The Philadelphia chromosome and Philadelphia chromosome mosaicism in chronic granulocytic leukemia.
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Bone Marrow↗
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Patient with B-cell neoplasia (immunoblastic sarcoma) and the Philadelphia chromosome.
Philadelphia chromosome-positive cells with a standard translocation (9;22) were found in bone marrow and peripheral blood samples from a patient with non-Hodgkin's lymphoma (immunoblastic sarcoma) in the final leukemic phase. The neoplastic clone was of monoclonal B-cell character with surface Ig (mu, kappa) and mouse red blood cell receptors. This is the first case with surface Ig and t(9;22) cells reported without evidence of chronic myeloid leukemia. Also, additional consistent chromosome aberrations were found.
B-Lymphocytes↗
Characterization of a 14q+ marker chromosome in philadelphia chromosome positive acute lymphoblastic leukemia by DNA analysis and fluorescence in situ hybridization.
We report a case of precursor-B acute lymphoblastic leukemia (ALL) with the Philadelphia chromosome (Ph) and a 14q+ chromosome whose additional material was a part of the long arm of der(9)t(9;22). A minor population carrying the standard Ph translocation without the 14q+ was also observed at the first presentation. The translocation of the BCR gene from chromosome 22 to the subtelomeric region of the 14q+ was confirmed by fluorescence in situ hybridization (FISH) using a yeast artificial chromosome (YAC) clone containing the BCR gene. The breakpoint of chromosome 14 could not be determined exactly but probably was at 14q24 or 14q32 by conventional chromosome analysis. Nevertheless, FISH using a YAC clone containing the human immunoglobulin heavy chain (IgH) gene locus, Southern blot, and pulsed-field gel electrophoresis (PFGE) analyses with IgJH probe, and loss of heterozygosity analysis at the alpha 1-antitrypsin (AT) gene locus showed lack of involvement of the IgH gene in the 14q+ and more centromeric breakage than the alpha 1-AT locus at 14q32.1. Thus, the formation of the 14q+ seemed to be a secondary genetic event after the Ph translocation and presumably played a minor role in the pathogenesis of B-cell malignancy in this case.
Base Sequence↗
8/21 translocation, loss of the Y chromosome and Philadelphia chromosome.
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Adolescent↗
Computer aided analysis of additional chromosome aberrations in Philadelphia chromosome positive acute lymphoblastic leukaemia using a simplified computer readable cytogenetic notation.
BACKGROUND: The analysis of complex cytogenetic databases of distinct leukaemia entities may help to detect rare recurring chromosome aberrations, minimal common regions of gains and losses, and also hot spots of genomic rearrangements. The patterns of the karyotype alterations may provide insights into the genetic pathways of disease progression. RESULTS: We developed a simplified computer readable cytogenetic notation (SCCN) by which chromosome findings are normalised at a resolution of 400 bands. Lost or gained chromosomes or chromosome segments are specified in detail, and ranges of chromosome breakpoint assignments are recorded. Software modules were written to summarise the recorded chromosome changes with regard to the respective chromosome involvement. To assess the degree of karyotype alterations the ploidy levels and numbers of numerical and structural changes were recorded separately, and summarised in a complex karyotype aberration score (CKAS). The SCCN and CKAS were used to analyse the extend and the spectrum of additional chromosome aberrations in 94 patients with Philadelphia chromosome positive (Ph-positive) acute lymphoblastic leukemia (ALL) and secondary chromosome anomalies. Dosage changes of chromosomal material represented 92.1% of all additional events. Recurring regions of chromosome losses were identified. Structural rearrangements affecting (peri)centromeric chromosome regions were recorded in 24.6% of the cases. CONCLUSIONS: SCCN and CKAS provide unifying elements between karyotypes and computer processable data formats. They proved to be useful in the investigation of additional chromosome aberrations in Ph-positive ALL, and may represent a step towards full automation of the analysis of large and complex karyotype databases.
Adolescent↗
p53 gene mutations and loss of a chromosome 17p in Philadelphia chromosome (Ph1)-positive acute leukemia.
We screened 23 cases of Philadelphia chromosome (Ph1)-positive acute leukemia (Ph1AL) for loss of a chromosome 17p and mutations in exons 2 to 11 of the p53 gene by single-strand conformation polymorphism (SSCP) analysis and DNA sequencing. Loss of a distal part of chromosome 17p including loss of a whole chromosome 17 emerged in three cases, among which two were Ph1-positive acute lymphoblastic leukemia (Ph1ALL) with point mutations within the highly conserved region of the p53 gene. Another case of Ph1-positive acute myelogenous leukemia (Ph1AML) also exhibited a p53 point mutation in company with loss of normal p53 allele, although showing normal chromosome 17 homologues. We also performed Southern blot hybridization analysis to examine p53 gene rearrangements in 13 cases of Ph1AL. We found a rearrangement in one case of Ph1ALL and a loss of heterozygosity (LOH) at the p53 locus without any rearrangement in another Ph1ALL. Both cases showed no abnormality within the entire coding region by SSCP analysis. Thus, p53 gene alterations were commonly involved in Ph1AL with loss of a 17p (two point mutations in three cases), while rarely in cases with normal chromosome 17s (one point mutation in 20 cases and one rearrangement in 13 cases). Rare p53 gene alterations in Ph1AL may therefore be related to low incidence of loss of a chromosome 17p.
Acute Disease↗
Acute myeloblastic leukaemia without Philadelphia chromosome developing after interferon therapy for chronic myelocytic leukaemia with Philadelphia chromosome.
We report a patient who developed Philadelphia chromosome negative acute myeloblastic leukaemia with trisomy 8 and trisomy 11 after receiving treatment with alkylating agents and interferon for chronic myelocytic leukaemia positive for Philadelphia chromosome. Leukaemic cells were positive for myeloperoxidase and expressed CD13, CD33 and DR; some expressed CD2, CD4 and CD34. The fluorescence in situ hybridization method revealed that bcr-abl fusion genes were absent from > 90% of the bone marrow cells. The major bcr rearrangement was not detected by Southern blot analysis. We conclude that the leukaemic cells negative for Philadelphia chromosome may have developed as a result of treatment with alkylating agents and interferon in the present case.
Aged↗
Acute lymphoblastic leukemia without the Philadelphia chromosome occurring in chronic myelogenous leukemia with the Philadelphia chromosome.
The blast crisis in chronic myelogenous leukemia (CML) is related to the evolution of a Philadelphia chromosome (Ph)-positive clone. Secondary chromosomal abnormalities accompanied by t(9;22) are found in 70-80% of blast crises. Here we describe a patient with Ph-positive CML, who developed Ph-negative acute lymphoblastic leukemia (ALL). A 52-year-old man was diagnosed with CML with the Ph chromosome in the chronic phase. He achieved a partial cytogenetic response after 4 months of imatinib mesylate therapy. After 8 months, common ALL occurred. At that time his karyotype was normal and the Ph chromosome was not noted.
Benzamides↗
Three-dimensional spectral precision distance microscopy of chromatin nanostructures after triple-colour DNA labelling: a study of the BCR region on chromosome 22 and the Philadelphia chromosome.
Topological analysis of the three-dimensional (3D) chromatin nanostructure and its function in intact cell nuclei implies the use of high resolution far field light microscopy, e.g. confocal laser scanning microscopy (CLSM). However, experimental evidence indicates that, in practice, under biologically relevant conditions, the spatial resolution of CLSM is limited to about 300 nm in the lateral direction and about 700 nm in the axial direction. To overcome this shortcoming, the use of a recently developed light microscopical approach, spectral precision distance microscopy (SPDM) is established. This approach is based on the precise localization of small labelling sites of a given target in spectrally differential images. By means of quantitative image analysis, the bary centres (intensity weighted centroid analogous to the centre of mass) of these independently registered labelling sites can be used as point markers for distance and angle measurements after appropriate calibration of optical aberrations (here, polychromatic shifts). In combination with specific labelling of very small chromatin target sites with dyes of different spectral signatures by fluorescence in situ hybridization (FISH), SPDM presently allows us to analyse the nuclear topology in three-dimensionally conserved nuclei with a 'resolution equivalent', many times smaller than the conventional optical resolution. Chronic myelogeneous leukaemia (CML) is genetically characterized by the fusion of parts of the BCR and ABL genes on chromosomes 22 and 9, respectively. In most cases, the fusion leads to a translocation t(9; 22) producing the Philadelphia chromosome. SPDM was applied to analyse the 3D chromatin structure of the BCR region on the intact chromosome 22 and the BCR-ABL fusion gene on the Philadelphia chromosome (Ph) by using a new triple-colour FISH protocol: two different DNA probes were used to detect the BCR region and the third DNA probe was used to identify the location of the ABL gene. Consistent 3D distance measurements down to values considerably smaller than 100 nm were performed. The angle distributions between the three labelled sites on the Philadelphia chromosome territory were compared to two state-of-the-art computer models of nuclear chromatin structure. Significant differences between measured and simulated angle distributions were obtained, indicating a complex and non-random angle distribution.
Bone Marrow Cells↗
Development and progression of a Philadelphia-chromosome-negative acute myelocytic leukemia clone in a patient with Philadelphia-chromosome-positive chronic myelocytic leukemia.
We report a patient with typical Philadelphia-chromosome-positive chronic myelocytic leukemia who developed Philadelphia-chromosome-negative acute myelocytic leukemia following autologous stem cell transplantation. The implications of this observation for disease monitoring and treatment are discussed.
Antineoplastic Agents↗
Philadelphia-chromosome-negative peripheral blood stem cells can be mobilized in the early phase of recovery after a myelosuppressive chemotherapy in Philadelphia-chromosome-positive acute lymphoblastic leukaemia.
Ten patients in first or second relapse with Philadelphia chromosome acute lymphoblastic leukaemia, ineligible for allogeneic sibling marrow transplantation, were treated with an intensive chemotherapy regimen including idarubicin, intermediate-dose arabinosylcytosine, etoposide and G-CSF. Peripheral blood stem cells were collected by leukapheresis during initial early WBC recovery from chemotherapy-induced aplasia. In 5/10 patients all metaphases in leukapheresis products were found to be Philadelphia-chromosome-negative and they have been used as autotransplants after conditioning with TBI/etoposide/cyclophosphamide (or idarubicin) and G-CSF. All five patients showed sustained engraftment and one of them is alive and well Philadelphia-chromosome-negative 18 months after transplant. These preliminary results suggest that it is possible to recover Philadelphia-chromosome-negative blood stem cells after intensive chemotherapy, even in advanced patients, and to perform autografting with these cells.
Adolescent↗
CGG-repeat polymorphism of the BCR gene rules out predisposing alleles leading to the Philadelphia chromosome.
The Philadelphia chromosome (Ph) is associated with leukemia, most frequently of the chronic myelogenous variety. The Ph chromosome is a translocation chromosome which gains oncogenic potential through the fusion of the ABL oncogene of chromosome 9 with the BCR gene of chromosome 22. The Ph is believed to arise from random chromosome rearrangement with a subsequent selective advantage of the malignant cell line. However, alleles may be present in the population which predispose toward this specific rearrangement. We used a highly polymorphic CGG-repeat polymorphism within the first exon of the BCR gene to determine BCR allele frequencies among 26 leukemia patients with the Ph chromosome and 63 control individuals. Eight BCR alleles of variable CGG-repeat length were present in both groups at statistically similar frequencies and in Hardy-Weinberg equilibrium. We therefore concluded that there are no alleles of the BCR gene that have a major predisposing influence on the development of the Ph chromosome and subsequent leukemia.
Alleles↗
Overlapping cDNA clones define the complete coding region for the P210c-abl gene product associated with chronic myelogenous leukemia cells containing the Philadelphia chromosome.
The Philadelphia chromosome, observed in greater than 90% of patients with chronic myelogenous leukemia, results from a reciprocal translocation between chromosomes 9 and 22. The translocation breakpoint on chromosome 9 occurs near the ABL gene and correlates with the production of a chronic myelogenous leukemia-specific 8.5-kilobase ABL-related mRNA species accompanied by a structurally altered ABL protein (P210c-abl). The N-terminal sequence of the protein is derived from the BCR gene on chromosome 22. We have isolated overlapping cDNA clones from the K-562 cell line corresponding to approximately 8.5 kilobases of mRNA and have sequenced 2550 nucleotides at the 5' end. Our results indicate that the 5' end of the 8.5-kilobase mRNA consists of greater than 400 nucleotides of noncoding sequence that are greater than 80% G + C rich. Based on our sequence analysis, we propose that initiation of translation occurs at nucleotide 471, such that the initial 927 amino acids of P210c-abl are derived from BCR sequences. Our cDNA clones thus define the complete coding sequences for the P210c-abl gene product.
Base Sequence↗
In vitro transformation of immature hematopoietic cells by the P210 BCR/ABL oncogene product of the Philadelphia chromosome.
The Philadelphia chromosome [t(9;22)-(q34;q11)] is the cytogenetic hallmark of human chronic myelogenous leukemia. RNA splicing joins sequences from a gene on chromosome 22 (BCR) across the translocation breakpoint to a portion of the ABL oncogene from chromosome 9, resulting in a chimeric protein (P210) that is an active tyrosine kinase. Although strongly correlated with this specific human neoplasm, and implicated as an oncogene by analogy to the gene product of the Abelson murine leukemia virus, the P210 gene had not been tested directly for oncogenic potential in hematopoietic cells. We have used a retroviral gene-transfer system to express P210 in mouse bone marrow cells. When infected bone marrow is plated under conditions for long-term culture of cells of the B-lymphoid lineage, cells expressing high amounts of P210 tyrosine kinase dominate the culture and rapidly lead to clonal outgrowths of immature lymphoid cells. Expression of P210 is growth-stimulatory but not sufficient for full oncogenic behavior. Some clonal lines progress toward a fully malignant phenotype as judged by increased cloning efficiency in agar suspension and frequency and rapidity of tumor induction in syngeneic mice. Such in vitro systems should be useful in evaluating the sequential and perhaps synergistic involvement of the P210 gene and other oncogenes as models for the progressive changes observed in human chronic myelogenous leukemia.
Animals↗
The role of molecular techniques in the clinical management of leukemia. Lessons from the Philadelphia chromosome.
The Philadelphia chromosome (Ph1) was the first genetic change to be associated consistently with leukemia, and it is one of the best understood on the molecular level. Because of this, it is an excellent model to investigate the application of molecular techniques to the clinical setting. These techniques are reviewed as are their clinical use in chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), and transplantation. The Ph1 is caused by the fusion of two genes on chromosomes 9 and 22, resulting in the BCR-ABL fusion gene. This new gene is believed to be the cause of these Ph1-positive leukemias. The ability to detect the BCR-ABL fusion gene evolved from cytogenetic detection to Southern blot analysis, and now includes sophisticated techniques such as polymerase chain reaction (PCR) methods and pulsed-field gels. Diagnosis of the BCR-ABL fusion gene by Southern blot detection of bcr genetic rearrangements is the prototype of molecular cancer diagnosis. The sensitivity and clinical uses of this test are reviewed, especially its application to monitoring the response to treatment. PCR methods enable the researcher to detect 1 CML cell in a population of 10(5) cells. Clinical experience with PCR, especially in transplantation medicine, is providing a better understanding of the meaning of the terms "remission" and "cure." Newer techniques using fluorescent in situ hybridization have considerable potential for BCR-ABL detection, but no clinical experience has been gained with these techniques currently. The diagnosis of the BCR-ABL fusion gene in ALL has important clinical implications because it is the most common molecular genetic change in adult ALL and is associated with short remissions and poor outcome in all age groups. Diagnosis of the BCR-ABL fusion in ALL is difficult because the molecular findings are more heterogeneous than they are in CML. The methods available and their accuracy and sensitivity are compared. A review of their clinical impact is included.
Fusion Proteins, bcr-abl↗
[Myeloblastic leukemia with the Philadelphia chromosome. Considerations on the meaning of the Philadelphia chromosome (author's transl)].
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Adolescent↗
Secondary chromosomal changes in 34 Philadelphia-chromosome-positive chronic myelocytic leukemia patients from the Mexican West.
The clonal evolution in t(9;22)-positive chronic myelocytic leukemia (CML) is well established. Four major changes occur in more than 70% of patients: +8, i(17q), +19, and an extra Philadelphia chromosome. The frequencies of secondary chromosomal changes in 34 patients from the states of Jalisco, Nayarit, Michoacán, and Colima (the Mexican West) with Philadelphia-chromosome-positive CML were assessed. The most frequent abnormalities were tetraploidy (12 cases); +8, inv(3)(q21q26), and octoploidy (3 cases each); and +der(22)(2 cases). Some translocations not previously associated with CML were observed, such as t(2;7)(p12;q36), t(3;6)(q26;p25), t(3;17)(q26;p13), and t(6;17)(q21;q23 approximately q25). Significant differences were found for +8 with respect to population results from Japan and from southern, eastern, and western Europe; for i(17)(q10) from eastern Europe; for +19 from Japan and western Europe; and for +der(22) from Japan, southern Europe, and western Europe. Although polyploidy could result from endomitosis, there is no direct evidence that the BCR/ABL protein influences such a process; however, protein kinases such as MAPK, which are involved in endomitosis, are activated by the BCR/ABL protein, and so the BCR/ABL protein could promote endomitosis through the MAPK pathway.
Adolescent↗
Complex chromosomal translocations in the Philadelphia chromosome leukemias. Serial translocations or a concerted genomic rearrangement?
Joining of the BCR and ABL genes is an essential feature of the group of human leukemias characterized by the Philadelphia chromosome and there is recent evidence that the human BCR-ABL fusion gene induces leukemia in experimental animals. Joining of these two genes is the result of cytogenetic translocation, usually the t(9;22)(q34;q11), but sometimes of more complex translocations involving one or more chromosomes in addition to chromosomes 9 and 22. The leukemic cells of some patients carry the BCR-ABL fusion gene but have an apparently normal karyotype. Recent studies show that these cells conceal complex chromosome rearrangements. Because the BCR-ABL fusion gene appears to be the result of cytogenetic rearrangement in all cases of these leukemias, the causes and mechanism of chromosome rearrangement will be relevant to the development of leukemia in man. We examine mechanisms of chromosome rearrangement and propose that both simple and complex chromosome translocations result from a single, though sometimes complex, interchange event.
Chromosomes, Human, Pair 20↗