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PubMed1996

A Philadelphia chromosome positive CML patient with a unique translocation studied via GTG-banding and fluorescence in situ hybridization.

The Philadelphia (Ph) chromosome was the first consistently occurring chromosome abnormality associated with a single cancer type, chronic myelogenous leukemia (CML). This translocation has since been reported with other chromosome abnormalities. The present report describes a case of Ph chromosome positive CML with a unique complex translocation identified using molecular cytogenetics in addition to routine techniques. GTG-banding revealed abnormalities in at least chromosomes 9, 13, 17, and 22. Fluorescence in situ hybridization (FISH) studies were performed as an adjunct to conventional cytogenetic analyses. Using FISH with the Oncor bcr/abl probe, the Ph translocation previously hypothesized was confirmed. Applying FISH with paired painting probes in various combinations, a complex translocation involving chromosomes 9, 13, 15, 17, and 22 was observed. The results of the GTG-banding and FISH studies were compared with each other and correlated with those of the hematological findings. In an extensive search of the medical literature database (Medline, Health, Cancerlit, Ovid, and CINAHL) spanning nearly three decades (1965-1994), we found no previous report of this specific translocation. Therefore, to the best of our knowledge, this is a unique translocation associated with Ph chromosome positive CML.

Aged↗
PubMed2002

Chromosome positioning in the interphase nucleus.

Chromosomes occupy distinct territories in the interphase cell nucleus. These chromosome territories are non-randomly arranged within the nuclear space. We are only just uncovering how chromosome territories are organized, what determines their position and how their spatial organization affects the expression of genes and genomes. Here, we discuss emerging models of non-random nuclear chromosome organization and consider the functional implications of chromosome positioning for gene expression and genome stability.

Animals↗
PubMed2002

Conservation of relative chromosome positioning in normal and cancer cells.

Chromosomes exist in the interphase nucleus as individual chromosome territories. It is unclear to what extent chromosome territories occupy particular positions with respect to each other and how structural rearrangements, such as translocations, affect chromosome organization within the cell nucleus. Here we analyze the relative interphase positioning of chromosomes in mouse lymphoma cells compared to normal splenocytes. We show that in a lymphoma cell line derived from an ATM(-/-) mouse, two translocated chromosomes are preferentially positioned in close proximity to each other. The relative position of the chromosomes involved in these translocations is conserved in normal splenocytes. Relative positioning of chromosomes in normal splenocytes is not due to their random distribution in the interphase nucleus and persists during mitosis. These observations demonstrate that the relative arrangement of chromosomes in the interphase nucleus can be conserved between normal and cancer cells and our data support the notion that physical proximity facilitates rearrangements between chromosomes.

Animals↗
PubMed2000

Chromosomal position effects reveal different cis-acting requirements for rDNA transcription and sex chromosome pairing in Drosophila melanogaster.

In Drosophila melanogaster, the rDNA loci function in ribosome biogenesis and nucleolar formation and also as sex chromosome pairing sites in male meiosis. These activities are not dependent on the heterochromatic location of the rDNA, because euchromatic transgenes are competent to form nucleoli and restore pairing to rDNA-deficient X chromosomes. These transgene studies, however, do not address requirements for the function of the endogenous rDNA loci within the heterochromatin. Here we describe two chromosome rearrangements that disrupt rDNA functions. Both rearrangements are translocations that cause an extreme bobbed visible phenotype and XY nondisjunction and meiotic drive in males. However, neither rearrangement interacts with a specific Y chromosome, Ymal(+), that induces male sterility in combination with rDNA deletions. Molecular studies show that the translocations are not associated with gross rearrangements of the rDNA repeat arrays. Rather, suppression of the bobbed phenotypes by Y heterochromatin suggests that decreased rDNA function is caused by a chromosomal position effect. While both translocations affect rDNA transcription, only one disrupts meiotic XY pairing, indicating that there are different cis-acting requirements for rDNA transcription and rDNA-mediated meiotic pairing.

Alleles↗
PubMedDate not supplied

Molecular diagnosis of Philadelphia chromosome-positive chronic myeloid leukemia.

BACKGROUND: In virtually all Ph1 chromosome-positive CML patients, the breakpoint on chromosome 22 maps in a very restricted area of 5.8 Kb, which has been named "breakpoint cluster region" or "bcr". Several molecular probes of this region are presently available, and this makes the molecular diagnosis of CML a useful approach which can be particularly important in those cases in which cytogenetic analysis does not reveal the presence of a Ph1 chromosome. Here we report the problems and our experience during the molecular analysis of the 478 patients examined so far. METHODS: Molecular analyses were performed after digestion of the DNA with 2 to 4 restriction enzymes and hybridization with different probes. Individual samples were subjected to PCR since no rearrangements had been obtained with Southern blotting. RESULTS: Rearrangement bands were detected in all the samples examined. In 473 cases the breakpoint was located within the bcr. In one of these cases, it was detected only after PCR analysis, and in two cases only after the use of the PHL/BCR probe. In 5 cases the breakpoint was localized either 5' or 3' with respect to the bcr. CONCLUSIONS: In this paper, the criteria for a correct molecular diagnosis of CML are presented. The "PHL/BCR" probe appeared to be very specific and time-saving, since it required only one digestion to evidence the rearrangement. Our results confirm the high specificity of the breakpoint on chromosome 22 in CML and the relatively rare incidence of molecular variants.

Base Sequence↗
PubMed1990

Expression of a foreign gene in a line of transgenic mice is modulated by a chromosomal position effect.

Unusual aberrant expression of a foreign gene in a particular transgenic mouse line is often attributed to chromosomal position effect, although proof of this is lacking. An alternative explanation is that expression has been modified by the arrangement of multiple copies of the foreign gene at the insertion site or by mutation or gene rearrangement. We have distinguished between these explanations in the case of one particular transgenic line by recovering the aberrantly expressed foreign DNA and reintroducing it into the mouse genome to produce secondary transgenic mice. The expression pattern of the gene in the secondary transgenic mice was normal, showing that this case of aberrant expression is due to a chromosomal position effect.

Animals↗
PubMed1986

Long survival in Philadelphia-chromosome-positive acute leukemia.

A case of Philadelphia (Ph)-chromosome-positive acute leukemia (AL) is presented who went into remission with disappearance of the Ph1 chromosome and later on developed the chronic phase of chronic granulocytic leukemia (CGL) with reappearance of the Ph1 chromosome. The patient is alive 6+ years following the diagnosis. The entity of Ph1-positive AL is discussed. It is suggested that the patients with Ph1-positive AL who develop CGL have a better prognosis than previously described.

Acute Disease↗
PubMed1994

Chromosomal position effects and the modulation of transgene expression.

Chromosomal position effects can influence strongly the transcription of foreign genes in transgenic animals. This results in low frequencies and levels of gene expression and, in some cases, in aberrant patterns of expression. Strategies for overcoming these effects are described with particular reference to their application in embryonic stem cells.

Animals↗
PubMed2004

CD19-targeting liposomes containing imatinib efficiently kill Philadelphia chromosome-positive acute lymphoblastic leukemia cells.

Patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) have poor prognosis despite intensive therapeutic intervention. Recently, imatinib, a BCR-ABL tyrosine kinase inhibitor, has been proven to be an effective treatment for Ph(+) ALL, but nearly all patients rapidly acquire resistance. High-dose imatinib administration might overcome this resistance; however, systemic toxicities would likely limit this approach. Therefore, a new delivery system allowing for the specific targeting of imatinib is urgently needed. Because almost all Ph(+) ALL cells express CD19 on their surface, we have developed an immunoliposome carrying anti-CD19 antibody (CD19-liposomes). The internalization efficiency of the CD19-liposomes approached 100% in all Ph(+) ALL cells but was very low in CD19(-) cells. The cytocidal effect of imatinib-encapsulated CD19-liposomes (imatinib-CD19-liposomes) on Ph(+) ALL cell lines and primary leukemia cells from patients with Ph(+) ALL was much greater than that of imatinib with or without control liposomes. Importantly, the imatinib-CD19-liposomes did not affect the colony formation of CD34(+) hematopoietic cells, even at inhibitory concentration of free imatinib. Taken together, these data clearly demonstrate that the imatinib-CD19-liposomes induced specific and efficient death of Ph(+) ALL cells. This new therapeutic approach might be a useful treatment for Ph(+) ALL with fewer side effects than free imatinib.

Antigens, CD19↗
PubMed2004

A novel maxizyme vector targeting a bcr-abl fusion gene induced specific cell death in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Patients with Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL) generally have a poor prognosis and would benefit from the development of new therapeutic approaches. We previously demonstrated that an allosterically controllable ribozyme, maxizyme (Mz), can induce apoptosis in chronic myelogenous leukemia (CML) cells. Ph(+) ALL cells harbor a bcrabl fusion gene (e1a2) encoding a 190-kDa fusion protein (p190) involved in disease pathogenesis. In this study, we have designed a Mz that specifically cleaves e1a2 mRNA and transduced this e1a2Mz into Ph(+) ALL cells using a third-generation lentiviral vector system. In 3 of 5 Ph(+) ALL cell lines, e1a2Mz transduction resulted in a significant decrease in viability and increased cell apoptosis. We observed a decrease in e1a2 mRNA in all Ph(+) ALL cells transduced with e1a2Mz, and the e1a2 mRNA level was higher in e1a2Mz-resistant cells than in e1a2Mz-sensitive cells. All samples of primary Ph(+) ALL cells tested showed e1a2Mz-induced growth inhibition and apoptosis. Importantly, e1a2Mz did not influence the colony formation of normal CD34(+) cord blood cells. These results indicate that e1a2Mz kills Ph(+) ALL cells specifically, suggesting that it may be used as a novel gene therapy strategy for Ph(+) ALL.

Apoptosis↗
PubMed1999

Transcribed genes are localized according to chromosomal position within polarized Drosophila embryonic nuclei.

When some genes are silenced, their positions within the nucleus can change dramatically [1] [2]. It is unclear, however, whether genes move to new positions when they are activated [3]. The chromosomes within the polarized nuclei of the fruit fly Drosophila have a well-characterized apical-basal orientation (the Rabl configuration [4]). Using a high-resolution in situ hybridization method [5], we found that each of 15 transcribed genes was localized as predicted by their chromosomal position and by the known polarized organization of the chromosomes. We also found that, within their specific apical-basal plane, most nascent transcript foci could occupy any radial position. There was no correlation between the apical-basal position of the transcribed locus and the final cytoplasmic site of localization of the RNA along the apical-basal axis of the cell. There was also no relationship between the distance of loci from the nuclear periphery and the amount of nascent mRNA decorating the gene. Our results are consistent with the view that effective transcription can occur without major re-localization of the genes themselves.

Animals↗
PubMed1993

Mutation induction by UV light in retroviral hprt cDNA integrated at various chromosomal positions in repair-deficient hamster cells.

Mutation induction by UV irradiation was studied in a retroviral vector integrated in one copy per cell at various chromosomal positions. As a mutational target, hamster hprt cDNA was present on the retroviral vector. To minimize the influence of repair we used repair-deficient hamster cells, V-H1 and UV5, as a recipient for the vector. There is no major influence of chromosomal position on UV-induced mutation frequency and spectrum because no statistically significant difference between mutation induction in retroviral cDNA copies integrated at different chromosomal sites was observed. However, a major difference was found in mutation induction between the endogenous hamster hprt gene and the retroviral cDNA copies. Most noticeable was the absence in the cDNA of the strong strand bias for mutation induction, which was reported for the endogenous hprt gene. Our results with the hprt cDNA exclude as a general phenomenon a difference in mutation induction for leading and lagging strand DNA replication, which was proposed as an explanation for this strand bias in the endogenous gene. The similarity of mutation induction in the different retroviral cDNA copies, all directly surrounded by the same DNA sequence elements, together with the marked difference between the mutation induction in the endogenous gene and the cDNA copies may point to an important role of chromatin structure in mutation induction.

Animals↗
PubMed1992

Control of growth and differentiation of Philadelphia chromosome-positive leukemia cells by tyrosine kinase inhibitors.

Herbimycin A, a selective inhibitor of tyrosine kinase activity, induced differentiation of leukemia cells isolated from Philadelphia chromosome-positive chronic myelogenous leukemia patients. However, it did not induce differentiation of leukemia cells from acute myelogenous leukemia patients, although these cells could be induced to differentiate by treatment with appropriate compounds. A selective inhibitor of tyrosine kinase might be useful in chemotherapy of Philadelphia chromosome-positive leukemia.

Antibiotics, Antineoplastic↗
PubMed2002

From genes to therapy: the case of Philadelphia chromosome-positive leukemias.

The Philadelphia chromosome (Ph-chromosome) has long represented the only cytogenetic abnormality known to be associated with a specific malignant disease in humans, being present in more than 95% of patients with chronic myelogenous leukemia. This abnormality is the result of a reciprocal translocation between the long arms of chromosome 9 and 22, t(9;22)(q34;q11), and its presence is not restricted to chronic myelogenous leukemia, but can also be found in 30% of cases of acute lymphoblastic leukemia in adults. In the 1980s, the molecular counterpart of the chromosomal rearrangement was identified to consist of the juxtaposition of parts of the BCR and ABL genes to form a BCR-ABL hybrid gene. The resulting chimeric proteins (P210 and P190), which retain constitutively activated tyrosine kinase activity, have demonstrated a causative role in the genesis of the leukemic process. Although many aspects of the BCR-ABL driven transformation remain unsolved, great advances in understanding the molecular pathology of Ph-positive leukemias resulted in meaningful improvement in the clinical setting. Molecular tools to diagnose disease (PCR, FISH, and southern blot) and to monitor minimal residual disease after potential curative treatment are now in current practice, and new powerful therapeutic tools have emerged that target the molecular oncogenic pathways activated in Ph-positive cells. Among them, specific ABL tyrosine kinase inhibitors recently obtained extraordinary results in many clinical protocols. This review summarizes the most recent advances in this field with special focus on the putative mechanisms of the transformation and progression of chronic myelogenous leukemia and on the major impact that understanding the molecular biology of these diseases is having in clinical practice.

Cell Transformation, Neoplastic↗
PubMed1998

Clinical significance of Philadelphia chromosome positive pediatric acute lymphoblastic leukemia in the context of contemporary intensive therapies: a report from the Children's Cancer Group.

BACKGROUND: Children with Philadelphia (Ph) chromosome positive (+) acute lymphoblastic leukemia (ALL) represent a subgroup at very high risk for treatment failure. In this report, the authors assessed the outcome of Ph+ ALL in a large cohort of children treated on contemporary intensive chemotherapy protocols of the Children's Cancer Group (CCG). METHODS: This study included 1322 children enrolled between 1988-1995 on CCG risk-adjusted studies for ALL who had centrally reviewed cytogenetic data. Thirty patients had a t(9;22)(q34;q11) translocation and were referred to as Ph+; 1292 were Ph negative(-). Outcome analyses used standard life table methods. RESULTS: Compared with Ph- ALL patients, Ph+ ALL patients were more likely to be black (P=0.008), age >10 years (P=0.02), and have a leukocyte count > or =50,000/L (P <0.0001). Nearly all Ph+ (96.7%) and Ph (98.3%) patients achieved remission after induction therapy, yet event free survival outcome was significantly worse for Ph+ patients compared with Ph- patients, with 4-year estimates of 20.1% (standard deviation [SD] = 9.1%) and 75.8% (SD =1.2%), respectively (P <0.0001). This difference was maintained among patients regardless of presenting leukocyte count, age, or early response to therapy. Ten Ph+ patients underwent bone marrow transplantation (BMT) at the time of first remission; six of these patients remained event free at the time of analysis, and represent the majority (six of eight) of patients surviving event free. CONCLUSIONS: The findings of the current study confirm that Ph chromosome positivity represents a significant independent adverse risk factor for childhood ALL that has not been abrogated by current intensive chemotherapy programs. BMT at the time of first remission, as well as other alternative strategies employing biotherapeutic agents, should be considered in future front-line trials for pediatric patients with Ph+ ALL.

Bone Marrow Transplantation↗
PubMed2002

Utility of chromosomal position of heterochromatin as a biomarker of radiation-induced genetic damage: a study of Chornobyl voles (Microtus sp.).

Biomarkers that effectively document effects of chronic multi-generational exposure to contaminated environments on chromosomes would be valuable in risk assessment, remediation, and environmental decisions. Native, free-ranging populations of voles inhabiting the highly radioactive regions surrounding Reactor 4 of the Chornobyl Nuclear Power Station provide a model system to evaluate biological and chromosomal effects of chronic multi-generational exposure to radioactivity and other reactor meltdown-related pollutants. Here, we explore the utility of heterochromatic elements as potentially informative biomarkers for genetic damage in voles from the radioactive environments surrounding Chornobyl. We analyzed chromosomal positions of heterochromatin from Microtus arvalis and M. rossiaemeridionalis using fluorescent in situ hybridization. Although intrapopulational variation existed in chromosomal position and abundance of heterochromatin, none of that variation could be assigned to environmental exposure.

Animals↗