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PubMed2002

Apoptosis and tumourigenesis.

Avoidance of apoptosis is a cornerstone of tumourigenesis. The functions of key molecules that either sense DNA damage or that commit cells to die are lost during tumorigenesis. Frequently, during tumourigenesis, cells increase their survival signals. The initiation of apoptosis by DNA damage signals was shown to absolutely depend on the expression of either Bax or Bak. Single oncogenes, such as BCR-ABL, which provide survival signals, were argued to be sufficient to support the oncogenic state; suppression-induced apoptosis and tumour regression in vivo. The concept of tumour maintenance by a single oncogene, inhibiting apoptosis, is of interest.

Animals↗
PubMed1998

Expression of p210 and p190 BCR-ABL due to alternative splicing in chronic myelogenous leukaemia.

The hallmark of chronic myelogenous leukaemia (CML) is the presence of the Philadelphia chromosome and its resultant fusion message, BCR-ABL, and fusion protein, p210. Patients with CML in blast crisis, or with Philadelphia positive acute lymphoblastic leukaemia (ALL), can have a smaller BCR-ABL fusion transcript possessing only the first exon of BCR fused to ABL. This smaller transcript encodes a 190 kD protein which is more strongly transforming than the p210 protein derived from the larger CML-associated transcript. We performed RT-PCR on samples from CML patients in chronic phase to determine the frequency and mechanism of p190 and p210 co-expression and to see if this correlated with clinical indices. We examined the peripheral blood or marrow of 67 patients with CML and found that 35 of them expressed both transcripts whereas the remainder expressed the p210-encoding transcript exclusively. Additional PCR products of an intermediate size were also frequently detected and have been isolated and sequenced. Data from two of these products indicate that they are the result of alternative splicing and include variable combinations of BCR exons. We believe that the expression of the p190-encoding transcript in the chronic phase of CML is also due to alternative splicing. A comparison of patients co-expressing the p190- and p210-encoding transcripts with those patients who expressed only the p210-encoding transcript detected significantly higher white blood cell (WBC) counts and blast cell counts at time of testing as well as significantly higher white blood cell counts at diagnosis.

Adolescent↗
PubMed2000

Novel type of BCR-ABL transcript in a chronic myelogenous leukaemia patient relapsed after bone marrow transplantation.

We identified a novel BCR-ABL transcript in a chronic myelogenous leukaemia (CML) patient who relapsed after bone marrow transplantation (BMT), containing a fusion between part of BCR exon 3, 44 nucleotides derived from ABL intron 1b and ABL exon 2. The breakpoints were located within BCR exon 3 on chromosome 22 and within the ABL intron 1b on chromosome 9, and the transcript derives from a splicing of ABL exon 2 to a putative splicing acceptor site 44 nucleotides downstream to the breakpoint on chromosome 9. The patient's clinical course strengthens the idea that short forms of BCR-ABL transcripts are associated with a more aggressive disease.

Adult↗
PubMed2001

Semiquantitative reverse transcription polymerase chain reaction analysis for detection of bcr/abl rearrangement using RNA extracts from bone marrow aspirates compared with glass slide smears after 0, 2 and 4 d of storage.

The polymerase chain reaction (PCR) is an established tool for the detection of specific chromosomal aberrations in different haematological malignancies. Owing to fast degradation of RNA, the immediate processing of samples is thought to have a major influence on the reliability of results. Any delay caused by transport may be an obstacle to reverse transcription PCR (RT-PCR)-based methods in multicentre studies. However, as air-dried bone marrow smears are usually available, we have improved a method to use smears as a source for routine RT-PCR investigations. We studied whether this source of RNA could overcome problems caused by delayed transport of samples. The aim of the present study was (i) to investigate the influence of a storage period of up to 4 d before processing of a specimen by nested bcr/abl RT-PCR, and (ii) to compare bone marrow aspirates with bone marrow smears stored at room temperature in parallel. Bone marrow aspirates and smears were taken from 11 patients with Ph-positive chronic myeloid leukaemia (CML). PCR results were semiquantified using a limiting dilution assay. We observed a loss of sensitivity < 1 log in stored bone marrow aspirates, even after 96 h. Results obtained from air-dried unstained glass slide smears were similar to investigations performed on approximately 1 x 10(5) cells of a bone marrow aspirate. We conclude that a storage period of up to 96 h has little influence on the detection of a bcr/abl fusion transcript in CML at diagnosis. Glass slide smears were equivalent to bone marrow aspirates in 8 out of 11 cases as a source for RT-PCR analysis when nested PCR was performed.

Bone Marrow Cells↗
PubMed2000

The putative DNA translocase SpoIIIE is required for sporulation of the symmetrically dividing coccal species Sporosarcina ureae.

The spoIIIE gene of Sporosarcina ureae encodes a 780-residue protein, showing 58% identity to the SpoIIIE protein of Bacillus subtilis, which is thought to be a DNA translocase. Expression of the S. ureae spoIIIE gene is able to restore sporulation in a B. subtilis spoIIIE mutant. Inactivation of the S. ureae spoIIIE gene blocks sporulation of S. ureae at stage III. Within the limits of detection, the sporulation division in S. ureae shows the same symmetry, or near symmetry, as the vegetative division (in contrast to the highly asymmetric location of the sporulation division for B. subtilis), and so it is inferred that SpoIIIE facilitates chromosome partitioning during sporulation, even when the division is not grossly asymmetric. It is suggested that chromosome partitioning lags behind division during sporulation but not during vegetative growth.

Bacillus subtilis↗
PubMed2001

p62(dok), a negative regulator of Ras and mitogen-activated protein kinase (MAPK) activity, opposes leukemogenesis by p210(bcr-abl).

p62(dok) has been identified as a substrate of many oncogenic tyrosine kinases such as the chronic myelogenous leukemia (CML) chimeric p210(bcr-abl) oncoprotein. It is also phosphorylated upon activation of many receptors and cytoplamic tyrosine kinases. However, the biological functions of p62(dok) in normal cell signaling as well as in p210(bcr-abl) leukemogenesis are as yet not fully understood. Here we show, in hemopoietic and nonhemopoietic cells derived from p62(dok)-(/)- mice, that the loss of p62(dok) results in increased cell proliferation upon growth factor treatment. Moreover, Ras and mitogen-activated protein kinase (MAPK) activation is markedly sustained in p62(dok)-(/)- cells after the removal of growth factor. However, p62(dok) inactivation does not affect DNA damage and growth factor deprivation-induced apoptosis. Furthermore, p62(dok) inactivation causes a significant shortening in the latency of the fatal myeloproliferative disease induced by retroviral-mediated transduction of p210(bcr-abl) in bone marrow cells. These data indicate that p62(dok) acts as a negative regulator of growth factor-induced cell proliferation, at least in part through downregulating Ras/MAPK signaling pathway, and that p62(dok) can oppose leukemogenesis by p210(bcr-abl).

Animals↗
PubMed1996

Molecular cloning and characterization of a cDNA clone that encodes a Cdc2 homolog from Nicotiana tabacum.

We have isolated a cDNA clone (cdc2Nt1) that encodes a homolog of p34(cdc2/CDC28) kinase from tobacco (Nicotiana tabacum). The cdc2Nt1 protein showed extensive similarity to other homologs of Cdc2 from plants. Complementation studies showed that the cdc2Nt1 gene was able to overcome cell cycle arrest at both the G1/S and the G2/M transitions of cdc28ts mutants of budding yeast, demonstrating that the cdc2Nt1 protein was able to replace the Cdc28 kinase at both the G1/S and the G2/M transitions. Analysis of gene expression demonstrated that the cdc2Nt1 gene was transcribed constitutively throughout the cell cycle but that it was preferentially expressed in activity dividing tobacco BY-2 cells.

Amino Acid Sequence↗
PubMed2003

Evolution of the chloroplast genome.

We discuss the suggestion that differences in the nucleotide composition between plastid and nuclear genomes may provide a selective advantage in the transposition of genes from plastid to nucleus. We show that in the adenine, thymine (AT)-rich genome of Borrelia burgdorferi several genes have an AT-content lower than the average for the genome as a whole. However, genes whose plant homologues have moved from plastid to nucleus are no less AT-rich than genes whose plant homologues have remained in the plastid, indicating that both classes of gene are able to support a high AT-content. We describe the anomalous organization of dinoflagellate plastid genes. These are located on small circles of 2-3 kbp, in contrast to the usual plastid genome organization of a single large circle of 100-200 kbp. Most circles contain a single gene. Some circles contain two genes and some contain none. Dinoflagellate plastids have retained far fewer genes than other plastids. We discuss a similarity between the dinoflagellate minicircles and the bacterial integron system.

Amino Acid Sequence↗
PubMed1996

Exogenous phytohormone-independent growth and regeneration of tobacco plants transgenic for the 6b gene of Agrobacterium tumefaciens AKE10.

The 6b gene of Agrobacterium tumefaciens AKE10 (AK-6b) induces crown gall tumors on certain plants but so far there have been no reports of the gene being able to induce tumors on culture medium. We cloned T-DNA segments containing the 6b gene but lacking the auxin and cytokinin biosynthesis genes from A. tumefaciens AKE10. Tobacco (Nicotiana tabacum) leaf discs infected with A. tumefaciens LBA4404 carrying the clones produced shooty calli on hormone-free Murashige-Skoog medium. The relevant T-DNA segment was integrated into plant DNA as determined by Southern hybridization. Some of these immature shoots spontaneously developed into mature shoots, of which several leaves displayed morphological abnormalities. When leaf discs of these mature plants were placed onto the same medium numerous shoots developed from the wounding sites, indicating that the transgenic plants possessed a high regenerative potential. Northern blot and reverse transcriptase-polymerase chain reaction analyses showed a large accumulation of the AK-6b transcripts in the shooty calli, but only a limited degree in mature plants, demonstrating that AK-6b expression is regulated in plants and essential for the early stages of regeneration. Cytokinin levels in the shooty calli were comparable to those in normal shoots, suggesting that shoot regeneration is not mediated by the modulation of cytokinin content.

Agrobacterium tumefaciens↗
PubMed1994

Long-term culture and molecular biological studies highlight differences in relative BCR-ABL expression levels in the peripheral blood and bone marrow of a patient with chronic granulocytic leukaemia.

A patient with accelerating Ph+ve chronic granulocytic leukaemia (CGL) was considered for autologous BMT using marrow 'purged' by 4 weeks long-term culture (LTC). Efficacy of purging was determined using reverse transcriptase PCR for BCR-ABL mRNA transcripts b2a2 and b3a2. Peripheral blood and bone marrow were compared. Three observations emerged: (i) the initial b2a2:b3a2 ratios for unmanipulated blood and marrow were different with values of 9:1 and 2:1 respectively; (ii) both transcripts were successfully 'purged' with LTC of blood but not marrow; and (iii) LTC of marrow caused a transient increase in relative levels of b3a2 mRNA and a corresponding reduction in the b2a2 signal. This is the first case where such differences have been demonstrated in association with LTC.

Bone Marrow↗
PubMed2005

CPCR1, but not its interacting transcription factor AcFKH1, controls fungal arthrospore formation in Acremonium chrysogenum.

Fungal morphogenesis and secondary metabolism are frequently associated; however, the molecular determinants connecting both processes remain largely undefined. Here we demonstrate that CPCR1 (cephalosporin C regulator 1 from Acremonium chrysogenum), a member of the winged helix/regulator factor X (RFX) transcription factor family that regulates cephalosporin C biosynthesis, also controls morphological development in the beta-lactam producer A. chrysogenum. The use of a disruption strain, multicopy strains as well as several recombinant control strains revealed that CPCR1 is required for hyphal fragmentation, and thus the formation of arthrospores. In a DeltacpcR1 disruption strain that exhibits only hyphal growth, the wild-type cpcR1 gene was able to restore arthrospore formation; a phenomenon not observed for DeltacpcR1 derivatives or non-related genes. The intracellular expression of cpcR1, and control genes (pcbC, egfp) was determined by in vivo monitoring of fluorescent protein fusions. Further, the role of the forkhead transcription factor AcFKH1, which directly interacts with CPCR1, was studied by generating an Acfkh1 knockout strain. In contrast to CPCR1, AcFKH1 is not directly involved in the fragmentation of hyphae. Instead, the presence of AcFKH1 seems to be necessary for CPCR1 function in A. chrysogenum morphogenesis, as overexpression of a functional cpcR1 gene in a DeltaAcfkh1 background has no effect on arthrospore formation. Moreover, strains lacking Acfkh1 exhibit defects in cell separation, indicating an involvement of the forkhead transcription factor in mycelial growth of A. chrysogenum. Our data offer the potential to control fungal growth in biotechnical processes that require defined morphological stages for optimal production yields.

Acremonium↗
PubMed1999

p190 bcr-abl rearrangement: a secondary cytogenetic event in some chronic myeloid disorders?

BACKGROUND AND OBJECTIVE: A small number of chronic myeloproliferative disorders with hematologic features of chronic myelomonocytic leukemia (CMML) or atypical chronic myeloid leukemia and Ph1 chromosome with m-BCR rearrangement have been reported (p190 CMPD). We report here 3 new cases of p190 CMPD that had unusual features. In 2 of the cases the m-BCR rearrangement appeared to be a secondary event. DESIGN AND METHODS: Patients were studied by cytogenetic, FISH, and molecular biology analyses and followed-up clinically. RESULTS: The first patient initially had typical 5q- syndrome, without m-BCR rearrangement. Five years later, she developed hematologic features of CMML, with t(9;22) translocation, m-BCR rearrangement and high levels of p190 BCR-ABL transcript. The second patient initially had hematologic characteristics of chronic myeloid leukemia (CML) with t(9;22) translocation and m-BCR rearrangement but also other complex cytogenetic findings including 17p rearrangement. Monocytosis developed during the course of the disease. The third patient initially had agnogenic myeloid metaplasia (AMM). Five years later, while the hematologic characteristics were still those of AMM, a first karyotype showed a t(9;22) translocation and molecular analysis showed a very low level of p190 BCR-ABL transcript. Four years later, the patient developed hematologic features of atypical CML with blood monocytosis, t(9;22) and much greater (100 fold) p190 BCR-ABL transcript levels. INTERPRETATION AND CONCLUSIONS: Our 3 cases and review of the previously published cases show the variability of clinical features of p190 positive CMPD. Our results also suggest that, at least in some cases, p190 BCR-ABL rearrangement could be a secondary event in the course of a myeloid disorder.

Chromosomes, Human, Pair 22↗
PubMed2000

BCR/ABL rearrangement in Philadelphia chromosome negative CML patients.

Reverse transcription-polymerase chain reaction (RT-PCR) was used to study 34 patients with chronic myelogenous leukemia (CML) associated with negative Philadelphia (Ph) chromosome. This report showed evidence of a chimeric BCR/ABL transcript in 18 (52.9%) and 28 (82.4%) cases by first PCR and seminested PCR, respectively. In these BCR/ABL transcript positive cases, the incidence of BCR exon3/ABL exon2 (B3A2) and BCR exon 2/ABL exon2 rearrangement was 25 (89.3%) and 3 (10.7%) cases, respectively. The other 6 Ph negative patients showed no evidence of reciprocal translocation of BCR to chromosome 9. This data demonstrates that seminested PCR is sufficiently sensitive to detect BCR/ABL fusion transcript in Ph chromosome negative CML patients.

Female↗
PubMed1999

[Influence of chemotherapeutants and cytokines on growth and transgene expression of bone marrow cells from MT/p210(bcr-abl) transgenic mice].

The bone marrow cells of CML(chronic myelogenous leukemia) transgenic mice carrying metallothionein(MT) promoter/enhancer, bcr-abl(p210) cDNA and SV40 splicing/poly(A) signal sequences were cultured in liquid and soft agar with hydroxyurea (Hu), 5-fluorouracil(5-Fu), mouse stem cell factor (mSCF) and mouse interleukin-3(mIL-3) independently or combinatively. The cell or colony counting and transgene RT-PCR analysis showed that the proliferation, colony formation and transgene expression of the bone marrow cells were advanced in the combinative culture of mSCF with mIL-3, but they were significantly inhibited in the culture without any growth factors, or with mSCF, mIL-3 and Hu or 5-Fu. These findings suggest that the combinative utilization of chemotherapeutants and cytokines is a potentially effective strategy of the clinical treatment for CML.

Animals↗