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PubMed2002

The molecular mechanism of chronic myelogenous leukemia and its therapeutic implications: studies in a murine model.

Chronic myelogenous leukemia (CML) is a malignant disease resulting from the neoplastic transformation of a hematopoietic stem cell. Generation of the BCR-ABL fusion gene plays an essential role in causing the vast majority of CML. Clinical and laboratory studies have indicated that development of CML involves both the effects of BCR-ABL within its correct target cells and interactions of BCR-ABL target cells with the rest of the in vivo environment, and that the progression of the disease to blast crisis involves multiple genetic alterations. An efficient mouse bone marrow transduction and transplantation model for CML has recently been developed. This review summarizes the analysis of the roles of functional domains and downstream signaling pathways of BCR-ABL, of altered cytokine production, of interferon signaling pathways and of oncogene cooperation in the pathogenesis of CML using this murine model. The in vivo studies of leukemogenesis will help to advance mechanism-based therapies for CML, as well as to understand fundamental rules of leukemogenesis and hematopoiesis.

Animals↗
PubMed1998

The novel core promoter element GAAC in the hgl5 gene of Entamoeba histolytica is able to direct a transcription start site independent of TATA or initiator regions.

Entamoeba histolytica, an enteric protozoa, is the third leading parasitic cause of death worldwide. Investigation of the transcriptional machinery of this eukaryotic pathogen has revealed an unusual core promoter structure that consists of nonconsensus TATA and initiator regions and a novel third conserved core promoter sequence, the GAAC element. Mutation of this region in the hgl5 promoter decreases reporter gene expression and alters the transcription start site. Using positional analysis of this element, we have now demonstrated that it is able to direct a new transcription start site, 2-7 bases downstream of itself, independent of TATA and Inr regions. The GAAC region was also shown to control the rate of transcription via nuclear run on analysis and an amebic nuclear protein was demonstrated to specifically interact with this sequence. This is the first description in the eukaryotic literature of a third conserved core promoter element, distinct from TATA or initiator regions, that is able to direct a transcription start site. We have formulated two models for the role of the GAAC region: (i) the GAAC-binding protein is a part of the TFIID complex and (ii) the GAAC-binding protein functions to "tether" TATA-binding protein to the TATA box.

Animals↗
PubMed1996

Deletion of exon b3 of the BCR gene in CML: easy breakpoint mapping by a two-round PCR.

We have performed the molecular analysis for the detection of the BCR-ABL and ABL-BCR fusion genes in 50 patients with myeloproliferative disorders. All patients diagnosed with CML (13 out of 50) were positive for the BCR-ABL hybrid. Six CML patients (46%) showed ABL-BCR amplifications of the Ib-BCR type. All rearrangements but one were concordant. The aberrant case presented a deletion of exon b3, in addition to the alternative Ib-BCR and Ia-BCR. Its possible origin and relevance are briefly discussed.

Exons↗
PubMed2006

Monitoring minimal residual disease and controlling drug resistance in chronic myeloid leukaemia patients in treatment with imatinib as a guide to clinical management.

Imatinib mesylate, binding to the inactive conformation of Bcr-Abl tyrosine kinase and suppressing the Ph chromosome positive clone, has revolutionized the treatment of chronic myeloid leukaemia (CML) patients. Given the high rates of clinical and cytogenetic remission achieved, the molecular monitoring of BCR-ABL transcript levels by RT-qPCR has become always more important to assess minimal residual disease. Recently, recommendations for harmonizing current methodologies for detecting and measuring BCR-ABL transcripts in CML patients have been suggested. Studies of imatinib-treated patients have determined that the BCR-ABL levels measured early in therapy may predict durable cytogenetic remission and in turn prolonged progression free-survival or acquisition of resistance. The major mechanism of imatinib resistance is clonal expansion of leukaemia cells with mutations in the Bcr-Abl fusion tyrosine kinase. The early reduction of such mutations may allow timely treatment intervention to prevent or overcome resistance. We review current trends in the management of chronic myeloid leukaemia patients undergoing treatment with tyrosine kinase inhibitors.

Benzamides↗
PubMed1995

Expression of the endothelin-converting enzyme gene in human tissues.

Based on the cDNA sequence of the human and bovine endothelin converting enzyme (ECE-1) we have developed a novel reverse transcription polymerase chain reaction to investigate the tissue expression of this gene. We were able to specifically detect the gene mRNA starting from very limited amount of tissue in all human as well as bovine tissues examined. Thus, our results confirm a widespread expression of the ECE-1 gene in human tissues, in keeping with the findings in other species, and suggest a major biological role of ECE-1.

Adrenal Gland Neoplasms↗
PubMed1996

The mouse BP-1 gene: structure, chromosomal localization, and regulation of expression by type I interferons and interleukin-7.

The BP-1/6C3 antigen is a homodimeric, phosphorylated type II membrane integral glycoprotein expressed on immature B-lineage cells, bone marrow stromal cells, thymic cortical epithelial cells, endothelial cells, enterocytes, and renal proximal tubular cells. Biochemical and molecular analysis identified BP-1 as glutamyl aminopeptidase, an ectoenzyme that catalyzes the hydrolysis of acidic amino acid residues from the amino termini of regulatory peptides. We have isolated genomic clones that encode the BP-1 gene (gene symbol Enpep). The gene spans more than 110 kb and contains 20 exons. Except for the first and the last exons, it is composed of small exons ranging from 56 to 171 bp that are separated by introns ranging from less than 100 bp to approximately 10 kb. The zinc binding motif HEXXH and the glutamic acid residue 19 amino acids downstream, which also binds zinc, are encoded in exons 5 and 6. Primer extension analysis revealed a common major transcriptional start site in a pre-B cell line, in a bone marrow stromal cell line, and in kidney cells. The promoter region contains a TATA-like element and potential DNA-binding motifs for lymphocyte-specific transcription factors including Ikaros, BSAP, PU.1, and octamer binding proteins, as well as DNA binding motifs for several ubiquitous transcription factors. An interferon responsive element also located in the promoter region appeared to be functional, since type I interferons (IFN-alpha/IFN-beta) upregulated BP-1 expression in pre-B cell lines. A 2.1-kb promoter fragment, when fused to a luciferase reporter gene, was able to drive luciferase expression in pre-B cells, which normally express BP-1, and the Ag8 cells, in which BP-1 expression is extinguished. The BP-1/ Enpep gene was localized to a distal region of mouse chromosome 3 in a region homologous to human chromosome 4q25. Interestingly, while interleukin-7 (IL-7) induced both cell growth and increased BP-1 expression, IFN-alpha/IFN-beta upregulated BP-1 expression but inhibited IL-7 induced proliferation. This finding indicates that the upregulated BP-1 expression can be disassociated from the cell growth signal.

Amino Acid Sequence↗
PubMed2002

Human influenza a viral genes responsible for the restriction of its replication in duck intestine.

Although influenza A viruses are occasionally transmitted from one animal species to another, their host range tends to be restricted. Currently circulating human influenza A viruses are thought to have originated from avian viruses, yet none of these strains replicate in duck intestine, a major site of avian virus replication. Although the hemagglutinin (HA) and neuraminidase (NA) genes are known to restrict human virus replication in ducks, the contribution of the other viral genes remains unknown. To determine the genetic basis for host range restriction of the replication of human influenza A virus in duck intestine, we first established a reverse genetics system for generating A/Memphis/8/88 (H3N2) (Mem/88) and A/mallard/New York/6750/78 (H2N2) (Mal/NY) viruses from cloned cDNAs. Using this system, we then attempted to generate reassortant viruses with various combinations of candidate genes. We were able to generate single-gene reassortants, which possessed PB2, NP, M, or NS from Mem/88, with the remainder from Mal/NY. Despite unsuccessful production of other single-gene reassortants from Mem/88, we did generate reassortant viruses comprised of both the HA and the NA, all three polymerase genes (PB2, PB1, and PA), or all polymerase genes and the NP gene from Mem/88, with the rest derived from Mal/NY. Among these reassortants, only those possessing the M or NS gene from Mem/88 and the remainder from Mal/NY replicated in duck intestine. These results indicate incompatibility between the genes of avian and human influenza A viruses and indicate that all genes other than the M and NS restrict replication of human influenza A virus in duck intestine.

Animals↗
PubMed2006

Discontinuation of imatinib therapy after achievement of complete molecular response in a Ph(+) CML patient treated while in long lasting complete cytogenetic remission (CCR) induced by interferon.

Imatinib has become the gold standard therapy for Ph(+) CML, as it induces complete cytogenetic remission (CCR) in 75-90% of patients in chronic phase (CP), and up to 40% of these patients obtain at least a 3 log reduction of BCR/ABL transcript [Kantarjian HM, Cortes JE, O'Brien S, Luthra R, Giles F, Verstovsek S, et al. Long-term survival benefit and improved complete cytogenetic and molecular response rates with imatinib mesylate in Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia after failure of interferon-alpha. Blood. 2004;104:1979-1988]. However, it is not yet stated whether continued therapy is required to maintain this response or whether imatinib may be discontinued after confirmation of a prolonged complete molecular remission (CMR). We here report on a Ph(+) CML case in long lasting CCR following interferon-alpha treatment (IFN) which reached CMR with imatinib but soon relapsed at molecular level after this latter drug discontinuation; we considered the present observation also in the light of previously reported data.

Adenocarcinoma↗
PubMed1995

Physiological consequences of over- or under-expression of fibrinolytic system components in transgenic mice.

Studies with transgenic mice over- or under-expressing components of the fibrinolytic system, have revealed a significant role of this system in fibrin clot surveillance, reproduction, (vascular) wound healing, brain function, health and survival. The distinct phenotypes associated with single loss and the more severe phenotype associated with combined loss of plasminogen activator gene function suggest that through evolution, both plasminogen activators have evolved with specific but overlapping biological properties. Interestingly, the role of the fibrinolytic system in thrombosis and vascular wound healing became more apparent after challenging mice single deficiencies of plasminogen activators with an inflammatory, or traumatic challenge, respectively. It therefore seems warranted to examine possible consequences of loss of plasminogen activator gene function in other processes including atherosclerosis, neoangiogenesis, inflammatory lung and kidney disease and malignancy. The plasminogen activator knock-out mice with their thrombotic phenotypes are also valuable models to evaluate whether adenoviral mediated gene-transfer of wild-type or mutant plasminogen activator genes is able to restore normal thrombolytic function and to prevent thrombosis. Preliminary evidence suggests that impaired thrombolysis of t-PA deficient mice can be completely restored using adenoviral-mediated gene transfer of rt-PA (Carmeliet et al, 1994c). In addition, analysis of neointima formation in plasminogen activator deficient mice suggests that controlled reduction of fibrinolytic activity in the vessel wall might be beneficial for the prevention or reduction of restenosis. Whether this can be achieved with gene transfer methodologies remains to be defined.

Animals↗
PubMed2003

Yeast genome duplication was followed by asynchronous differentiation of duplicated genes.

Gene redundancy has been observed in yeast, plant and human genomes, and is thought to be a consequence of whole-genome duplications. Baker's yeast, Saccharomyces cerevisiae, contains several hundred duplicated genes. Duplication(s) could have occurred before or after a given speciation. To understand the evolution of the yeast genome, we analysed orthologues of some of these genes in several related yeast species. On the basis of the inferred phylogeny of each set of genes, we were able to deduce whether the gene duplicated and/or specialized before or after the divergence of two yeast lineages. Here we show that the gene duplications might have occurred as a single event, and that it probably took place before the Saccharomyces and Kluyveromyces lineages diverged from each other. Further evolution of each duplicated gene pair-such as specialization or differentiation of the two copies, or deletion of a single copy--has taken place independently throughout the evolution of these species.

Evolution, Molecular↗
PubMed2002

Tumor-targeted gene delivery: an attractive strategy to use highly active effector molecules in cancer treatment.

We have developed surface-shielded ligand-polycation based gene delivery systems which are able to target gene expression to distant tumors after systemic application. Tumor-specific targeting is achieved by (1) incorporation of cell-binding ligands; and (2) shielding of the complexes from non-specific interactions with blood components and non-target cells. Shielding of polycation/DNA complexes can be achieved by coating with either polyethylene glycol or by incorporating the ligand transferrin at high densities. Following systemic application, surface-shielded DNA complexes coding for a highly active, yet highly toxic cytokine, tumor necrosis factor-alpha (TNFalpha), localized gene expression to distant tumors, resulting in hemorrhagic tumor necrosis and inhibition of tumor growth. TNFalpha activity was confined to the tumor without systemic TNF-related toxicity. These results indicate that targeted gene delivery may be an attractive strategy to use highly potent molecules in cancer treatment.

Animals↗
PubMed2006

Overexpression of the heat-shock protein 70 is associated to imatinib resistance in chronic myeloid leukemia.

Imatinib is an effective therapy for chronic myeloid leukemia (CML), a myeloproliferative disorder characterized by the expression of the recombinant oncoprotein Bcr-Abl. In this investigation, we studied an imatinib-resistant cell line (K562-r) generated from the K562 cell line in which none of the previously described mechanisms of resistance had been detected. A threefold increase in the expression of the heat-shock protein 70 (Hsp70) was detected in these cells. This increase was not associated to heat-shock transcription factor-1 (HSF-1) overexpression or activation. RNA silencing of Hsp70 decreased dramatically its expression (90%), and was accompanied by a 34% reduction in cell viability. Overexpression of Hsp70 in the imatinib-sensitive K562 line induced resistance to imatinib as detected by a large reduction in cell death in the presence of 1 muM of imatinib. Hsp70 level was also increased in blast cells of CML patients resistant to imatinib, whereas the level remained low in responding patients. Taken together, the results demonstrate that overexpression of Hsp70 can lead to both in vitro and in vivo resistance to imatinib in CML cells. Moreover, the overexpression of Hsp70 detected in imatinib-resistant CML patients supports this mechanism and identifies potentially a marker and a therapeutic target of CML evolution.

Biomarkers, Tumor↗
PubMed2006

Reduction of apoptosis in Rb-deficient embryos via Abl knockout.

The retinoblastoma protein RB regulates cell proliferation, differentiation and apoptosis. Homozygous knockout of Rb in mice causes embryonic lethality owing to placental defects that result in excessive apoptosis. RB binds to a number of cellular proteins including the nuclear Abl protein and inhibits its tyrosine kinase activity. Ex vivo experiments have shown that genotoxic or inflammatory stress can activate Abl kinase to stimulate apoptosis. Employing the Rb-null embryos as an in vivo model of apoptosis, we have shown that the genetic ablation of Abl can reduce apoptosis in the developing central nervous system and the embryonic liver. These results are consistent with the inhibitory interaction between RB and Abl, and provide in vivo evidence for the proapoptotic function of Abl.

Animals↗
PubMed2002

Philadelphia chromosome-positive mature B-cell (Burkitt cell) leukaemia.

Philadelphia chromosome-positive (Ph+) acute leukaemia usually shows lymphoblastic morphology and a B-precursor phenotype. The bone marrow aspirate of a 9-year-old boy showed a L3 blast cell morphology in 90% of cells; immunophenotyping revealed a mature B-blast population. The translocation t(9;22) (q34;q11) was seen in 45 out of 50 metaphases, and expression of the corresponding bcr1/abl fusion transcripts, but no IgH/myc co-localization or splitting of c-myc, was demonstrated. Chemotherapy according to the Berlin-Frankfurt-Munster non-Hodgkin's lymphoma (NHL-BFM 95) protocol with maintenance according to the BFM acute lymphoblastic leukaemia (ALL-BFM 90) protocol resulted in continuing complete remission of 54 months. The occurrence of Ph+ Burkitt's leukaemia might reflect multiple-step cancer development.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1975

Cell interactions between histoincompatible T and B lymphocytes. VII. Cooperative responses between lymphocytes are controlled by genes in the I region of the H-2 complex.

The results of this study provide compelling evidence for the existence of the gene or genes controlling optimal T-B-cell cooperative interactions in the designated I region of the H-2 gene complex. Previously, we have speculated that the relevant gene(s) involved may well be located in this region based on several observations from our earlier work in this area (3, 5, 6). Thus, in the preceding paper, we showed that T and B cells from B10.BR and A strain mice developed effective cooperative interactions in vitro to DNP-KLH in a system identical to the one reported herein. Since these mice differ for genes in the S and D regions of H-2 but are identical for K and I region genes, we were able to localize the critical genes to the K-end of H-2.

Animals↗