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PubMed1990

Regulatory elements controlling pituitary-specific expression of the human prolactin gene.

We have performed transfection and DNase I footprinting experiments to investigate pituitary-specific expression of the human prolactin (hPRL) gene. When fused to the chloramphenicol acetyltransferase (CAT) reporter gene, 5,000 base pairs of the 5'-flanking sequences of the hPRL gene were able to drive high cat gene expression in prolactin-expressing GH3B6 cells specifically. Deletion analysis indicated that this pituitary-specific expression was controlled by three main positive regulatory regions. The first was located just upstream from the TATA box between coordinates -40 and -250 (proximal region). We have previously shown that three motifs of this region bind the pituitary-specific Pit-1 factor. The second positive region was located in the vicinity of coordinates -1300 to -1750 (distal region). DNase I footprinting assays revealed that eight DNA motifs of this distal region bound protein Pit-1 and that two other motifs were recognized by ubiquitous factors, one of which seems to belong to the AP-1 (jun) family. The third positive region was located further upstream, between -3500 and -5000 (superdistal region). This region appears to enhance transcription only in the presence of the distal region.

Animals↗
PubMed2004

Midkine promoter can mediate transcriptional activation of a fused suicide gene in a broader range of human breast cancer compared with c-erbB-2 promoter.

We examined the expression level of the midkine (MK) and c-erbB-2 genes in both tumorous and matched nontumorous specimens from 18 patients with breast cancer. Expression of the MK and c-erbB-2 genes in nontumorous regions was relatively low, and the expression levels of both genes were not markedly different among the nontumorous samples. In contrast, the expression of the MK and c-erbB-2 genes in tumorous specimens was upregulated in 18 and 6 specimens, respectively. Regulatory regions of the MK gene were able to activate a reporter gene to a similar degree as those of the c-erbB-2 gene in the human breast cancer cell lines tested. Transfection of breast cancer cells with either the MK promoter- or the c-erbB-2 promoter-linked herpes simplex virus thymidine kinase gene increased their sensitivity to the prodrug ganciclovir. These data showed that the MK promoter activated a therapeutic gene in a wider range of human breast cancer than the c-erbB-2 promoter and suggest that MK promoter-mediated gene therapy is potentially more favorable in clinical settings.

Adult↗
PubMed2002

Haemophilus influenzae and Vibrio cholerae genes for mutH are able to fully complement a mutH defect in Escherichia coli.

MutH, MutL and MutS are essential components of the mismatch repair system in Escherichia coli. Whereas mutS and mutL genes are found in most organisms, the mutH gene is limited to some proteobacteria. We show here that the cloned genes of MutH from Vibrio cholerae and Haemophilus influenzae are able to fully complement a mutH defect in E. coli. Moreover, the purified proteins were shown to be dam methylation sensitive endonucleases, which can be activated by the E. coli MutL protein. These results allow to narrow down regions that are important for the interaction of MutH with MutL.

Adenosine Triphosphatases↗
PubMed2002

[Signal transduction inhibitor--STI571--a new treatment for chronic myeloid leukemia (CML), which opens a new targeted approach to cancer therapy].

Chronic myeloid leukemia (CML), in most of the cases, is the molecular consequence of the t(9,22) translocation, resulting in the Philadelphia (Ph) chromosome and the creation of the fusion gene BCR-ABL. The fusion gene is translated to the protooncogen BCR-ABL, a constitutively activated tyrosine kinase that is linked to the malignant transformation. Thus, this tyrosine kinase became an attractive target for drug design. The development of the novel investigational drug STI 571 is based on its potent and selective ability to inhibit this fusion tyrosine kinase. In preclinical studies, STI 571 selectively inhibited the growth of CML cells that carry the Ph chromosome. In this review we discuss the drug development and design, its mechanism of action, the preclinical studies and the results of phase I and II clinical trials.

Antineoplastic Agents↗
PubMed1990

New type of Bcr/Abl junction in Philadelphia chromosome-positive chronic myelogenous leukemia.

A new and rare type of Bcr/Abl junction between exon C3 of the 3' portion of the Bcr gene and Abl exon 2 has been identified in the leukemic cells of two Ph1-positive chronic myelogenous leukemia patients in chronic phase. This is the fourth type of Bcr/Abl junction so far identified in Ph1-positive hematologic malignancies and is a consequence of an unusual breakpoint position on chromosome 22 that falls approximately 20 kb downstream of the major breakpoint cluster region (bcr) of the Bcr gene. The new hybrid mRNA is 540 base pairs (bp) longer than that expressed by the K562 cell line and could codify for a Bcr/Abl protein carrying 180 additional aminoacids with respect to the larger P210 protein so far identified. The hematologic phenotype expressed by the two patients carrying this unusual type of Bcr/Abl rearrangement does not significantly differ from that commonly seen in chronic myelogenous leukemia.

Amino Acid Sequence↗
PubMed1993

Influence of M-BCR breakpoint sites on the duration of chronic phase in 100 patients with chronic myelocytic leukemia.

Rearrangements of the bcr (M-BCR) gene were studied in 100 patients with chronic myelocytic leukemia (CML). To determine the significance of a chimeric gene expression in the progression of CML, we analyzed 43 patients for bcr-ABL chimeric mRNA expression. Both DNA and RNA analyses revealed a possible influence of breakpoint sites in the bcr region on the duration of the chronic phase. Patients with the breakpoint located at about the 1-kb region between BamHI and HindIII in bcr exon 3 (region C2) had a significantly shorter chronic phase (31 months) (p = 0.028) than patients in whom the breakpoint was located in other regions. When the bcr locus was divided into 5' and 3' regions as for the BamHI cleavage site located near the 5' region of bcr exon 3, the chronic phase duration in patients with the 5' site (HindIII-BamHI) and 3' site (BamHI-EcoRI site) was 75 and 38 months, respectively. However, the difference was not statistically significant (p = 0.128). These results suggest that only the breakpoint site at C2 on the bcr locus, rather than breakpoint sites in other regions, has an important role in the progression of CML.

Chromosome Mapping↗
PubMed1988

Heterogeneity of genomic fusion of BCR and ABL in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Philadelphia chromosome-positive acute lymphoblastic leukemia occurs in two molecular forms, those with and those without rearrangement of the breakpoint cluster region on chromosome 22. The molecular abnormality in the former group is similar to that found in chronic myelogenous leukemia. To characterize the abnormality in the breakpoint cluster region-unrearranged form, we have mapped a 9;22 translocation from the Philadelphia chromosome-positive acute lymphoblastic leukemia cell line SUP-B13 by using pulsed-field gel electrophoresis and have cloned the DNA at the translocation junctions. We demonstrate a BCR-ABL fusion gene on the Philadelphia chromosome. The breakpoint on chromosome 9 is within ABL between exons Ia and II, and the breakpoint on chromosome 22 is approximately equal to 50 kilobases upstream of a breakpoint cluster region in an intron of the BCR gene. This upstream BCR breakpoint leads to inclusion of fewer BCR sequences in the fusion gene, compared with the BCR-ABL fusion gene of chronic myelogenous leukemia. Consequently, the associated mRNA and protein are smaller. The exons from ABL are the same. Analysis of leukemic cells from four other patients with breakpoint cluster region-unrearranged Philadelphia chromosome-positive acute lymphoblastic leukemia revealed a rearrangement on chromosome 22 close to the breakpoint in SUP-B13 in only one patient. These data indicate that breakpoints do not cluster tightly in this region but are scattered, possibly in a large intron. Given the large size of BCR and the heterogeneity in breakpoint location, detection of BCR rearrangement by standard Southern blot analysis is difficult. Pulsed-field gel electrophoresis should allow detection at the DNA level in every patient and thus will permit clinical correlation of the breakpoint location with prognosis.

Chromosome Mapping↗
PubMed2002

[Cytokine-induced killer cells induce apoptosis of K562 cells expressed bcr-abl].

In order to investigate whether cytokine-induced killer (CIK) cells can induce apoptosis of bcr-abl(+) K562 cells, apoptosis of K562 cells and CEM cells induced by CIK cells, etoposide or camptothecin was detected with flow cytometry DNA assay. RT-PCR showed that K562 cells expressed the bcr-abl fusion gene, K 562 cells, K562 cells/etoposide or K562 cells/camptothecin groups showed no sub-G(1) peak. K562 cells/CIK cells group showed sub-G(1) peak (38.1%). CEM cells showed no sub-G(1) peak. CEM cells/camptothecin or CEM cells/etoposide groups showed sub-G(1) peak (23.5% or 32.3% respectively). CEM cells/CIK cells group showed sub-G(1) peak (45.4%). Etoposide or camptothecin did not induce apoptosis of K562 cells. CIK cells induce apoptosis of K562 cells. Bcr-abl fusion gene prevented apoptosis induced by etoposide or camptothecin, but did not prevent apoptosis induced by CIK cells. This property may support the observed adoptive immunologic effect of allogeneic bone marrow transplantation and donor lymphocyte transfusions of CML case relapsing after allogeneic bone marrow transplantation.

Antineoplastic Agents, Phytogenic↗
PubMed1996

Functional conservation of yeast mtTFB despite extensive sequence divergence.

Transcription of mtDNA in the yeast S. cerevisiae depends on recognition of a consensus nonanucleotide promoter sequence by mtRNA polymerase acting with a 40-kDa dissociable factor known as mtTFB or Mtflp. mtTFB has been cloned and characterized in S. cerevisiae, but has not been studied in similar detail in any other organism. Although it is known that mitochondrial transcription in the dairy yeast, Kluyveromyces lactis, initiates within the same consensus promoter sequence used in S. cerevisiae, no previous studies have focused on the proteins involved in transcription initiation in K. lactis. In this article, we report the cloning of mtTFB from K. lactis and from a yeast more closely related to S. cerevisiae, S. kluyveri. Both novel mtTFB genes were able to substitute for the MTF1 gene in S. cerevisiae. Both proteins purified following expression in E. coli were able to support specific transcription initiation in vitro with the S. cerevisiae mtRNA polymerase. The S. kluyveri and K. lactis mtTFB proteins share only 56% and 40% identity with S. cerevisiae mtTFB, respectively. Alignments of the three mtTFB sequences did not reveal any regions larger than 30 amino acids with greater than 60% amino acid identity. In particular, regions proposed to show sequence similarity to bacterial sigma factors were not more highly conserved than other regions of the mtTFB proteins. All three yeast mtTFB genes lack conventional amino-terminal mitochondrial targeting sequences, suggesting that all three proteins may be imported into mitochondria by the same unusual mechanism reported for S. cerevisiae mtTFB.

Amino Acid Sequence↗
PubMedDate not supplied

Persistence of transcriptionally silent BCR-ABL rearrangements in chronic myeloid leukemia patients in sustained complete cytogenetic remission.

Persistence of BCR-ABL rearrangements was demonstrated by D-FISH technique in chronic myeloid leukemia (CML) patients in complete cytogenetic response (CCR) after allogeneic bone marrow transplantation (BMT) or interferon-alpha therapy (IFN-alpha). Samples from bone marrow aspirate or peripheral blood or both were analyzed by conventional cytogenetics, Southern blot, fluorescent interphase in situ hybridization (FISH), and quantitative reverse transcription polymerase chain reaction (Q-RT-PCR). In all patients, FISH detected 1% to 12% nuclei with a BCR-ABL fusion gene, whereas Q-RT-PCR were negative or weakly positive. Based on these results, we hypothesize that the BCR-ABL genomic rearrangement remains unexpressed in a small percentage of cells whatever the treatment (IFN-alpha or BMT), and this in spite of the negativity of the RT-PCR-based classical molecular remission criterion. These data corroborate those obtained by other investigators and point to the need for follow-up of CML patients in CCR over an extensive period, at the DNA level to evaluate the residual disease and at the RNA level (Q-RT-PCR) to estimate the risk of relapse and guide the therapeutic decision. Experimental models suggesting the persistence of positive BCR-ABL cells are discussed and tentative explanations of tumor "dormancy" are proposed.

Chromosomes, Human, Pair 22↗
PubMed1998

The BCR gene recombines preferentially with Alu elements in complex BCR-ABL translocations of chronic myeloid leukaemia.

Chronic myeloid leukaemia (CML) develops when two genes, BCR on chromosome 22 and ABL on chromosome 9, recombine to form a hybrid BCR-ABL gene with leukaemogenic properties. The mechanism which underlies this recombination is unknown, but additional chromosome sites may be involved to form complex BCR-ABL rearrangements. The majority of breakpoints in BCR occur within a 5 kb major breakpoint cluster region, M-Bcr. Here, we show that the 3' part of M-Bcr recombined within, or immediately adjacent to, Alu elements at the additional sites in all five complex BCR-ABL rearrangements that have been examined so far. This is a new finding which suggests that Alu sequences have an affinity for the BCR-ABL recombination process in complex rearrangements, and provides additional evidence for the association of these elements with somatic rearrangements which cause human leukaemia. We further show that sequence motifs similar to IgH switch pentamers and consensus binding sites of the lymphoid-associated Translin protein are present on one or more participating strands at 3'M-Bcr recombination sites. Motifs similar to Translin-binding sites were also identified within the Alu consensus. Expressed sequences mapped close to the breakpoint sites on other chromosomes in three of the five cases examined.

Base Sequence↗
PubMed1995

[Cytogenetics and molecular studies confirm the histopathologic diagnosis of chronic myeloproliferative diseases].

The histopathological classification of chronic myeloproliferative disorders can be supported by applying cytogenetics and molecular genetics to the analysis of bone marrow or blood cells, as demonstrated in 253 cases evaluated. The Philadelphia translocation (9;22) is the most important genetic parameter, being specific for chronic myeloid leukemia. Conventional methods for the detection of the t(9;22) are karyotyping and Southern blot analysis of the bcr gene. The newly established technique of fluorescence in situ hybridization (FISH) allows visualization of bcr-abl fusion even in non dividing cells. Molecular cytogenetics for t(9;22) yield results that are rapid and reliable as well as easily quantifiable.

Biopsy↗
PubMed1999

Clinical implications of fluorescence in situ hybridization analysis in 13 chronic myeloid leukemia cases: Ph-negative and variant Ph-positive.

Thirteen chronic myeloid leukemia (CML) patients, 10 with variant Philadelphia (Ph) translocations and 3 Ph negative cases, were analyzed by fluorescence in situ hybridization (FISH) with the use of BCR and ABL cosmid probes and a chromosome 22 painting probe. In the variant Ph translocations, the BCR-ABL fusion gene was located on the Ph chromosome; in 1 CML Ph-negative patient, the BCR-ABL fusion gene was located on the Ph chromosome; and, in 2 patients, it was located on chromosome 9. The chromosome 22 painting probe was detected on the third-party chromosome of the variant translocation, and in none of the variant translocations was there any detectable signal on chromosome 9. In CML patients with clonal evolution of a simple Ph, a signal of the chromosome 22 painting probe was detected on the der(9) of the Ph translocation. It was concluded that the variant Ph translocations evolved simultaneously in a three-way rearrangement. The clinical parameters of the 13 patients were similar to those of a large group of CML patients with a simple Ph translocation. It is suggested that, to determine the prognosis of CML patients with a complex karyotype, FISH analysis with a chromosome 22 painting probe be performed.

Adult↗
PubMed2005

A versatile promoter for the expression of proteins in glandular and non-glandular trichomes from a variety of plants.

A DNA regulatory fragment was isolated from the promoter region of the OASA1 gene, encoding the cytosolic O-acetylserine(thiol)lyase enzyme that is highly expressed in Arabidopsis thaliana trichomes. This DNA fragment has been named an ATP fragment and comprises 1435 bp of the genomic region upstream of the OASA1 gene and 375 bp of the transcriptional initiation start site containing the first intron of the gene. The ATP fragment, fused to the green fluorescent protein (GFP) and beta-glucuronidase (GUS) reporter genes, is able to drive high-level gene expression in A. thaliana trichomes. Deletion analysis of the ATP fragment determined that the region from -266 to -66 contains regulatory elements required for trichome expression. In addition, the region from +112 to +375, comprising the first intronic region of the gene, is also essential for trichome gene expression. Expression of the full-length ATP fragment in tobacco and peppermint shows that this fragment is also able to drive expression in glandular trichomes and suggests additional biotechnological applications for this promoter.

Arabidopsis↗
PubMed2002

Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571).

The inadvertent fusion of the bcr gene with the abl gene results in a constitutively active tyrosine kinase (Bcr-Abl) that transforms cells and causes chronic myelogenous leukemia. Small molecule inhibitors of Bcr-Abl that bind to the kinase domain can be used to treat chronic myelogenous leukemia. We report crystal structures of the kinase domain of Abl in complex with two such inhibitors, imatinib (also known as STI-571 and Gleevec) and PD173955 (Parke-Davis). Both compounds bind to the canonical ATP-binding site of the kinase domain, but they do so in different ways. As shown previously in a crystal structure of Abl bound to a smaller variant of STI-571, STI-571 captures a specific inactive conformation of the activation loop of Abl in which the loop mimics bound peptide substrate. In contrast, PD173955 binds to a conformation of Abl in which the activation loop resembles that of an active kinase. The structure suggests that PD173955 would be insensitive to whether the conformation of the activation loop corresponds to active kinases or to that seen in the STI-571 complex. In vitro kinase assays confirm that this is the case and indicate that PD173955 is at least 10-fold more inhibitory than STI-571. The structures suggest that PD173955 achieves its greater potency over STI-571 by being able to target multiple forms of Abl (active or inactive), whereas STI-571 requires a specific inactive conformation of Abl.

Amino Acid Sequence↗
PubMed2003

Evidence from a leukemia model for maintenance of vascular endothelium by bone-marrow-derived endothelial cells.

The maintenance of tissues of virtually all organs depends on a sufficient blood supply. During embryogenesis, primitive blood vessels are formed de novo by the aggregation of angioblasts, a process that is termed vasculogenesis. In postnatal life, the development of new blood vessels is restricted to the female reproductive tract (during the ovulatory cycle) and to sites of wound healing, and occurs through a process called angiogenesis, i.e. the sprouting of new vessels from the preexisting vasculature. However, neovascularization can also occur under pathological conditions, e.g. tumor cells can "switch on" angiogenesis. New blood vessels bring in nutrients and proteins, so the tumor mass can expand. In fact, neovascularization appears to be one of the crucial steps in the transition of a tumor from a small cluster of malignant cells to a visible macroscopic tumor capable of spreading to other organs via the vasculature throughout the body. The association of tumor growth with the development of a vascular network was recognized nearly a century ago. Using a leukemia model, chronic myelogenous leukemia (CML), we were able to provide evidence for the existence of a hemangioblastic progenitor cell in the bone marrow of adult humans. Using the pathognomonic BCR-ABL-fusion gene as a genetic marker present in virtually all bone marrow derived cells of patients with CML, we were able to show that endothelial cells belong to the malignant cell clone, since they also contain the BCR-ABL-fusion gene. Our data suggest that CML arises from a hemangioblastic progenitor cell, the progeny of which are malignant blood cells and genotypically clonal endothelial cells. Thus, we provide substantial evidence that indeed a hemangioblast exists in the bone marrow of human adults. In addition, our data imply that normal as well as genotypically malignant bone-marrow-derived endothelial cells can contribute to maintenance angiogenesis in the vascular endothelium, a condition that is consistent with postnatal vasculogenesis. These findings were recently confirmed by other groups and should help in elucidating the pathophysiology of malignant and nonmalignant disorders. The integration of bone-marrow-derived endothelial cells into the vascular endothelium has implications for the development of vascular targeting strategies (e.g., gene therapy) for vascular diseases, inflammatory disorders, and cancer. The characterization of the hemangioblast at a clonal level as well as the translation of these findings into a clinically applicable concept for the delivery of therapeutic genes to malignant tumors is currently in progress in our laboratory.

Animals↗
PubMed2006

Surface immunoglobulin positive lymphoblastic leukemia in adults; a genetic spectrum.

Precursor B-lymphoblastic leukemia is typically surface immunoglobulin (sIg) negative. Although rare cases of sIg+ precursor lymphoblastic leukemia are recognized, sIg+ leukemia often represent leukemic phase of Burkitt lymphoma or other non-Hodgkin lymphoma such as blastic mantle cell lymphoma. This study reports four adults, two women (56 and 58 years old) and two men (35 and 41 years old) with lymphoblastic leukemia that displayed lambda, surface immunoglobulin restriction (sIg+). The leukemic cells were all dim CD45 positive with side scatter light characteristic of blasts. Two cases were positive with the blasts associated with antigens TdT and CD34. Genetic abnormalities were detected in all cases and in three cases included abnormalities commonly present in precursor lymphoblastic leukemia. Translocation (1;19) (q23;p13) was present in the first case. Deletion of the 3' region of the mixed lineage leukemia (MLL) gene at chromosome 11q23 as well as t(14;18) were detected in the second case. In the 3rd case, a BCR-ABL fusion gene was detected as part of a complex abnormal karyotype. Translocation (1;19)(q23;p13) was present in one case. Deletion of the 3' region of the mixed lineage leukemia (MLL) gene at chromosome 11q23 as well as t(14;18) were detected in one case. BCR-ABL fusion gene was detected as part of a complex abnormal karyotype in one case. These cases illustrate that lymphoblastic leukemias occurring in adults exhibit a morphologic, immunophenotypic as well as a genetic spectrum and represent either non-Hodgkin lymphoma or precursor lymphoblastic leukemia. A multi-parameter approach including flow cytometric and genetic studies is crucial in separating these cases.

Adult↗
PubMed1998

Changes in oncogene expression implicated in evolution of chronic granulocytic leukemia from its chronic phase to acceleration.

Expression of nine oncogenes was investigated in cell samples from fifteen patients with Philadelphia chromosome (Ph)-positive chronic granulocytic leukemia (CGL) both at diagnosis and at the onset of accelerated phase (AP) of the disease. The bcr-abl fusion gene, the H-ras gene and the c-myb gene were universally expressed. In comparison with the chronic phase (CP) of the disease, an increase in the levels of bcr-abl-, c-myb- and H-ras-related transcripts was found in three, two and three AP samples, respectively. Elevation of the bcr-abl-related message was associated with duplication of the Ph chromosome and amplification of the bcr-abl fusion gene in one AP sample. No CP samples were positive for c-myc or c-sis expression. On the contrary, c-myc and c-sis were expressed in three and four AP samples, respectively. The presence of c-myc-related transcript was associated with trisomy 8 with or without amplification of the c-myc oncogene in leukemia cells of two patients with CGL in AP. No changes of oncogene expression were found in four AP samples. However, we observed deletions of chromosome 13 and 17 or i(17q) in three of them, suggesting that tumor suppressor gene alterations may also be responsible for the development of AP of CGL. Our data indicate that heterogeneous alterations in oncogenes and tumor suppressor genes accompany the evolution of CGL-CP to the AP of the disease.

Acute-Phase Reaction↗