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PubMed1999

Simultaneous occurrence of chronic myelogenous leukemia and non-Hodgkin lymphoma at diagnosis.

We describe a case with the simultaneous occurrence of chronic myelogenous leukemia (CML) and non-Hodgkin lymphoma (NHL). Peripheral blood (PB) and bone marrow (BM) smears showed typical CML features. Lymph node biopsy exhibited a large-cell NHL. The Philadelphia chromosome or its molecular counterpart, the BCR-ABL gene fusion, by detecting with dual color-(DC) fluorescence in situ hybridization (FISH), was detected reliably both in metaphase spreads from BM and in interphase nuclei from BM and follow-up PB cells, but was not detected in the lymph node cells. Clinical features and laboratory findings show this case having a coexistence of CML and NHL.

Adult↗
PubMed1982

Transforming gene of a human leukaemia cell is unrelated to the expressed tumour virus related gene of the cell.

The virally encoded oncogenes (v-onc) of avian and mammalian retroviruses are the recombinant products of normal cellular genes (c-onc) and a retroviral genome. These cellular homologues have been highly conserved during evolution and are found in human DNA. The expression of at least one c-onc under the control of a viral promoter results in transformation of cells in a manner resembling that displayed by the v-onc counterpart; the inappropriate expression of c-onc in the absence of viral influences could likewise result in the malignant state. This proposal would be strongly supported by the presence of c-onc RNAs in a variety of human tumours were they not also demonstrable in normal tissues. The role of these RNAs in the oncogenic process remains unclear. Here we report that RNA homologous to the oncogene (v-abl) of Abelson murine leukaemia virus (A-MLV) is expressed in a unique human leukaemia in a fashion different from that of other human tissues and tumours. In addition, DNA from this tumour transforms NIH-3T3 cells at a high efficiency in a transfection assay. The transfected sequences are not related to the v-abl gene, but the NIH-3T3 transformants manufacture a transforming growth factor which behaves similarly to factors produced by A-MLV-transformed NIH-3T3 fibroblasts.

Abelson murine leukemia virus↗
PubMed1998

High rate of chromosome abnormalities detected by fluorescence in situ hybridization using BCR and ABL probes in adult acute lymphoblastic leukemia.

The value of dual-color fluorescence in situ hybridization (FISH) with BCR and ABL probes for the detection of the Philadelphia (Ph) translocation and of other alterations involving ABL and/or BCR was evaluated in adult acute lymphoblastic leukemia (ALL). One hundred and four patients were studied prospectively using interphase nuclei FISH, chromosome analysis (CA), and PCR assays for the chimeric BRC/ABL transcript. FISH detected a Ph translocation in 24 cases (23.1%), as was confirmed by CA and/or PCR. FISH revealed a false positive diagnosis of a Ph translocation in four cases (5% false positive rate). Among 54 cases with combined FISH, CA and PCR assays, FISH failed to establish a correct diagnosis in 3.7%, PCR in 5.6%, and CA in 7.4%. The combination of two screening methods led to discrepant results in 9.3% (FISH + PCR), 11.1% (FISH + CA), or 13% (CA + PCR) of the cases. In seven of 80 (8.8%) Ph-negative patients, gain of BCR and/or ABL was identified. Overall, FISH detected alterations of the BCR and/or ABL genes with an incidence of 29.8% of the current study. Due to the possibility of false positive diagnosis of a Ph translocation using dual-color FISH the combination with chromosome and/or RT-PCR analyses is recommended in adult ALL patients.

Adolescent↗
PubMed1997

BCR/ABL transcripts and leukemia phenotype: an unsolved puzzle.

The Philadelphia chromosome, arising as a consequence of the t(9;22) translocation, is one of the most frequent and certainly the most known cytogenetic abnormality present in human hematological malignancies. Unlike the vast majority of the other translocations, its presence is not restricted to a specific leukemia phenotype, but is found associated with chronic myelogenous leukemia as well as with a large percentage of acute lymphoblastic leukemias, particularly in elderly patients. Although its molecular counterpart is always represented by a rearrangement between the BCR and the ABL genes, this shows a certain degree of molecular variability. The pathogenetic relationship with the different leukemia phenotypes which have been found to be associated still awaits to be fully elucidated. However, a number of old and more recent observations seem to suggest that not only qualitative differences in the type of BCR/ABL proteins expressed, but also quantitative variations in their total level within the cells may have an important role in determining the leukemia phenotype.

Animals↗
PubMed2002

[Resistance to tumor specific therapy with imatinib by clonal selection of mutated cells].

HISTORY AND CLINICAL FINDINGS: A 60-year-old woman presented with night-sweats and increasing weakness. Physical examination revealed no abnormalities. For 27 years she had been treated for Philadelphia-positive chronic myeloid leukemia (CML). Because of progressive disease treatment with the tyrosine kinase inhibitor imatinib (STI571, Glivec (R)) had been started 9 months before. She had achieved complete hematological remission within 8 weeks, but not a cytogenetic response. INVESTIGATIONS: Elevated WBC count (26.7/nl) with a differential displaying typical features of acceleration in bone marrow aspirate confirmed CML in accelerated phase. Sequencing of the ATP binding site of the BCR-ABL gene, which - at protein level - is the target for imatinib, revealed the clonal selection of cells harboring a point mutation leading to the exchange of amino acid 253 from tyrosine to histidine. This was considered to be the cause of resistance to imatinib. TREATMENT AND COURSE: Dose increase of imatinib up to 600 mg daily and administration of cytarabine did not overcome resistance. Imatinib therapy was discontinued; hematologic remission was induced by oral therapy with hydroxyurea and mercaptopurine. In the course of the following 6 months a gradual decrease of the resistant clone from 100 % down to lower than the detection limit of the method was demonstrated. CONCLUSIONS: Clonal mutations are often the cause of resistance to imatinib therapy. They can be detected by sequencing of the ATP binding site of BCR-ABL in specialized laboratories. This case shows that discontinuation of imatinib therapy can significantly reduce the mutated (resistant) clone and thereby restore sensitivity to imatinib.

Amino Acid Substitution↗
PubMed1997

Use of herpes simplex virus thymidine kinase to improve the antiviral activity of zidovudine.

Many antiviral drugs must be metabolized to their active form by cellular enzymes. Their antiviral activity may therefore be limited by an inefficient metabolism, leading to low intracellular concentration of the active form or to the accumulation of toxic intermediate metabolites. Gene transfer might be used to overcome such limitations by transducing a gene able to increase intracellular drug metabolism. To prove such a concept, we chose the well-studied paradigm of zidovudine (AZT) metabolism and anti-HIV activity. AZT-triphosphate is the active form of AZT, acting through inhibition of HIV reverse transcription. In human cells, the rate-limiting step for AZT phosphorylation is catalyzed by the thymidylate kinase. We thus tested the capacity of herpes simplex virus type 1 thymidine kinase, which possesses a thymidylate kinase activity, to improve AZT metabolism and antiviral activity. Our results show enhanced AZT phosphorylation in HSV-1 TK-expressing lymphoid and monoblastoid cells, which correlated with significantly improved antiviral activity against different strains of HIV-1. The antiviral activity of Foscarnet, another reverse transcriptase inhibitor that does not require phosphorylation, remained unchanged. These results suggest that gene transfer might be envisioned for genetic pharmacomodulation of antiviral drugs.

Animals↗
PubMed2006

Heterogeneity in detecting Abl kinase mutations and better sensitivity using circulating plasma RNA.

Most studies test for mutations in the kinase domain of the abl gene in chronic myeloid leukemia (CML) using peripheral blood (PB) cells. Frequently, progression of the disease manifests with increased blasts in bone marrow (BM) and not in PB. Simultaneous analysis of plasma, PB cells and BM cells from 41 imatinib-resistant CML patients showed mutations in 63% of PB cells and 68% of plasma or BM cells (P = 0.04). In discordant patients, 13 mutations were detected in plasma, 11 in BM cells and 9 in PB cells. The T315I mutation was detected in plasma and BM but not PB cells in one patient. We detected no mutations in the plasma of 45 previously untreated CML patients, but two of these patients showed mutations in plasma and not cells by 9 months on therapy. Circulating plasma mRNA is a reliable alternative to BM mRNA for detecting ABL mutations.

Antineoplastic Agents↗
PubMed1993

Identification of masked and variant Ph (complex type) translocations in CML and classic Ph in AML and ALL by fluorescence in situ hybridization with the use of bcr/abl cosmid probes.

In the present study, three chronic myelogenous leukemia (CML) patients with variant Philadelphia (Ph) chromosomes (complex types), two CML patients with a masked Ph, one case with Ph positive acute lymphocytic leukemia (ALL), and one with Ph positive acute myelocytic leukemia (AML) were analyzed by standard cytogenetic techniques (G-banding), Southern blot studies, and fluorescence in situ hybridization (FISH) procedures using probes from portions of the bcr and abl genes. It has been previously shown that this FISH approach could detect the bcr/abl fusion event in CML patients with classic or variant (simple type) Ph. Our results demonstrate that this FISH assay can also detect the bcr/abl fusion status in CML patients with masked or variant (complex type) Ph chromosomes and in some patients with Ph positive ALL or AML.

Adult↗
PubMed1983

Increased expression of myc-related oncogene mRNA characterizes most BALB/c plasmacytomas induced by pristane or Abelson murine leukemia virus.

RNA blots of poly(A)-containing RNA from normal livers and spleens and from a number of transplantable hematopoietic and lymphoid BALB/c tumors, including early and late generation plasmacytomas, were hybridized with probes for four onc genes. abl RNA was abundant only in those tumors producing Abelson virus, bas RNA was found in approximately equal amounts in normal tissues and plasmacytomas, and myb RNA was absent in normal liver and plasmacytomas. Normal liver and spleen RNA showed faint traces of myc hybridization, but myc RNA was increased in most plasmacytomas. In one plasmacytoma, TEPC 1165, a particularly abundant amount of myc RNA was found, principally as a 3.5-kilobase band. In the other plasmacytomas, bands of 2.4- or 1.8-kilobase myc RNA were found. Southern blots of DNA from tumors that contained 2.4-kilobase or larger myc RNA showed myc hybridization to an EcoRI fragment of about 21 kilobase pairs, similar to the myc band in normal DNA. EcoRI digests of DNA from two tumors that expressed myc RNA of 1.8 kilobases showed an additional smaller myc band, suggesting that the myc gene is rearranged in these plasmacytomas. The basis for increased myc gene transcription in plasmacytomas is not understood, but the evidence suggests that different mechanisms may be operating in different plasmacytomas. Apparently, neither myc gene amplification nor myc gene rearrangement is required for increased myc transcription.

Abelson murine leukemia virus↗
PubMed2005

Use of imatinib mesylate for favorable control of hypercalcemia mediated by parathyroid hormone-related protein in a patient with chronic myelogenous leukemia at blast phase.

The case of a 72-year-old woman with chronic myelogenous leukemia in blast phase (BP) with hypercalcemia is reported. Bone x-ray examination revealed multiple osteolytic lesions throughout the body. The serum level of parathyroid hormone-related protein (PTHrP) was elevated, and PTHrP messenger RNA (mRNA) was detectable in the peripheral blood mononuclear cells (PBMNC) at BP but was not detectable at chronic phase (CP).Treatment with conventional chemotherapy did not completely control either serum calcium level or serum PTHrP level. Treatment with imatinib mesylate (imatinib) alone rapidly normalized these parameters in parallel with a decrease in the number of blast cells. The treatment also maintained the patient in good condition for approximately 3 months, even though the number of blast cells, serum calcium level, serum PTHrP level, and PTHrP mRNA level increased at the terminal stage. Mutations of the p53, K-Ras, and BCR-ABL genes in PBMNC at BP were absent. A noteworthy feature in this patient was that PBMNC at BP but not at CP showed high Lyn mRNA expression. Taken together the findings showed that production of PTHrP by blast cells was favorably controlled by imatinib therapy alone. Imatinib may prolong survival time at BP even though the patients have the complication of PTHrP-mediated hypercalcemia.

Aged↗
PubMed1997

Nitrogen starvation in a Saccharomyces cerevisiae strain deleted in the trehalose-6-phosphate synthase complex.

Little is known about the mechanisms by which nutrient limitation leads to G1 arrest in Saccharomyces cerevisiae. We have shown that mutant cells deleted in the trehalose-6-phosphate synthase gene able to grow on glucose, when starved for nitrogen, did not arrest in the G1 phase of the cell cycle. We attribute this effect to an increase in the activity of cAMP-dependent protein kinase. When grown on maltose without nitrogen they arrested properly in G1. Tests with a mutant cell deleted in the specific trehalose phosphatase proved that the presence of the trehalose precursor, trehalose-6-phosphate, was sufficient to trigger the negative sign during nitrogen starvation, leading the cells to arrest in the G1 phase of the cell cycle.

Cell Cycle↗
PubMed1999

[Syngeneic peripheral blood stem cell transplantation for chronic myelogenous leukemia associated with Klinefelter's syndrome].

We report on a patient with Klinefelter's syndrome who underwent successful syngeneic peripheral blood stem cell transplantation (PBSCT) for chronic myelogenous leukemia (CML). A-46-year-old man was given a diagnosis of chronic phase CML in May 1994 on the basis of findings of leukocytosis (54,000/microliter) and bone marrow chromosomal abnormalities [47, XXY, t(9; 22; 14) (q34; q11; q24)]. Hydroxyurea and interferon alpha were administered. In August 1996, a syngeneic transplant was performed following myeloablative therapy, using peripheral blood stem cells collected from the patient's identical twin brother, who had been pretreated with rhG-CSF. Following transplantation (4.0 x 10(6) CD34+ cells/kg) and the subsequent administration of rhG-CSF, the patient rapidly achieved normal tri-lineage hematopoiesis. A post-transplant chromosomal analysis of the patient's bone marrow cells detected the 47, XXY karyotype. Although the major BCR-ABL gene had been detected in bone marrow by RT-PCR methods prior to the syngeneic PBSCT (August 1996), it was not detected after PBSCT (January 1997). In March 1998, interphase fluorescence in situ hibridization (FISH) procedures disclosed XXY signal patterns in peripheral blood lymphocyte samples from the patient and donor, at frequencies of 96% and 97%, respectively. Both the patient and donor had high levels of serum FSH and LH and low levels of serum testosterone.

Diseases in Twins↗
PubMed2002

Double Ph-positive megakaryoblastic transformation of chronic myeloid leukemia.

A 64-yr-old Japanese man presented with mild anemia, leukocytosis, and thrombocytosis in November 1999. A diagnosis of chronic myeloid leukemia was made with a positive Ph chromosome, and interferon alpha treatment was started, 6 million units a day. Two years later, in October 2001, the patient developed leukocytosis, an increased LDH level, and large blasts with basophilic cytoplasm with cytoplasmic projections appeared in the peripheral blood. Bone marrow aspiration revealed increased blasts (59.6%). These blasts were negative on peroxidase stain, positive on acid phosphatase, and weakly positive on alpha naphthyl butyrate esterase stain and periodic acid-Schiff stain. Immunohistochemical staining with monoclonal antibodies revealed that these blasts were strongly positive with anti-CD41 (glycoprotein IIb/IIIa), weakly positive with CD7, CD33, and CD34, and negative with other monoclonal antibodies. A diagnosis of megakaryoblastic transformation from chronic myeloid leukemia was therefore made. Two-color fluorescence in situ hybridization (FISH) for portions of the major-bcr and abl genes from bone marrow cells revealed two fused signals in 90.6% and one fused signal in 5.8% of 106 cells. A cytogenetic study revealed that bone marrow cells were 69, XYY, +6, -7, +8, -9, t(9;22)(q34;q11), +11, +13, -15, -16, dic(17;18)(p11;p11), -18, +19, +21, der(22)t(9;22) in six of nine examined cells. These findings confirmed that these megakaryoblasts originated from megakaryocytes of the chronic myeloid leukemia clone.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Repair of UV damage in actively transcribed ribosomal genes.

Repair of UV-induced cyclobutane pyrimidine dimers (CPDs) was measured in the individual strands of transcriptionally active ribosomal genes in mouse Friend erythroleukemia cells. Ribosomal genes (rDNA) are multicopied, but only a fraction is transcriptionally active (or transcriptionally "poised"). Selective psoralen binding was used to separate the active fraction, which has an open chromatin structure, from inactive rDNA. EcoRI digestion was used to selectively release the active fraction from nuclei for DNA repair studies. UV dose response curves indicate there is no significant bias for CPD formation in either strand of both types of rDNA chromatin. More importantly, there was no evidence for transcription repair coupling in the individual strands of active and total rDNA. Indeed, over an 8 h period (one cell-cycle), repair of CPDs was almost nonexistent in either strand of active and total rDNA. Furthermore, the fraction of each chromatin structure remains constant during these repair times, suggesting that chromatin rearrangements observed during excision repair of nonnucleolar chromatin do not occur following UV damage of rDNA. However, CPDs are removed efficiently from the transcribed strand of the constitutively expressed c-abl gene (transcribed by Pol II), demonstrating that these cells are capable of transcription repair coupling.

Animals↗
PubMed1987

Absence of the hybrid bcr-abl mRNA in Ph1-positive B lymphoblastoid cell lines established from a patient with chronic myelogenous leukemia.

The expression of c-abl, c-sis, c-myc and N-ras oncogenes was examined in 2 lymphoblastoid cell lines, one with Ph1 (PB-1049) and the other without Ph1 (LN-1049), both established from a patient with chronic myelogenous leukemia (CML), and in a Ph1-positive cell line (PB-1049-T) derived from a tumor formed after transplantation of PB-1049 cells in a nude mouse with reference to their tumorigenic potential in nude mice. The normal transcripts of c-abl were detected in all 3 lymphoblastoid cell lines. Although in situ hybridization of v-abl proved, and restriction endonuclease analyses of the bcr region strongly indicated the occurrence of bcr-abl rearrangement in PB-1049 and PB-1049-T, we could not obtain any evidence for the expression of the hybrid bcr-abl mRNA. These results indicate that the Ph1 translocation does not ensure the production of the hybrid bcr-abl mRNA, and that the expression of hybrid bcr-abl gene is not essential for the maintenance of tumorigenicity of these cell lines. Expression of c-sis was not detected in any of the cell lines examined, whereas the expression of c-myc was uniformly higher in the 3 cell lines than in normal control cells. The levels of N-ras expression varied considerably, probably in parallel with the changes in tumorigenicity of the cell lines. N-ras expression in the PB-1049 and PB-1049-T cell lines was higher than that in the LN-1049 line when they retained tumorigenic potential, but it fell to the level of LN-1049 with loss or decline of tumorigenicity.

Fusion Proteins, bcr-abl↗
PubMed1993

Application of chromosome microdissection probes for elucidation of BCR-ABL fusion and variant Philadelphia chromosome translocations in chronic myelogenous leukemia.

Fluorescence in situ hybridization (FISH) has become an increasingly important method for assessing chromosome rearrangement. The reciprocal translocation constituting the Philadelphia (Ph) chromosome [t(9;22)(q34;q11)] characterizes more than 90% of patients with chronic myelogenous leukemia (CML). However, in the remaining cases the Ph chromosome (genetically characterized by the fusion of the BCR-ABL genes) is thought to arise through complex translocations that are often not readily apparent using routine chromosome-banding analysis. For this reason we have developed unique band-specific probes for two-color FISH that detect unequivocally the Ph chromosome, and its derivatives. Results of the application of these probes are illustrated by analysis of 11 cases of CML (9 of which contain "variant" translocations). The probes were generated by chromosome microdissection and in vitro amplification of the bands involved in the Ph translocation, leading to an extremely fast and sensitive approach to identify this alteration in leukemic cell populations.

Base Sequence↗
PubMed2004

Imatinib attenuates diabetes-associated atherosclerosis.

OBJECTIVE: Diabetes is associated with accelerated atherosclerosis, the major factor contributing to increased mortality and morbidity in the diabetic population. The molecular mechanisms by which diabetes promotes atherosclerosis are not fully understood. Platelet-derived growth factor has been shown to play a major role in the pathology of vascular diseases, but whether it plays a role in atherosclerosis associated with diabetes remains unknown. The aims of this study were to assess whether platelet-derived growth factor-dependent pathways are involved in the development of diabetes-induced atherosclerosis and to determine the effects of platelet-derived growth factor receptor antagonism on this disorder. METHODS AND RESULTS: Diabetes was induced by injection of streptozotocin in 6-week-old apolipoprotein E knockout mice. Diabetic animals received treatment with a tyrosine kinase inhibitor that inhibits platelet-derived growth factor action, imatinib (STI-571, 10 mg/kg per day), or no treatment for 20 weeks. Nondiabetic apolipoprotein E knockout mice served as controls. Induction of diabetes was associated with a 5-fold increase in plaque area in association with an increase in aortic platelet-derived growth factor-B expression and platelet-derived growth factor-beta receptor phosphorylation as well as other prosclerotic and proinflammatory cytokines. Imatinib treatment prevented the development of atherosclerotic lesions and diabetes-induced inflammatory cytokine overexpression in the aorta. CONCLUSIONS: Tyrosine kinase inhibition with imatinib appears to be a novel therapeutic option to retard the development of atherosclerosis, specifically in the context of diabetes.

Animals↗