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PubMed1991

Mice homozygous for the ablm1 mutation show poor viability and depletion of selected B and T cell populations.

The c-abl gene, originally identified as the cellular homolog of the transforming gene of the Abelson murine leukemia virus, encodes a protein-tyrosine kinase of unknown function that is expressed in all mammalian tissues. We have previously described the introduction of a mutation in the c-abl gene into the mouse germline via targeted gene disruption of embryonic stem cells. We now show that mice homozygous for this mutation are severely affected, displaying increased perinatal mortality, runtedness, and abnormal spleen, head, and eye development. We have examined components of the immune system and have found major reductions in B cell progenitors in the adult bone marrow, with less dramatic reductions in developing T cell compartments.

Animals↗
PubMed2003

Genesis of variant Philadelphia chromosome translocations in chronic myelocytic leukemia.

The Philadelphia (Ph) chromosome is found in more than 90% of chronic myelocytic leukemia (CML) patients. In most cases, it results from the reciprocal t(9;22)(q34;q11), with the ABL proto-oncogene from 9q34 fused to the breakpoint cluster region (BCR) locus on 22q11. In 5%-10% of patients with CML, the Ph chromosome originates from variant translocations, involving various breakpoints in addition to 9q34 and 22q11. In our investigation, three CML cases with complex Ph translocations have been analyzed by G-banding and fluorescence in situ hybridization (FISH). FISH with breakpoint-spanning probes for the BCR and ABL genes revealed information about the genesis of complex Ph translocations. The occurrence of one fusion signal indicates a one-step mechanism (case 1). Two fusion signals indicate a two-step mechanism (case 2). Lack of signals indicates deletions of parts of the BCR and ABL genes or of adjacent regions (case 3).

Adult↗
PubMed2004

[New approach in the diagnosis and monitoring of treatment in chronic myelogenous leukemia].

The chronic myelogenous leukemia is a pluripotent hemopoietic stem cell disease characterized by the t(9;22) (q34;q11) reciprocal chromosomal translocation (Philadelphia chromosome). The translocation result the fusion of the ABL gene located at the long arm of chromosome 9 with the BCR gene located at the long arm of chromosome 22. The BCR/ABL fusion gene encodes a chimeric protein with elevated tyrosine kinase activity, that plays an important role in the pathogenesis of the disease. In the diagnosis of chronic myelogenous leukemia and in the evaluation of the therapeutic effect, the detection of the t(9;22)(q34;q11) translocation and BCR/ABL fusion gene plays an important role. The authors in the present paper provides a review on the recently used methods of the detection of t(9;22)(q34;q11) chromosomal translocation and BCR/ABL fusion gene and their role in the diagnosis, monitoring and evaluation of therapeutic effect in chronic myelogenous leukemia.

Chromosomes, Human, Pair 9↗
PubMed1988

Activation of the abl oncogene and its involvement in chromosomal translocations in human leukemia.

Activation of the abl gene and its involvement in human leukemia is one of the most thoroughly characterized examples of the structural alterations of chromosomes associated with the conversion of a normal cell into a cancer cell. The abl oncogene as first identified on the Abelson murine leukemia virus (A-MuLV). Activation of the viral oncogene is associated, in part, with the truncation of the gene at its 5' end. As in studies with other retroviruses, results with A-MuLV presaged the mechanism of activation by abl in naturally occurring human malignancies. Thus, chronic myelogenous leukemia (CML) is consistently associated with a translocation of a piece of chromosome 9 onto chromosome 22 creating what is known as the Philadelphia chromosome (Ph1). The result of this translocation is the truncation of the 5' end of the cellular abl gene, which is located at the breakpoint of chromosome 9. The function of the abl gene product is poorly understood but is thought to participate in an, as yet, undefined pathway of growth control signals, which originate outside the cell, and traverse through the cell into its nucleus. The loss of the gene product's N-terminal amino acid sequences brought about by the truncation of the 5' portion of the gene is consistent with the hypothesis that the protein's growth-controlling activity is deregulated by the structural alterations which occur in the cancer cells. The abl gene and CML serve as a paradigm of the mechanism of activation of proto-oncogenes by chromosomal alterations. The case of CML and the Ph1 chromosome illustrates the findings we might expect as other chromosomal abnormalities are characterized at the molecular level.

Abelson murine leukemia virus↗
PubMed1991

bcr-abl mRNA lacking abl exon a2 detected by polymerase chain reaction in a chronic myelogeneous leukemia patient.

Using the polymerase chain reaction and Southern blot analysis the expression was detected of a bcr-abl mRNA lacking abl exon a2. This was due to a corresponding unusual localization of the breakpoint in the c-abl gene and was seen in a patient with Philadelphia (Ph) chromosome positive chronic myelogeneous leukemia in chronic phase. This type of mRNA has been described only once before in two Ph-positive acute lymphoblastic leukemia patients, by Soekarman et al. (1). The abl exon a2 sequences, which are missing in the three reported patients, code for a part of the SH3 region of the abl protein, which is supposed to be involved in negative regulation of the kinase domain. The clinical significance of this finding is discussed.

Blotting, Southern↗
PubMed1985

Variable breakpoints on the Philadelphia chromosome in chronic myelogenous leukemia.

The abl oncogene is translocated from chromosome 9 to 22 in the creation of the Philadelphia (Ph1) chromosome. This article describes new translocation breakpoints identified in two patients with chronic myelogenous leukemia using Southern blotting and cloned human DNA probes from chromosome 9. The translocation breakpoints on chromosome 9 in both of these patients lie closer to the human cellular abl (c-abl) gene, and the chromosome 22 breakpoints are distributed more widely than previously reported. These data help to define more clearly the chromosomal span of the breakpoints and indicate that some translocations include very little chromosome 9 sequence located 5' to the c-abl gene.

Chromosome Aberrations↗
PubMed1987

Nucleotide sequence of testis-derived c-abl cDNAs: implications for testis-specific transcription and abl oncogene activation.

The c-abl gene codes for a protein-tyrosine kinase and is expressed in most examined murine cell types as two distinct mRNA species of 5.5 kilobases (kb) and 6.5 kb. In mouse testis, an additional species of 4.0 kb is expressed in very high levels. To study the interrelationship between various c-abl transcripts and to compare their sequence with the v-abl transcript, we prepared c-abl-specific cDNA clones from mouse testis and determined the complete nucleotide sequence of the 4.0-kb cDNA that appears to be the reverse transcript of the testis-specific mRNA. In addition, we have determined the 3' sequence of an additional clone derived from the larger mRNA species that is expressed in somatic as well as germ-line cells. These cDNA sequences have been compared with the v-abl sequences to understand the mechanism of activation of this oncogene. The results demonstrate that (i) testis-specific c-abl mRNAs arise as a result of 3' truncation, and (ii) the v-abl gene has arisen from its cellular homologue as a result of an extensive deletional/mutational process.

Amino Acid Sequence↗
PubMed1992

Polymerase chain reaction analysis of BCR-ABL sequences in adult Philadelphia chromosome-negative acute lymphoblastic leukemia patients.

The Philadelphia (Ph) translocation is the most common cytogenetic abnormality in adult acute lymphoblastic leukemia (ALL) and is associated with an adverse prognosis. Using polymerase chain reaction (PCR) technology we recently observed a remarkably high incidence (55%) of BCR-ABL rearrangements in adult common ALL patients. In the present study we asked whether a subset of Ph-negative cALL, similarly to Ph-negative chronic myelocytic leukemia (CML) patients, exhibit BCR-ABL transcripts. PCR analysis of 58 adult Ph-negative cALL patients, including 47 cases with a normal karyotype revealed no evidence of chimeric BCR-ABL genes. We conclude that Ph-negative BCR/ABL-positive ALL is very rare entity if existing at all.

Adult↗
PubMed1995

A correlation between the expression of the bcr-abl chimeric gene and severity of the clinical state of CML patients with time.

Using the reverse polymerase chain reaction, four Ph' positive CML patients were followed for 2 years; a correlation between the severity of the clinical state and the b3a2 expression was noted with time. Additionally, amplification of the c-myc proto-oncogene was observed, using Southern blot analysis, in one patient prior to his entry to the blast phase. No reorganization of the bcr-abl rearrangement site was found in the latter patient. The data suggest that a routine follow-up of CML patients using the Southern blot analysis and the reverse transcription-polymerase chain reaction might be of importance in evaluating the progression of the disease.

Adult↗
PubMed1996

Value of PCR analysis for long term survivors after allogeneic bone marrow transplant for chronic myelogenous leukemia: a comparative study.

At present, allogeneic bone marrow transplantation (BMT) seems to be the only curative treatment for patients with chronic myeloid leukemia (CML). The mechanisms of this therapeutic approach probably include anti-leukemic immune response or "graft-versus-leukemia" (GVL) reaction against leukemic cell clones, since even aggressive chemotherapy is not sufficient per se to cure this type of disease. In many patients, allogeneic BMT results in the disappearance of the Ph chromosome; this negativity does not exclude the presence of residual leukemic cells since sensitivity of cytogenetic analysis is low. The chimeric BCR-ABL gene in CML is a tumor-specific marker that is well suited to allowing detection of low numbers of residual leukemic cells through the extremely sensitive detection method of polymerase chain reaction (PCR). Using this method, 1 leukemic cell in 10(5) or 10(6) normal cells can be detected. Many studies have evaluated the clinical significance and predictive value of BCR-ABL gene rearrangement detected by PCR assay after BMT, most often on heterogeneous populations. Results from such studies have been conflicting. We have conducted a review of the literature, focussing on long-term survivors (> 3 years from BMT) of CML to determine the value of PCR in such patients (n = 183). With the consideration that such a population is obviously heterogenous, long-term PCR negativity strongly correlated with achieving a cure since no patient relapsed in this population (n = 117). Among the PCR positive patients (n = 66), only 5 (8%) relapsed, suggesting a poor prognostic value for a PCR+ test > 36 months post-transplant. Besides the potential clinical value of these data, they contribute to the understanding of the biology of the disease and may suggest a crucial role for the long term GVL effect of marrow transplantation.

Bone Marrow Transplantation↗
PubMed2007

Mesenchymal stem cells from patients with chronic myeloid leukemia do not express BCR-ABL and have absence of chimerism after allogeneic bone marrow transplant.

Bone marrow is a heterogeneous cell population which includes hematopoietic and mesenchymal progenitor cells. Dysregulated hematopoiesis occurs in chronic myelogenous leukemia (CML), being caused at least in part by abnormalities in the hematopoietic progenitors. However, the role of mesenchymal stem cells (MSCs) in CML has not been well characterized. The objectives of the present study were to observe the biological characteristics of MSCs from CML patients and to determine if MSCs originate in part from donors in CML patients after bone marrow transplantation (BMT). We analyzed MSCs from 5 untreated patients and from 3 CML patients after sex-mismatched allogeneic BMT. Flow cytometry analysis revealed the typical MSC phenotype and in vitro assays showed ability to differentiate into adipocytes and osteoblasts. Moreover, although some RT-PCR data were contradictory, combined fluorescence in situ hybridization analysis showed that MSCs from CML patients do not express the bcr-abl gene. Regarding MSCs of donor origin, although it is possible to detect Y target sequence by nested PCR, the low frequency (0.14 and 0.34%) of XY cells in 2 MSC CML patients by fluorescence in situ hybridization analysis suggests the presence of contaminant hematopoietic cells and the absence of host-derived MSCs in CML patients. Therefore, we conclude that MSCs from CML patients express the typical MSC phenotype, can differentiate into osteogenic and adipogenic lineages and do not express the bcr-abl gene. MSCs cannot be found in recipients 12 to 20 months after BMT. The influence of MSCs on the dysregulation of hematopoiesis in CML patients deserves further investigation.

Adolescent↗
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↗