Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Blast cells obtained from 104 children with untreated acute lymphoblastic leukaemia were analysed for the expression of P-glycoprotein (P-170) and glutathione S-transfer pi (GST-pi) using immunohistochemistry. Expression of P-170 was detected in 36 of 104 patients (35%) and increased GST-pi was seen in 52 patients (50%). Coexpression of both resistance proteins was observed in 22 leukaemias (21%), whereas no evidence of the resistance markers was found in 38 cases (37%). In patients with P-170-positive leukaemic cells, a significantly lower probability of remaining in first continuous complete remission (CCR) was observed when compared with patients with P-170-negative tumours (P < 0.05). However, only a trend for a more frequent expression of P-170 was found in the leukaemic cells of patients who experienced relapses (P = 0.099). Overexpression of GST-pi was correlated with a higher relapse rate (P = 0.001) and a lower probability of remaining in first CCR (P = 0.01). Expression of P-170 and GST-pi was independent of sex, FAB type, immunological subtype and initial blast cell count. The multivariate analysis indicated that only the expression of P-170 is an unfavourable prognostic factor for children with acute lymphoblastic leukaemia in addition to the prognostic clinical factors.
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PMID:P-glycoprotein and glutathione S-transferase pi in childhood acute lymphoblastic leukaemia. 798 Oct 66

CD30 is a member of the tumor necrosis factor receptor superfamily, which is expressed on some activated lymphocytes, virus-infected cells and transformed lymphocytes. To facilitate our understanding of biological functions and functional domains, we isolated rat cDNA clones encoding the rat homolog of human CD30 from a cDNA library of a rat T-cell line, TARL-2. The nucleotide sequence of the cDNA showed 73% homology with that of human CD30. The deduced rat CD30 protein consisted of 493 amino acids with an M(r) of 59 160 and contained a single transmembrane domain. It lacked the second repeat of the cysteine-rich motif in the extracellular domain found in human CD30. The amino acid sequence showed 51.8 and 61.2% identity with the cysteine-rich and the cytoplasmic domains, respectively. In the cytoplasmic domain, however, the amino acid sequence was highly conserved in about 100 residues near the C-terminus showing 77.7% identity, whereas the rest of the cytoplasmic domain showed 45.2% identity. This conservation suggests the functional importance of this region. Comparison with the recently reported mouse CD30 revealed 83.7% conservation of the amino acid sequence and a common structure of the extracellular domain which lacks the second cysteine-rich motif. Northern blots revealed a 3.4-kb mRNA in the PHA-activated spleen cells and human T-cell leukemia virus type 1 (HTLV-1)-infected rat T-cell lines, whereas smaller transcripts of 2.3 kb were found in the lung. A rabbit polyclonal antibody raised against GST-fusion protein of the cytoplasmic domain detected bands with an apparent M(r) of 80 kDa and 100- 110 kDa expressed in TARL-2 and spleen cells. Transient overexpression of rat CD30 in TARL-2 cells activated HIV LTR in a NF-kappa B site-dependent manner, indicating that CD30 signals activate NF-kappa B. The chromosomal location of the gene was identified by fluorescence in situ hybridisation at 5q36.2, and appeared to correspond to human 1p36, where human CD30 has been mapped. The identification and characterization of the rat counterpart of human CD30 will facilitate studies of the biological function of this molecule.
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PMID:Cloning and characterization of a cDNA for rat CD30 homolog and chromosomal assignment of the genomic gene. 898 82

BCR-ABL is a chimeric oncoprotein that exhibits deregulated tyrosine kinase activity and is implicated in the pathogenesis of Philadelphia chromosome (Ph1)-positive leukemia. We have previously shown SH2-containing phosphotyrosine phosphatase SHP-2 forms stable complexes with BCR-ABL and Grb2 in BCR-ABL-transformed cells (Tauchi, T., Feng, G. S., Shen, R., Song, H. Y., Donner, D., Pawson, T., and Broxmeyer, H. E. (1994) J. Biol. Chem. 269, 15381-15387). To elucidate the structural requirement of BCR-ABL for the interactions with SH2-containing signaling molecules, we examined a series of BCR-ABL mutants which include the Grb2 binding site-deleted BCR-ABL (1-63 BCR/ABL), the tetramerization domain-deleted BCR-ABL (64-509 BCR/ABL), and the SH2 domain-deleted BCR-ABL (BCR/ABL deltaSH2). These BCR-ABL mutants were previously shown to reduce the transforming activity in fibroblasts. We found that the tetramerization domain-deleted BCR-ABL did not induce the tyrosine phosphorylation of SHP-2 and the interactions of BCR-ABL, SHP-2, and Grb2. In vitro kinase assays have also shown that the tetramerization domain-deleted BCR-ABL mutant did not phosphorylate GST-SHP-2 in vitro. SHP-2 was co-immunoprecipitated with phosphatidylinositol 3-kinase in BCR/ABL p210-transformed cells; however, this interaction was not observed in the tetramerization domain-deleted BCR-ABL mutant. Therefore the tetramerization domain of BCR-ABL is essential for interactions of these downstream molecules.
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PMID:A coiled-coil tetramerization domain of BCR-ABL is essential for the interactions of SH2-containing signal transduction molecules. 899 49

The Philadelphia chromosome translocation generates a chimeric oncogene, BCR/ABL, which causes chronic myelogenous leukemia (CML). In primary leukemic neutrophils from patients with CML, the major tyrosine phosphorylated protein is CRKL, an SH2-SH3-SH3 adapter protein which has an overall homology of 60% to CRK, the human homologue of the v-crk oncogene. In cell lines transformed by BCR/ABL, CRKL was tyrosine phosphorylated, while CRK was not. We looked for changes in CRK- and CRKL-binding proteins in Ba/F3 hematopoietic cell lines which were transformed by BCR/ABL. Anti-CRK II or anti-CRKL immunoprecipitates were probed by far Western blotting with CRK II- or CRKL-GST fusion proteins to display CRK- and CRKL-coprecipitating proteins. There was a striking qualitative difference in the proteins coprecipitating with CRKL and CRK II. In untransformed cells, three major proteins coprecipitated with CRKL, identified as C3G, SOS and c-ABL. Each of these proteins was found to interact with the CRKL-SH3 domains, but not the SH2 domain. After BCR/ABL transformation, the CRKL SH3-domain binding proteins did not change, with the exception that BCR/ABL now coprecipitated with CRKL. Compared to CRKL, very few proteins coprecipitated with CRK II in untransformed, quiescent cells. After BCR/ABL transformation, both the CRKL- and CRK-SH2 domains bound to a new complex of proteins of approximate molecular weight 105-120 kDa. The major protein in this complex was identified as p120CBL. Thus, in these hematopoietic cell lines, CRKL is involved to a greater extent than CRK II in normal signaling pathways that involve c-ABL, C3G and SOS. In BCR/ABL-transformed cells, CRKL but not CRK II, appears to form complexes which potentially link BCR/ABL, c-ABL, C3G, and SOS to the protooncoprotein, p120CBL.
Leukemia 1997 Mar
PMID:The BCR/ABL oncogene alters interaction of the adapter proteins CRKL and CRK with cellular proteins. 906 77

Grb2/Ash and Shc are the adapter proteins that link tyrosine-kinase receptors to Ras and make tyrosine-kinase functionally associated with receptors and Ras in fibroblasts and hematopoietic cells. Grb2/Ash and Shc have the SH3, SH2, or phosphotyrosine binding domains. These domains bind to proteins containing proline-rich regions or tyrosine-phosphorylated proteins and contribute to the association of Grb2/Ash and Shc with other signaling molecules. However, there could remain unidentified signaling molecules that physically and functionally interact with these adapter proteins and have biologically important roles in the signaling pathways. By using the GST fusion protein including the full length of Grb2/Ash, we have found that c-Cbl and an unidentified 135-kD protein (pp135) are associated with Grb2/Ash. We have also found that they become tyrosine-phosphorylated by treatment of a human leukemia cell line, UT-7, with granulocyte-macrophage colony-stimulating factor (GM-CSF). We have purified the pp135 by using GST-Grb2/Ash affinity column and have isolated the full-length complementary DNA (cDNA) encoding the pp135 using a cDNA probe, which was obtained by the degenerate polymerase chain reaction based on a peptide sequence of the purified pp135. The cloned cDNA has 3,958 nucleotides that contain a single long open reading frame of 3,567 nucleotides, encoding a 1,189 amino acid protein with a predicted molecular weight of approximately 133 kD. The deduced amino acid sequence reveals that pp135 is a protein that has one SH2, one SH3, and one proline-rich domain. The pp135, which contains two motifs conserved among the inositol polyphosphate-5-phosphatase proteins, was shown to have the inositol polyphosphate-5-phosphatase activity. The pp135 was revealed to associate constitutively with Grb2/Ash and inducibly with Shc using UT-7 cells stimulated with GM-CSF. In the cell lines derived from human chronic myelogenous leukemia, pp135 was constitutively tyrosine-phosphorylated and associated with Shc and Bcr-Abl. These facts suggest that pp135 is a signaling molecule that has a unique enzymatic activity and should play an important role in the signaling pathway triggered by GM-CSF and in the transformation of hematopoietic cells caused by Bcr-Abl.
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PMID:Purification and molecular cloning of SH2- and SH3-containing inositol polyphosphate-5-phosphatase, which is involved in the signaling pathway of granulocyte-macrophage colony-stimulating factor, erythropoietin, and Bcr-Abl. 910 92

BCR-ABL is a chimeric oncoprotein that exhibits deregulated tyrosine kinase activity and is implicated in the pathogenesis of Philadelphia chromosome (ph1)-positive leukemia. We have previously shown SH2-containing phosphotyrosine phosphatase SHP-2 forms stable complexes with BCR-ABL and Grb2 in BCR-ABL transformed cells (T., Tauchi, et al. J. Biol. Chem. 269, 15381, 1994). To elucidate the structural requirement of BCR-ABL for the interactions with SH2-containing signaling molecules, we examined a series of BCR-ABL mutants which include the Grb2 binding site deleted BCR-ABL (1-63 BCR/ABL), the tetramerization domain deleted BCR-ABL (64-509 BCR/ABL), and the SH2 domain deleted BCR-ABL (BCR/ABL delta SH2). These BCR-ABL mutants were previously shown to reduce the transforming activity in fibroblasts. We found that the tetramerization domain deleted BCR-ABL did not induce the tyrosine phosphorylation of SHP-2 and the interactions of BCR-ABL, SHP-2, and Grb2. In vitro kinase assays have also shown the tetramerization domain deleted BCR-ABL mutant did not phosphorylate GST-SHP-2 in vitro. SHP-2 was co-immunoprecipitated with P13Kinase in BCR/ABL p210 transformed cells, however this interaction was not observed in the tetramerization domain deleted BCR-ABL mutant. Therefore the tetramerization domain of BCR-ABL is essential for interactions of these downstream molecules.
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PMID:A coiled-coil tetramerization domain of BCR-ABL is essential for the interactions of SH2-containing signal transduction molecules. 918 66

The Tax protein of the Human T-cell Leukemia Virus (HTLV) activates the expression of viral mRNA through a three 21 bp repeat enhancer located within the HTLV-1 LTR. Since Tax does not bind to the 21 bp DNA repeats directly, it has been speculated that Tax interacts with cellular protein(s) which mediate binding to the enhancer. We employed the yeast two hybrid system to identify host proteins that are potentially relevant to Tax transactivation. We identified a Tax binding protein encoded from a cDNA expression library derived from peripheral blood lymphocytes. The corresponding cDNA has sequence identity with a known transcription factor, activating factor-4 (ATF-4). ATF-4 also binds to GST-Tax fusion protein in vitro. Tax mutants that did not transactivate the HTLV-1 LTR also failed to bind ATF-4. The critical domain for Tax binding resides in a 85 amino acid stretch in the C-terminus of ATF-4, which contains the basic domain and leucine zipper. We further demonstrated that both full length and N-terminal truncated ATF-4 were able to enhance Tax transactivation. Thus, ATF-4 may act as an adapter between Tax and the TRE (Tax responsive element), and play an important role in Tax-mediated transactivation.
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PMID:Functional interaction of the HTLV-1 transactivator Tax with activating transcription factor-4 (ATF4). 919 Aug 94

Grb2/Ash is composed of one SH2 and two SH3 domains and functions as an adapter linking tyrosine-kinase receptors and Ras in fibroblasts. The SH2 domain binds to tyrosine-phosphorylated proteins and the SH3 domain binds to protein containing proline-rich regions. However, the mechanisms of signal transduction through Grb2/Ash in hematopoietic cells are still unclear. By means of the binding experiments using the GST fusion protein including the full length Grb2/Ash, we have found that Shc and unidentified 130-kDa and 135-kDa proteins are associated with Grb2/Ash and that they are tyrosine-phosphorylated by treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (EPO) in a human leukemia cell line UT-7. We have purified the 130-kDa protein (pp 130) using GST-GRB2/Ash affinity column. The amino-acid sequence analysis showed that the pp130 was identical to the human c-cbl proto-oncogene product (c-Cbl). c-Cbl constitutively binds to the SH3 domain of Grb2/Ash both in vitro and in vivo but not to the SH2 domain of Grb2/Ash. Moreover, c-Cbl (pp 130) becomes tyrosine-phosphorylated rapidly and transiently depending on GM-CSF and EPO stimulation. However, we could not find the homologous regions with guanine nucleotide exchange factors or GTPase-activating proteins in the c-cbl gene. These findings strongly suggest that c-Cbl is implicated in the signal transduction of GM-CSF and EPO in hematopoietic cells, and c-Cbl and Grb2/Ash might also transduce a signal that is different from the signal leading to Ras regulation. Recently, we have shown that the proto-oncogene vav product (Vav) is also tyrosine-phosphorylated by treatment with GM-CSF and EPO and is constitutively associated with the SH3 domain of Grb2/Ash in UT-7. Another guanine nucleotide exchange factor Sos is also associated with Grb2/Ash in UT-7. It has been reported that Vav has guanine nucleotide exchange activity and activates Ras in vitro and in vivo. These data suggest that tyrosine kinases, the adapter Grb2/Ash, and the guanine nucleotide exchange factor Vav and Sos are members of a signaling pathway leading to Ras activation in hematopoietic cells.
Leukemia 1997 Apr
PMID:The signal transduction through Grb2/Ash in hematopoietic cells. 920 6

The expression of the resistance-related proteins P-glycoprotein 170 (P-170), glutathione-S-transferase pi (GST-pi), topoisomerase II (Topo II), thymidylate synthase (TS) and metallothionein (MT) was investigated in leukemic cells of 19 children with newly diagnosed acute nonlymphoblastic leukemia. P-170 was expressed in 84%, GST-pi in 37%, TS in 47%, MT in 68%, and Topo II was downregulated in 37% of the cases investigated. No resistance factors were found in two patients, one positive factor was found in two patients, three factors in three patients, four factors in 7 patients, and all resistance factors investigated were present in one patient. Patients who developed a relapse expressed more than two resistance mechanisms significantly more often than patients who remained in remission (p = 0.005). The probability of continuous first remission was significantly lower where more than two resistance mechanisms were expressed. The results indicate that the higher the number of resistance-related proteins in childhood ANLL the poorer the prognosis of the patients.
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PMID:Multiple resistance mechanisms in acute nonlymphoblastic leukemia (ANLL). 961 93

Hypermethylation in cancer often occurs in CpG islands that span the promoter regions of tumor suppressor genes. However, it is not clear if hypermethylation is limited to single target genes or if multiple genes are simultaneously methylated. To understand the extent of aberrant de novo methylation, we have analyzed the methylation pattern of a number of tumor-related genes in leukemia from the same cohort of patients. We used bisulfite genomic sequencing to characterize the methylation pattern of the CpG islands associated with the calcitonin, estrogen receptor, E-cadherin, p15, p16, Rb, GST-Pi, and HIC1 genes in the bone marrow from 9 normal and 20 patients with acute myeloid leukaemia (AML). All of the normal control samples were essentially unmethylated for each of the eight tumor-related genes studied. In contrast, 19 of 20 (95%) of the AML patients had an abnormal methylation pattern in at least one gene, and 15 of 20 (75%) had abnormal methylation patterns in two or more of the target genes. We conclude that there is a general deregulation of CpG island methylation in leukemia and that hypermethylation is not limited to single genes, but a number of genes are methylated concurrently. Moreover, the subset of genes that are commonly methylated in leukemia appear to be cancer type specific.
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PMID:Concurrent DNA hypermethylation of multiple genes in acute myeloid leukemia. 1044 89


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