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PubMed1995

c-fos is not essential for v-abl-induced lymphomagenesis.

Recent studies have suggested that cellular transformation by abl oncoproteins may be mediated by the ras signaling pathway. One of the main nuclear targets of this signal transduction cascade is the Fos and Jun family of transcription factors. To test the relevance of the c-fos proto-oncogene for v-abl-induced cancer development, we inoculated c-fos-deficient mice with the Abelson murine leukemia virus. Neonatal c-fos-deficient mice infected with the Abelson complex are able to develop the pre-B-cell lymphoma that characterizes Abelson disease. c-fos-deficient animals succumb to the disease with similar kinetics as their wild-type and heterozygous littermates. Moreover, the transformed cell that brings about the malignancy in mutant mice is the same pre-B-cell lymphoblast that is seen in control animals. These results demonstrate that c-fos is not required for in vivo transformation by v-abl.

Abelson murine leukemia virus↗
PubMed1991

Missing Y chromosome in Ph1-negative chronic myeloid leukemia with bcr rearrangement. Evidence for a bcr-abl recombination on chromosome 22 by in situ hybridization.

In a case of Philadelphia chromosome (Ph1)-negative chronic myeloid leukemia (CML) without the Y chromosome, we investigated the differences, at the molecular level, from Ph1-positive CML. Using Southern blot analysis and in situ hybridization studies, we could demonstrate a rearrangement within the breakpoint cluster region (bcr), and the location of a bcr-abl fusion gene on chromosome 22. To our knowledge, this is the first case of Ph1-negative CML with a loss of the Y chromosome in which the molecular abnormalities are shown to be identical with those in Ph1-positive CML.

Chromosome Aberrations↗
PubMed2005

C-Abl as a modulator of p53.

P53 is renowned as a cellular tumor suppressor poised to instigate remedial responses to various stress insults that threaten DNA integrity. P53 levels and activities are kept under tight regulation involving a complex network of activators and inhibitors, which determine the type and extent of p53 growth inhibitory signaling. Within this complexity, the p53-Mdm2 negative auto-regulatory loop serves as a major route through which intra- and extra-cellular stress signals are channeled to appropriate p53 responses. Mdm2 inhibits p53 transcriptional activities and through its E3 ligase activity promotes p53 proteasomal degradation either within the nucleus or following nuclear export. Upon exposure to stress signals these actions of Mdm2 have to be moderated, or even interrupted, in order to allow sufficient p53 to accumulate in an active form. Multiple mechanisms involving a variety of factors have been demonstrated to mediate this interruption. C-Abl is a critical factor that under physiological conditions is required for the maximal and efficient accumulation of active p53 in response to DNA damage. C-Abl protects p53 by antagonizing the inhibitory effect of Mdm2, an action that requires a direct interplay between c-Abl and Mdm2. In addition, c-Abl protects p53 from other inhibitors of p53, such as the HPV-E6/E6AP complex, that inhibits and degrades p53 in HPV-infected cells. Surprisingly, the oncogenic form of c-Abl, the Bcr-Abl fusion protein in CML cells, also promotes the accumulation of wt p53. However, in contrast to the activation of p53 by c-Abl, its oncogenic form, Bcr-Abl, counteracts the growth inhibitory activities of p53 by modulating the p53-Mdm2 loop. Thus, it appears that by modulating the p53-Mdm2 loop, c-Abl and its oncogenic forms critically determine the type and extent of the cellular response to DNA damage.

Animals↗
PubMed2004

Rearrangements of the telomeric region of mouse chromosome 11 in Pre-B ABL/MYC cells revealed by mBANDing, spectral karyotyping, and fluorescence in-situ hybridization with a subtelomeric probe.

Previous work has demonstrated that chromosome 11 is trisomic or shows a duplicated region encompassing the E1/E2 band of chromosome 11 in 90% of v-abl/myc-induced plasmacytomas (Wiener et al. 1995). In the present report, we have studied BALB/c PreB lymphocytes that were immortalized by v-abl and stably transfected with a conditional MycER vector (Mai et al. 1999). These cells, termed PreB ABL/MYC, showed changes in the E1/E2 bands of chromosome 11 that are similar to those reported previously for v-abl/myc-induced plasmacytomas. This was shown by the use of chromosome painting, SKY, FISH and mBAND. Our findings suggest that the Pre-B ABL/MYC cells may be used to analyse the genetic changes affecting chromosome 11 that are associated with v-abl/myc-dependent tumorigenesis in mouse B cells.

Animals↗
PubMed2001

Inhibition of cell migration by Abl family tyrosine kinases through uncoupling of Crk-CAS complexes.

c-Abl and the Abl-related gene product (Arg) are nonreceptor tyrosine kinases that regulate the actin cytoskeleton of cells by direct association with F-actin and localization to focal contacts. However, the biological significance of this interaction is not known. We show here that transfection of COS-7 cells with a kinase-inactive form of c-Abl (Abl) promotes c-Crk II/p130(CAS) (Crk-CAS) coupling, enhancing cell migration. Moreover, embryonic fibroblast cells isolated from mice devoid of endogenous Abl and Arg (abl-/- arg-/-) demonstrate increased Crk-CAS coupling and motility. Conversely, expression of a kinase-active form of Abl or reconstitution of abl-/- arg-/- cells with wild-type Abl prevents Crk-CAS coupling and inhibits cell migration. Thus, Abl and Arg kinases play a critical role in preventing cell migration through regulation of Crk and CAS adaptor protein complexes, which are necessary for cell movement.

Animals↗
PubMed2005

N-acetyl-cysteine enhances growth in BCR-ABL-transformed cells.

N-acetyl-cysteine (NAC) has been reported to have anticancer properties such as counteractions against mutagens and prevention of tumor progression by scavenging reactive oxygen species (ROS). However, here we report that NAC can enhance the anchorage-independent growth of cells transformed by activated ABL tyrosine kinases or Ras. This effect was not dependent on loss of focal adhesion kinase activation. NAC rescued cell growth that was suppressed by heat shock protein (Hsp) 90 inhibitors possibly by chemical modification of their quinone moiety. NAC rendered Rat1/BCR-ABL cells resistance to a Ras inhibitor manumycin in soft agar colony formation. In the absence of Hsp90 inhibitors, NAC stimulated the activation of MAP kinase in BCR-ABL-transformed but not in the parental Rat1 cells. We propose that NAC should be used carefully in cancer treatment.

Acetylcysteine↗
PubMed1994

Detection of minimal residual disease using clonospecific primers for CDRIII in patients with acute B lymphocytic leukemia with or without Philadelphia chromosome: possibility of clinical application as a tool for improving prognosis.

We attempted to identify the minimal residual leukemic clone as related to the clinical course in patients with acute B lymphocytic leukemia (B-ALL). DNA was extracted from stored bone marrow slides, and the third complementarity determining region (CDRIII) was amplified by polymerase chain reaction (PCR) using primers with consensus sequences for VH and JH. After amplification of the CDRIII band, the DNA fragment of CDRIII was inserted into the cloning vector PUC118. After cloning, the DNA sequences for CDRIII were determined. Clonospecific DNA sequences in CDRIII were selected, and clonospecific primers for each patient were synthesized. Using the clonospecific primers, we carried out second-round PCR to detect minimal residual disease (MRD) during several stages of the clinical course. Basically, the sensitivity of detection for MRD was between 10(-4) and 10(-5) cells. Even when leukemic cells were not detected in the morphologic study, with this detection system, the MRD was identified as an amplified CDRIII band stained with ethidium bromide on agarose gel. After bone marrow transplantation (BMT), MRD was detected for at least 4 months. In this article, we discuss the difference in sensitivity of detection for MRD between the BCR-ABL fusion gene and CDRIII in Philadelphia chromosome-positive (Ph+) B-ALL, as well as the possible clinical application of this method to predict relapse and prognosis.

Adolescent↗
PubMed1991

The v-abl, c-fms, or v-myc oncogene induces gamma radiation resistance of hematopoietic progenitor cell line 32d cl 3 at clinical low dose rate.

A variety of viral and cellular oncogenes have been described with differing mechanisms of action but with the common property of inducing morphologic alteration of cells in culture. Subclonal lines of oncogene expressing cells have been shown to produce tumors in vivo. Expression of the N-ras oncogene in embryo fibroblast NIH/3T3 cells has been demonstrated to increase radioresistance in vitro, and these results have been confirmed and extended to human cell lines expressing the c-raf oncogene. In the present report, we have examined the effects of expression of the c-fms, v-abl, or v-myc oncogene in a clonal hematopoietic progenitor cell line 32D cl 3. The 32D cell line is nonmalignant in vivo and is dependent upon a source of Interleukin-3 (IL-3) for growth in vitro. The radiation survival of 32D cl 3 cells transfected and expressed in the c-fms oncogene showed significant increase in the radioresistance at both 5 cGy/min and 116 cGy/min. A clone of 32D cl 3 transfected and expressing the v-myc oncogene demonstrated increased radioresistance at both dose rates. Results of split dose experiments suggested significant repair of sublethal irradiation damage of 32D-v-abl cells. Results were compared with expression of the same v-abl oncogene in the NIH/3T3 embryo fibroblast cell line. The data demonstrate that gamma irradiation resistance is significantly increased by each oncogene expressed in 32D cl 3 cells. The data on cell line 32D cl 3 may correlate with the radioresistance of v-abl expressing human hematopoietic cell malignancies treated by irradiation therapy.

Animals↗
PubMed2000

Working at the cutting edge: the creation of allosteric ribozymes.

The appropriate folding of catalytic RNA is a prerequisite for effective catalysis. A novel ribozyme, the maxizyme, has been generated and its activity can be controlled allosterically. The maxizymes work both in vitro and in vivo indicating the potential utility of this novel class of ribozyme as a gene-inactivating agent with a biosensor function.

Adenosine Triphosphate↗
PubMed1995

v-Abl activates c-myc transcription through the E2F site.

The v-abl oncogene of Abelson murine leukemia virus encodes a deregulated form of the cellular nonreceptor tyrosine kinase. v-Abl activates c-myc transcription, and c-Myc is an essential downstream component in the v-Abl transformation program. To explore the mechanism by which v-Abl activates c-myc transcription, a cotransfection assay was developed. We show that transactivation of a c-myc promoter by v-Abl requires the SH1 (tyrosine kinase) and SH2 domains of v-Abl; the C-terminal domains are not required for transactivation. The assay also identified the E2F site in the c-myc promoter as a v-Abl-responsive element. In addition, multimerized E2F sites were shown to be sufficient to confer v-Abl-dependent activation on a minimal promoter. This is the first identification of a v-Abl response element for transcriptional activation. v-Abl tyrosine kinase-dependent changes in proteins binding the c-myc E2F site were also demonstrated, including induction of a complex containing DP1, p107, cyclin A, and cdk2. Identification of v-Abl-dependent changes in E2F-binding proteins provides an important link between v-Abl, transcription, cell cycle regulation, and control of cellular growth.

Abelson murine leukemia virus↗
PubMed2000

Detailed mapping of methylcytosine positions at the CpG island surrounding the Pa promoter at the bcr-abl locus in CML patients and in two cell lines, K562 and BV173.

Chronic myelogenous leukemia (CML) is associated with a translocation of the protooncogene c-abl from chromosome 9 to chromosome 22, where it fuses to proximal exons of the bcr gene. The expression of the hybrid gene bcr-abl is regulated by the bcr promoter and results in a translation product with high tyrosine kinase activity. In most CML cases, one of two abl promoters (Pa) is nested within the bcr-abl transcription unit, but appears to be usually silent. Recently, de novo methylation of the Pa region and its correlation with disease progression were reported. As these previous studies were limited to the use of methylation-sensitive restriction endonucleases, our aim here was to obtain a complete map of methylcytosines and its variants in CML patients and in model cell lines. To achieve this, bisulfite conversion of cytosines (but not methylcytosines) to uracils in genomic DNA was employed. After modification, the region of interest was PCR-amplified and the products were cloned and sequenced. The results show methylation at a high level and in a homogenous pattern in the BV173 cell line, corresponding to the translocated abl alleles. Variant methylation observed in K562 cells correlates with multiple bcr-abl loci and an intact chromosome 9. Patients that were methylation-positive in restriction analysis showed sporadic and heterogenous occurrence of methylcytosines in bisulfite modification assays. Corresponding results were obtained using a quantitative Southern analysis of the extent of methylation. We conclude that restriction analysis combined with PCR is able to find rare cases of hypermethylation, e. g., for diagnostic purposes, but does not reflect the dominating level of methylation in Ph-positive cells.

Base Sequence↗
PubMed1991

Tumorigenic transformation of spontaneously immortalized fibroblasts from patients with a familial cancer syndrome.

Immortal cell lines arose spontaneously during in vitro culture of initially normal fibroblasts, MDAH041 and MDAH087, from patients with Li-Fraumeni familial cancer syndrome. Fibroblasts from a control donor, MDAH170, maintained a normal morphology and senesced at 31 population doublings. The immortal fibroblasts have several properties of transformed cells. In addition to having acquired an altered morphology and chromosomal anomalies, MDAH041 and MDAH087 have escaped from senescence, growing beyond 300 and 100 population doublings (pd), respectively. As early as 50 pd, these cells can be transformed by an activated H-ras oncogene to form tumors in nude mice. However, MDAH041 immortal cells were resistant to tumorigenic transformation by transfection with the v-abl oncogene.

Animals↗
PubMed1998

Dual rearrangement of immunoglobulin and T-cell receptor genes in a case of Philadelphia chromosome-positive acute leukemia.

A 48-year-old patient was admitted to our hospital for leukocytosis. The blast cells were positive for peroxidase and he was tentatively diagnosed as acute myeloid leukemia according to the French-American-British criteria. By flow cytometry, the bone marrow cells were positive for CD10, CD13, CD33 and HLA-DR, but two-color analysis revealed that most of the CD13- and CD33-positive cells did not express CD10. The marrow cells had Philadelphia chromosome with no additional abnormalities. Major bcr-abl fusion gene was observed by the reverse transcriptase-polymerase chain reaction method. Southern blot analysis disclosed rearrangement of both immunoglobulin heavy chain and T-cell receptor beta chain genes. He received combined chemotherapy for myeloid lineage and lymphoid lineage, but the response was quite poor. He died 64 days after admission due to pulmonary bleeding. Although the association of Ph1 with multilineage differentiation is unclear, our case has significant implication for further investigation of the relationship between Ph1-positive cells and lineage selection.

Acute Disease↗
PubMed1996

Overexpression of v-abl uniquely cooperates with c-myc dysregulation in induction of plasma cell tumors, bypassing the need for T-lymphocytic help and overcoming T-lymphocytic interference.

We have investigated the effects of T lymphocytes on induction of mouse plasma cell tumors. We show that ABL-MYC, a plasmacytomagenic retrovirus that constitutively expresses v-abl and c-myc, is able to induce plasmacytomas in 100% of athymic BALB/c mice, with or without intraperitoneal pristane pretreatment. Other induction regimens are ineffective under these conditions, indicating that the combination of v-abl and c-myc oncogenes is uniquely able to transform plasma cells in mice that are deficient in T lymphocytes. Furthermore, in the absence of pristane, ABL-MYC-infected athymic congenics developed plasmacytomas in half the time required for euthymic BALB/c mice, suggesting that T lymphocytes can have a negative effect and can retard, but not totally inhibit, the outgrowth of plasmacytomas. This phenomenon could not be appreciated in other regimens of plasmacytoma induction, because only ABL-MYC is sufficient to induce plasmacytomas in athymic mice or in euthymic mice in the absence of pristane pretreatment.

Animals↗
PubMed2007

Chronic myeloid leukemia blast crisis arises from progenitors.

Chronic myeloid leukemia (CML) progresses through three distinct clinical stages: chronic phase, accelerated phase, and blast crisis. The progression to accelerated phase and blast crisis is driven by activation of oncogenes, inactivation of tumor suppressor genes, and/or amplification of the BCR-ABL fusion gene, which causes the chronic phase of the disease. The cell of origin of blast crisis is a subject of speculation. Here, I develop a simple mathematical model of CML blast crisis to investigate whether blasts arise from leukemic stem cells or more differentiated leukemic cells. I use data of patients treated with imatinib and previous agents to estimate the effects of therapy on the rate of progression. Imatinib reduces the progression rate 10-fold as compared with previous (ineffective) therapies. If blasts were produced by leukemic stem cells, there would be no difference in the rate of progression between patients treated with imatinib and previous therapies, because imatinib seems to be incapable of depleting leukemic stem cells. Imatinib does, however, deplete leukemic progenitors. Therefore, CML blasts are likely to arise from leukemic progenitors. Disclosure of potential conflicts of interest is found at the end of this article.

Benzamides↗