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Query: UNIPROT:P06889 (Mol)
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The ubiquitin-mediated proteolytic system has been implicated in the turnover of a number of intracellular proteins. In the present study, we investigated the novelty and potential role of bryostatin 1, a macrocyclic lactone isolated from the marine bryozoan, Bugula neritina, in inducing the ubiquitin-mediated proteolysis of the oncoprotein Bcl-2. Immunoprecipitation and immunoblotting analyses revealed that Bcl-2 is ubiquitinated following exposure of the acute lymphoblastic leukemia (ALL) cell line Reh to 1 nM bryostatin 1. Bcl-2 protein rapidly decreases to 50% of that recorded in the control after 24 h of bryostatin 1 treatment. In the subsequent 24 h, Bcl-2 protein again rapidly decreases to 6% of its pre-bryostatin 1 level at which time a plateau is reached and maintained for another 72 h. Furthermore, ubiquitin-Bcl-2 conjugates are detected in untreated as well as bryostatin 1 treated cells, indicating that ubiquitin-dependent proteolysis plays a role in the normal turnover of Bcl-2. However, ubiquitin-Bcl-2 conjugates increase in a time-dependent manner following bryostatin 1 treatment. Lactacystin, which inhibits the proteinase activities of the proteasome, inhibited the bryostatin 1-induced decrease of Bcl-2 protein. The effect of bryostatin 1 on the proteolytic efficiency of the 26S proteasome in Reh cell extracts was also investigated and shown to increase following 1 h of bryostatin 1 treatment. Proteolytic activity reached its highest point by 3 h, and subsequently returned to control levels by 12 h, post-bryostatin 1 treatment. In addition, bryostatin 1 treatment of the Reh cell line decreased expression of bcl-2 mRNA within 3 h. However, bcl-2 mRNA expression returned after 24 h. We speculate that this decrease in mRNA together with increased 26S proteolytic activity accounts for the initial rapid decrease recorded in Bcl-2 protein. These findings indicate that bryostatin 1 treatment of Reh ALL cells decreases Bcl-2 expression through two processes: a) enhanced Bcl-2 protein degradation through the activation of the ubiquitin-proteasome pathway and b) decreased bcl-2 mRNA expression.
Int J Mol Med 2000 Feb
PMID:Bryostatin 1 induces ubiquitination and proteasome degradation of Bcl-2 in the human acute lymphoblastic leukemia cell line, Reh. 1063 96

Cytogenetic changes are of pivotal prognostic significance in patients with de novo acute lymphoblastic leukemia (ALL). However, in some cases leukemic blasts can harbor gene lesions on a submicroscopic level without evidence of a corresponding abnormality by conventional cytogenetic studies. This can result in failure to recognize chromosomal abnormalities and inappropriate evaluation with respect to therapy assignments. To study the discrepancy in the detection of deletions of the short arm of chromosome 9 and deletions of tumor suppressor genes p15/p16/p14 on chromosome 9p21, we analyzed bone marrow samples from 92 patients with ALL both by cytogenetic analysis and by Southern blot. In 41 patients (45%), we found deletions of p15/p16/p14, which were homozygous in 27 and hemizygous in 14. Cytogenetic analysis demonstrated abnormalities of the short arm of chromosome 9 in the form of 9p- or del(9p21-22) in only 5 of the 41 patients (12%). Only 2 of 51 patients without gene deletions as detected by Southern blot revealed a 9p- abnormality, which was found only in a subpopulation of the cells. We demonstrate that deletions of the p15/p16/p14 genes on chromosome 9p21 are more frequent than indicated by cytogenetic analysis. Molecular techniques in addition to cytogenetic studies are necessary to detect otherwise-unrecognized genetic lesions of the short arm of chromosome 9.
Cytokines Cell Mol Ther 1999 Sep
PMID:The incidence of chromosome 9p21 abnormalities and deletions of tumor suppressor genes p15(INK4b)/p16(INK4a)/p14(ARF) in patients with acute lymphoblastic leukemia. 1064 74

Previously, a specific angiogenesis inhibitor, angiostatin, discovered in urine and serum of tumor-bearing mice, was reported to potently block tumor growth and metastasis in animal models. Detection of angiostatin and its precursor proteins in urine from cancer patients has not been reported. Now, we report the development of an antibody-based analysis system that allows us to detect angiostatin and plasminogen/plasmin (Pgn/plasmin) in the urine of cancer patients. The detection system is a combination of a novel lysine-ELISA assay and Western immunoblot analysis using a specific antibody to human angiostatin and Pgn/plasmin. High levels of Pgn/plasmin were detected in the urine from various cancer patients, whereas healthy individuals showed relatively low levels of urine Pgn/plasmin. Of interest, angiostatin is detectable in urine samples of patients with various cancers, including acute lymphoblastic leukemia, suggesting that angiogenesis may play an important role in the development and progression of leukemia. Our data for the first time show that angiostatin and Pgn/plasmin are present at relatively high levels in the urine of human cancer patients. Detection of urine angiostatin in cancer patients helps us not only to understand the role of this angiogenesis inhibitor in cancer development and progression but also allows us to develop tools of cancer diagnosis and prognosis. Thus angiostatin has both therapeutic and diagnostic implications in cancer disease.
Int J Mol Med 2000 May
PMID:Elevated levels of urine angiostatin and plasminogen/plasmin in cancer patients. 1076 60

The chromosomal translocation t(12;21) (p12;q22) which results in the TEL-AML1 fusion gene is the most frequent genetic rearrangement in childhood B-lineage acute lymphoblastic leukemia (ALL). The rearrangement in this locus, however, is only rarely observed by routine karyotypic analysis. We established a nested-reverse transcriptase-polymerase chain reaction (nested-RT-PCR) technique for the detection of the TEL-AML1 transcript, and used this to investigate the incidence of the rearrangement, and to characterize the disease present in TEL-AML1-positive B-lineage ALL patients. The TEL-AML1 fusion transcript was detected in nine of fourteen patients. These patients were relatively homogeneous in that they were young and had low presenting leukocyte counts, both features of which are associated with a favorable prognosis. Furthermore, we could detect the TEL-AML1 transcript in the peripheral blood of t(12;21)-positive patients and we used this to assess minimal residual disease (MRD) in patients during chemotherapy. The data demonstrate that nested-RT-PCR is a suitable tool for diagnosing t(12;21)-positive ALL, that these patients constitute a clinically distinct subgroup of ALL patients, and that the method could also be used to monitor MRD in these patients.
Mol Cells 2000 Feb 29
PMID:Molecular detection of TEL-AML1 transcripts as a diagnostic tool and for monitoring of minimal residual disease in B-lineage childhood acute lymphoblastic leukemia. 1077 53

The human AF9 gene at 9p22 is one of the most common fusion partner genes with the MLL gene at 11q23, resulting in the t(9;11)(p22;q23). The MLL-AF9 fusion gene is associated with de novo acute myelo-genous leukemia (AML), rarely with acute lymphocytic leukemia (ALL) and with therapy related leukemia (t-AML). The AF9 gene is >100 kb and two patient breakpoint cluster regions (BCRs) have been identified; BCR1 is within intron 4, previously called site A, whereas BCR2 or site B spans introns 7 and 8. Patient breakpoint locations were determined previously by RT-PCR and by genomic DNA cloning. In this study, we defined the exon-intron boundaries and identified several different structural elements in AF9 including a co-localizing in vivo DNA topo II cleavage site and an in vitro DNase I hypersensitive (DNase 1 HS) site in intron 7 in BCR2. Reversibility experiments demonstrated a religation of the topo II cleavage sites. The location of the in vivo topo II cleavage site was confirmed in vitro using a topo II cleavage assay. In addition, two scaffold associated regions (SARs) are located centromeric to the topo II and DNase I HS cleavage sites and border both patient breakpoint regions: SAR1 is located in intron 4, whereas SAR2 encompasses parts of exons 5-7. This study demonstrates that the patient breakpoint regions of AF9 share the same structural elements as the MLL BCR. We describe a DNA breakage and repair model for non-homologous recombination between MLL and its partner genes, particularly AF9.
Hum Mol Genet 2000 Jul 01
PMID:DNA structural properties of AF9 are similar to MLL and could act as recombination hot spots resulting in MLL/AF9 translocations and leukemogenesis. 1086 Dec 94

The oncogenic transcription factor E2a-Pbx1 is expressed in some cases of acute lymphoblastic leukemia as a result of chromosomal translocation 1;19. The early observation that E2a-Pbx1 incorporates transcriptional activation domains from E2a and a DNA-binding homeodomain from Pbx1 inspired a model in which E2a-Pbx1 promotes leukemogenic transformation of lymphoid progenitor cells through transcriptional induction of target genes defined by the Pbx1 portion of the molecule. However, the subsequent demonstration that the only known DNA-binding module on the molecule, the Pbx1 homeodomain, is dispensable for the induction of lymphoblastic lymphoma in transgenic mice called into question the contribution made by the Pbx1 portion. In this study, we have used a domain swap approach coupled with a fibroblast-based focus formation assay to evaluate further the requirement for PBX1-encoded peptide elements in growth deregulation by E2a-Pbx1. No impairment of focus formation was observed when the entire Pbx1 portion was replaced with DNA-binding/dimerization domains derived from yeast transcription factor GAL4 or GCN4. Furthermore, replacement of Pbx1 with tandem FKBP domains that mediate homodimerization in the presence of a synthetic ligand led to striking growth deregulation exclusively in the presence of the dimerizing agent. N-terminal elements encoded by E2A, including the AD1 transcriptional activation domain, were required for dimerization-induced focus formation. We conclude that transcriptional target genes defined by heterologous C-terminal DNA-binding modules are not required in growth deregulation by E2a fusion proteins. We speculate that interactions between N-terminal E2a elements and undefined proteins that could function as components of a transcriptional coactivator complex may be more important.
Mol Cell Biol 2000 Aug
PMID:Role for homodimerization in growth deregulation by E2a fusion proteins. 1091 62

Numerical and structural chromosomal abnormalities occur in up to 90% of cases of childhood acute lymphoblastic leukemia (ALL). Two-thirds of these abnormalities are recurrent. The most common abnormalities are pseudodiploidy and t(1;19), occurring 40 and 5-6% of the time. Hyperdiploidy has the best prognosis, with an 80-90% 5-year survival. The 4;11 translocation has the worst prognosis, with a 10-35% 5-year survival. We report a patient with infant acute lymphoblastic leukemia and nonrecurrent rearrangements of chromosomes 10 and 11. Structural rearrangements between chromosomes 10 and 11 have been observed in 0.5% of all cases of childhood ALL with cytogenetic abnormalities. The identification of the apparently unique structural abnormalities was achieved using fluorescent in situ hybridization (FISH) with chromosome 10- and chromosome 11-specific painting probes as an adjunct to conventional cytogenetics. As is often the case, suboptimal preparations often preclude unequivocal identification of complex rearrangements by conventional banding techniques. The cytogenetic diagnosis of our patient was established as 46,XY, der(10)-t(10;11)(p15;q14)t(10;11)(q25;p11), der(11)t(10;11)(p15;q14)t(10;11)-(q25;p11). The benefits of FISH serve to increase the resolution of detection for chromosomal abnormalities and the understanding of the pathogenic mechanisms of childhood ALL.
Exp Mol Pathol 2000 Oct
PMID:Cytogenetic study of a patient with infant acute lymphoblastic leukemia using GTG-banding and chromosome painting. 1100 63

Notch receptors participate in a conserved signaling pathway that controls the development of diverse tissues and cell types, including lymphoid cells. Signaling is normally initiated through one or more ligand-mediated proteolytic cleavages that permit nuclear translocation of the intracellular portion of the Notch receptor (ICN), which then binds and activates transcription factors of the Su(H)/CBF1 family. Several mammalian Notch receptors are oncogenic when constitutively active, including Notch1, a gene initially identified based on its involvement in a (7;9) chromosomal translocation found in sporadic T-cell lymphoblastic leukemias and lymphomas (T-ALL). To investigate which portions of ICN1 contribute to transformation, we performed a structure-transformation analysis using a robust murine bone marrow reconstitution assay. Both the ankyrin repeat and C-terminal transactivation domains were required for T-cell leukemogenesis, whereas the N-terminal RAM domain and a C-terminal domain that includes a PEST sequence were nonessential. Induction of T-ALL correlated with the transactivation activity of each Notch1 polypeptide when fused to the DNA-binding domain of GAL4, with the exception of polypeptides deleted of the ankyrin repeats, which lacked transforming activity while retaining strong transactivation activity. Transforming polypeptides also demonstrated moderate to strong activation of the Su(H)/CBF1-sensitive HES-1 promoter, while polypeptides with weak or absent activity on this promoter failed to cause leukemia. These experiments define a minimal transforming region for Notch1 in T-cell progenitors and suggest that leukemogenic signaling involves recruitment of transcriptional coactivators to ICN1 nuclear complexes.
Mol Cell Biol 2000 Oct
PMID:Essential roles for ankyrin repeat and transactivation domains in induction of T-cell leukemia by notch1. 1100 47

A translocation resulting in a fusion of ETV6 (TEL) gene at 12p13 and CBFA2 (AML1) gene at 21q22 is variably reported in 16-36% of cases of childhood acute lymphoblastic leukemia (ALL). This t(12;21)(p13;q22) is not detectable by conventional cytogenetic methods and was reported to be associated with B-cell precursor ALL with presumed favorable prognosis. We have examined 18 cases of well characterized childhood B-cell precursor ALL with cytogenetic, immunophenotypic, and clinical data for the presence of the t(12;21) using fluorescence in situ hybridization (FISH). Fourteen of the 18 cases (78%) were positive for fusion ETV6/CBFA2. One of seven adult ALL patients was positive (12% of cells positive in this 21 year old patient). By contrast, no evidence of t(12;21) by FISH was noted in two childhood T-ALL cases and 10 normal bone marrow samples. Twelve of the 14 positive childhood cases had CD13 and/or CD33 expression (myeloid markers) while only one of the four negative cases was CD13 and CD33 positive. Eight of 12 cases positive for t(12;21), and with conventional cytogenetic data, had structural and/or numerical chromosome abnormalities other than the detected t(12;21). One case had relapse with gradual increase in percentage of cells positive for t(12;21) and development of an isochromosome 21 carrying the fusion signals. The data reveal a strong association of t(12;21) with B-cell precursor ALL, especially with myeloid marker expression.
Diagn Mol Pathol 2000 Dec
PMID:ETV6/CBFA2 fusions in childhood B-cell precursor acute lymphoblastic leukemia with myeloid markers. 1112 41

A multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) assay for both major forms of BCR-ABL was compared with fluorescence in situ hybridization (FISH), karyotyping, and Southern blotting for disease monitoring in 37 follow-up bone marrow samples from 32 patients with Ph1-positive leukemia. Of these 37 samples, 33 were from patients with chronic myeloid leukemia (CML) (26 post allogeneic bone marrow transplantation [AlloBMT] and seven during interferon-alpha therapy) and 4 from Ph1-positive acute lymphoblastic leukemia (ALL) patients (1 post AlloBMT and 3 post high dose chemotherapy). For the 27 samples studied after AlloBMT (26 CML and 1 Ph1-positive ALL) the time after transplantation ranged from 1 to 107 months (median 47.5 months). In 8 (22%) of the 37 samples there were discrepant results among methods. The discrepancy rates relative to other techniques were: karyotyping 17% (5 of 29), Southern blotting 18% (6 of 33), multiplex RT-PCR 8% (3 of 37), and FISH 8% (3 of 37). Therefore, the relative accuracy of each method for disease monitoring in Ph1-positive leukemia was: 83% (24 of 29) for karyotyping, 82% (27 of 33) for Southern blotting, 92% (34 of 37) for FISH, and 92% (34 of 37) for multiplex RT-PCR. This multiplex RT-PCR assay appears equivalent to FISH in terms of accuracy, simplicity, and turnaround time and both are superior to Southern blot and conventional cytogenetics in the laboratory monitoring of Ph1-positive leukemias.
Diagn Mol Pathol 2000 Dec
PMID:Comparison of a multiplex reverse transcriptase-polymerase chain reaction for BCR-ABL to fluorescence in situ hybridization, Southern blotting, and conventional cytogenetics in the monitoring of patients with Ph1-positive leukemias. 1112 44


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