinase at an early stage of myeloid differentiation when the ABL kinase is active. CRK, CRKL, and other SH2 (SRC homology domain)/SH3-containing proteins function as adaptor molecules in nonreceptor tyrosine kinase signalling pathways. Although the CRKL protein is present in normal neutrophils, it is not tyrosine-phosphorylated, and the inability to induce such phosphorylation in normal neutrophils suggests a special role of this phosphoprotein in the pathogenesis of CML. Constitutive phosphorylation of CRKL is unique to CML, indicating that it may be a useful target for therapeutic intervention.
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PMID:Identification of CRKL as the constitutively phosphorylated 39-kD tyrosine phosphoprotein in chronic myelogenous leukemia cells. 752 58

BCR-ABL is a deregulated tyrosine kinase expressed in Philadelphia chromosome-positive human leukemias. Prolongation of hematopoietic cell survival by inhibition of apoptosis has been proposed to be an integral component of BCR-ABL-induced chronic myelogenous leukemia. BCR-ABL elicits transformation of both fibroblast and hematopoietic cells and blocks apoptosis following cytokine deprivation in various factor-dependent cells. To elucidate the mechanisms whereby BCR-ABL induces transformation and blocks apoptosis in hematopoietic cells, we examined the biological effects of expression of a series of BCR-ABL mutants. Single amino acid substitutions in the GRB2 binding site (Y177F), Src homology 2 domain (R552L), or an autophosphorylation site in the tyrosine kinase domain (Y793F) do not diminish the antiapoptotic and transforming properties of BCR-ABL in hematopoietic cells, although these mutations were previously shown to drastically reduce the transforming activity of BCR-ABL in fibroblasts. A BCR-ABL molecule containing all three mutations (Y177F/R552L/Y793F) exhibits a severe decrease in transforming and antiapoptotic activities compared with the wild-type BCR-ABL protein in 32D myeloid progenitor cells. Ras is activated, the SHC adapter protein is tyrosine phosphorylated and binds GRB2, and myc mRNA levels are increased following expression of all kinase active BCR-ABL proteins with the exception of the Y177F/R552L/Y793F BCR-ABL mutant in 32D cells. We propose that BCR-ABL uses multiple pathways to activate Ras in hematopoietic cells and that this activation is necessary for the transforming and antiapoptotic activities of BCR-ABL. However, Ras activation is not sufficient for BCR-ABL-mediated transformation. A BCR-ABL deletion mutant (delta 176-427) that activates Ras and blocks apoptosis but has severely impaired transforming ability in 32D cells has been identified. These data suggest that BCR-ABL requires additional signaling components to elicit tumorigenic growth which are distinct from those required to block apoptosis.
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PMID:Structural and signaling requirements for BCR-ABL-mediated transformation and inhibition of apoptosis. 756 5

The BCR/ABL oncogene causes chronic myelogenous leukemia (CML) in humans and induces growth factor independence of hematopoietic cell lines in tissue culture. p210BCR/ABL is localized at least in part to the cytoskeleton, and has been shown to interact directly with actin filaments through an actin binding domain located in the C-terminus of ABL. CML cells have reduced adhesion to some extracellular matrix components but the mechanism of this phenomenon is unknown. In this study we examined tyrosine phosphorylation of focal adhesion proteins in cells expressing p210BCR/ABL. An interleukin-3 (IL-3)-dependent cell line, 32Dc13, was transformed with a BCR/ABL cDNA, and the patterns of localization, expression, and tyrosine phosphorylation of focal adhesion proteins were compared among untransformed 32Dc13 cells with and without IL-3 stimulation and BCR/ABL-transformed 32Dc13 cells. Of the focal adhesion proteins examined, only paxillin exhibited tyrosine phosphorylation in response to IL-3; while in cells transformed by p210BCR/ABL, paxillin, vinculin, p125FAK, talin and tensin were constitutively tyrosine phosphorylated. IL-3 induced a transient association between paxillin and vinculin, while in BCR/ABL-transformed cells, several proteins coimmunoprecipitated with paxillin, including vinculin, p125FAK, talin and tensin. Pseudopodia enriched in focal adhesion proteins were transiently detected in 32Dc13 cells in response to IL-3, but constitutively detected in cells expressing p210BCR/ABL. p210BCR/ABL protein was also found concentrated in punctate structures adjacent to the cell membrane in myeloid cell lines, which often contained vinculin and paxillin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Increased tyrosine phosphorylation of focal adhesion proteins in myeloid cell lines expressing p210BCR/ABL. 756 75

Src-homology region 2 (SH2) domains, by binding to tyrosine-phosphorylated sequences, mediate specific protein-protein interactions important in diverse signal transduction pathways. Previous studies have shown that activated forms of the Abl tyrosine kinase, including P210BCR/ABL of human chronic myelogenous leukemia, require the SH2 domain for the transformation of fibroblasts. To determine whether SH2 is also required for Bcr/Abl to transform hematopoietic cells, we have studied two SH2 domain mutations in P210BCR/ABL: a point mutation in the conserved FLVRES motif (P210/R1033K), which interferes with phosphotyrosine-binding by SH2, and a complete deletion of SH2 (P210/delta SH2). Despite a negative effect on intrinsic Abl kinase activity, both P210 SH2 mutants were still able to transform the hematopoietic factor-dependent cell lines Ba/F3 and FDC-P1 to growth factor independence. Unexpectedly, both mutants showed greater transforming activity than wild-type P210 in a quantitative transformation assay, probably as a consequence of increased stability of the SH2 mutant proteins in vivo. Cells transformed by both P210 SH2 mutants were leukemogenic in synaptic mice and P210/r1053K mice exhibited a distinct disease phenotype, reminiscent of that induced by v-Abl. These results demonstrate that while the Abl SH2 domain is essential for BCR/ABL transformation of fibroblasts, it is dispensable for the transformation of hematopoietic factor-dependent cell lines.
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PMID:The SH2 domain of P210BCR/ABL is not required for the transformation of hematopoietic factor-dependent cells. 757 59

The BCR/ABL oncogenic tyrosine kinase is responsible for initiating and maintaining the leukemic phenotype of Philadelphia chromosome (Ph1)-positive cells. Phosphatidylinositol-3 (PI-3) kinase is known to interact with and be activated by receptor and nonreceptor tyrosine kinases. We investigated whether PI-3 kinase associates with and/or is regulated by BCR/ABL, whether this interaction is functionally significant for Ph1 cell proliferation, and, if so, whether inhibition of PI-3 kinase activity can be exploited to eliminate Ph1-positive cells from bone marrow. We show that the p85 alpha subunit of PI-3 kinase associates with BCR/ABL and that transient expression of BCR/ABL in fibroblasts and down-regulation of BCR/ABL expression using antisense oligodeoxynucleotides (ODNs) in Ph1 cells activates and inhibits, respectively, PI-3 kinase enzymatic activity. The use of specific ODNs or antisense constructs to downregulate p85 alpha expression showed a requirement for p85 alpha subunit in the proliferation of BCR/ABL-dependent cell lines and chronic myelogenous leukemia (CML) primary cells. Similarly, wortmannin, a specific inhibitor of the enzymatic activity of the p110 subunit of PI-3 kinase, inhibited growth of these cells. The growth of normal bone marrow and erythromyeloid, but not megakaryocyte, progenitors was inhibited by p85 alpha antisense [S]ODNs, but wortmannin, at the concentrations tested, did not affect normal hematopoiesis. The proliferation of two BCR/ABL- and growth factor-independent cell lines was not affected by downregulation of the expression of the p85 alpha subunit or inhibition of p110 enzymatic activity, confirming the specificity of the observed effects on Ph1 cells. Thus, PI-3 kinase is one of the downstream effectors of BCR/ABL tyrosine kinase in CML cells. Moreover, reverse transcriptase-polymerase chain reaction performed on single colonies to detect BCR-ABL transcripts showed that wortmannin was able to eliminate selectively CML-blast crisis cells from a mixture of normal bone marrow and Ph1 cells.
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PMID:Phosphatidylinositol-3 kinase activity is regulated by BCR/ABL and is required for the growth of Philadelphia chromosome-positive cells. 760 2

The c-kit proto-oncogene encodes a receptor tyrosine kinase that is considered to play important roles in hematopoiesis. The proto-oncogene c-kit product is expressed on various types of human cell lines derived from leukemic cells of erythroid, megakaryocytic and mast-cell lineages. Also, the c-kit product is detectable in blast cells in most cases of acute myeloblastic leukemia (AML) and in some cases of chronic myelogenous leukemia (CML) in blastic crisis (BC). By contrast, little or no expression of c-kit is observed in human leukemia cell lines of lymphoid lineage and in blast cells in acute lymphoblastic leukemia (ALL). Tyrosine phosphorylation and activation of the c-kit product with the ligand for c-kit (stem cell factor: SCF) results in proliferation of some human leukemia cell lines, such as M07E, and blast cells in a substantial fraction of AML cases. In addition, SCF appears to have an activity in inducing differentiation of certain types of leukemic cells. In some cases, further, the c-kit product is found to be activated in leukemic cells even before the stimulation with SCF. These results suggest that c-kit may be involved in excessive proliferation and aberrant differentiation of human leukemia cells.
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PMID:Expression, function and activation of the proto-oncogene c-kit product in human leukemia cells. 769 Jun 31


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