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At least 307 records · Page 17Linked to original sources
PubMed2005

ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia.

PURPOSE: Point mutations within the ABL kinase domain of the BCR-ABL gene have been associated with clinical resistance to imatinib mesylate in chronic myeloid leukemia (CML) patients. To shed further light on the frequency, distribution, and prognostic significance of ABL mutations, we retrospectively analyzed a homogeneous cohort of late chronic phase CML patients who showed primary cytogenetic resistance to imatinib. PATIENTS AND METHODS: Using denaturing high-performance liquid chromatography (D-HPLC) and sequencing, we screened for ABL mutations in a total of 178 bone marrow and/or peripheral blood samples from 40 late chronic phase CML patients homogeneously treated with imatinib 400 mg/d, who did not reach a major cytogenetic response at 12 months. RESULTS: Mutations were found in 19 of 40 patients (48%). Mutations were already detectable by D-HPLC at a median of 3 months from the onset of therapy. The presence of a missense mutation was significantly associated with a greater likelihood of subsequent progression to accelerated phase/blast crisis (P = .0002) and shorter survival (P = .001). Patients carrying mutations falling within the P-loop seemed to have a particularly poor outcome in terms of time to progression (P = .032) and survival (P = .045). CONCLUSION: Our results show that, irrespective of the hematologic response, monitoring for emerging mutations in the first months of therapy may play a role in detecting patients with worse prognosis, for whom a revision of the therapeutic strategy should be considered.

Adult↗
PubMed2001

Adult precursor B-ALL with BCR/ABL gene rearrangements displays a unique immunophenotype based on the pattern of CD10, CD34, CD13 and CD38 expresssion.

The Philadelphia chromosome (Ph+) reflects a balanced reciprocal translocation between the long arms of chromosomes 9 and 22 [t(9;22)(q34;q11.2] involving the BCR and ABL genes. At present, detection of BCR/ABL gene rearrangements is mandatory in precursor-B-ALL patients at diagnosis for prognostic stratification and treatment decision. In spite of the clinical impact, no screening method, displaying a high sensitive and specificity, is available for the identification of BCR/ABL+ precursor-B-ALL cases. The aim of the present study was to explore the immunophenotypic characteristics of precursor B-ALL cases displaying BCR/ABL gene rearrangements using multiple stainings analyzed by quantitative flow cytometry in order to rapidly (<1 h) identify unique phenotypes associated with this translocation. From the 82 precursor-B-ALL cases included in the study 12 displayed BCR/ABL gene rearragements, all corresponding to adult patients, four of which also displayed DNA aneuploidy. Our results show that BCR/ABL+ precursor B-ALL cases constantly displayed a homogeneous expression of CD10 and CD34 but low and relatively heterogeneous CD38 expression, together with an aberrant reactivity for CD13. In contrast, this unique phenotype was only detected in three out of 70 BCR/ABL cases. Therefore, the combined use of staining patterns for CD34, CD38 and CD13 expression within CD10-positive blast cells is highly suggestive of BCR/ABL gene rearrangements in adults with precursor B-ALL.

Adult↗
PubMed1991

Molecular studies of chronic myelogenous leukemia using the polymerase chain reaction.

Thirty-two cases of chronic myelogenous leukemia (CML) were studied to determine whether there was a correlation between the position of the chromosome breakpoint within the breakpoint cluster region (bcr) on chromosome 22 and the type of chimeric mRNA expression. One case with the chromosome breakpoint in zone 2 of the major bcr (Mbcr) and six cases with breakpoints in zone 3 expressed Mbcr exon 2-abl (b2-a) mRNA, and they were in distinguishable at the level of mRNA expression. The remaining ten cases with breakpoints in zone 3 and all ten cases with breakpoints in zone 4 expressed Mbcr exon 3-abl (b3-a) mRNA with or without b2-a mRNA. Three cases with breakpoints in zone 5 expressed b3-a mRNA, and none of these expressed Mbcr exon 4-abl(b4-a) mRNA. The cases with breakpoints in zones 4 or 5 had b3-a mRNA expression indistinguishable from those with breakpoints in zone 3. In two patients, the breakpoint in the bcr could not be determined by Southern hybridization using the 3' bcr probe or the large bcr probe. However, when analyzed for chimeric mRNA expression, both of them exhibited b3-a chimeric mRNA, suggesting the possibility that the entire Mbcr is deleted in the majority of leukemic cells in these patients. These studies indicate that Southern hybridization analysis combined with the polymerase chain reaction assay is a useful approach to understanding the pathologic role of bcr-abl gene recombination and expression in the development of CML.

Adolescent↗
PubMedDate not supplied

Meeting report: antisense oligonucleotides.

The use of antisense oligonucleotides as a therapeutic tool in modulating gene expression represents a newly established strategy for treating diseases. Such oligomers may be designed to complement a region of a specific gene or messenger RNA. Using this approach, oligonucleotides can serve as a potential block of transcription or translation through sequence-specific hybridization with targeted genetic segments. In the Fourth Meeting of the Italian Society of Experimental Hematology "Discutiamone Insieme", authors reported the use of in vitro synthesized oligonucleotides to inhibit normal and chimeric gene expression of bcl-2 in normal and neoplastic cell lines, respectively, that carry the t(14;18) translocation. The roles of c-myb and B-myb in the control of the proliferation and differentiation of normal hematopoietic cell lines have been investigated by selective inhibition of the expression of specific transcripts. To get some insight into the correlation between proliferation and differentiation in myeloid cells, some authors studied and reported the differentiation potential of G1-arrested cells obtained by a specific oligodeoxynucleotide complementary to the 5' region of the c-myb mRNA. The use of anti-P53 antisense oligos in the modulation of the growth of normal and neoplastic bone marrow progenitors was presented and confirmed the pivotal role of this gene in cell cycle control. The role of abl gene expression in normal and chronic myelogenous leukemia (CML) cells is not yet completely understood. Selective inhibition of this proto-oncogene and of the abl-bcr oncogene have been achieved by using of c-abl sequence specific antisense oligonucleotides; this approach sheds new light on the function of this gene in CML.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

FISH analysis for CML monitoring?

Conventional cytogenetics is considered the gold standard for evaluating CML during interferon (IFN) treatment. Drawbacks to this approach are the small number of metaphases available during IFN therapy and the impossibility of scoring interphase cells. We applied, besides cytogenetics, double-color FISH (dc-FISH) detection of BCR-ABL gene fusion to monitor 20 CML patients on IFN. dc-FISH easily detected 200 cells per specimen, while with cytogenetic examination a mean of 16.1 mitoses per sample were scored. Though the correlation of dc-FISH and cytogenetic data was good (r = 0.77, p < 0.001), the discrepancy between the two methods as regards the proportion of leukemic cells in the marrow was often important dc-FISH detected a relevant proportion of BCR-ABL+ cells in three patients classified as complete cytogenetic responders and showed that, after 9-12 months of IFN treatment, a significant reduction of BCR-ABL+ cells was present in all the 20 patients tested. This might suggest that all CML patients are potentially responsive to IFN. Though more data are required, we think that dc-FISH is more informative than cytogenetic analysis for CML monitoring. Notably because of the simplicity of the procedure, this method could be easily standardized among different laboratories, thus permitting cross-comparison in therapeutic trials.

Cytogenetics↗
PubMed1990

Rearrangement of the human ABL oncogene in a glioblastoma.

A number of protooncogenes have been implicated in human tumorigenesis. The ABL oncogene is consistently rearranged and activated as a consequence of the translocation t(9;22) that gives rise to the Philadelphia chromosome in chronic myeloid leukemia and in some cases of acute lymphoblastic leukemia. Here we describe rearrangement of ABL in a different type of malignancy. The glioblastoma cell line A172 lacks germline alleles of ABL. A recombination event, presumably followed by a duplication, has created two ABL alleles in which exon 11 is joined to chromosome 16 sequences. Although the main body of ABL exons was still present, two considerably shortened ABL mRNAs of 3.8 and 2.8 kilobases were detected; the 3.8-kilobase mRNA hybridized exclusively to an exon IB probe. Neither mRNA hybridized to an ABL probe encompassing part of the tyrosine kinase domain. Thus, the cell line A172 is able to survive in the absence of a functional ABL gene product, indicating that the role of ABL is unlikely to be "housekeeping."

Base Sequence↗
PubMed1993

Inhibition of P210 expression in chronic myeloid leukaemia: oligonucleotides and/or transduced antisense sequences.

There is now strong evidence that the BCR-ABL gene product (P210) of the Philadelphia chromosome plays a crucial role in the pathogenesis of chronic myeloid leukaemia (CML). That is why antisense strategies aiming at inhibiting P210 expression for research or therapeutic purposes are increasingly investigated. Two main tools are currently available in this respect: oligonucleotides and retrovirally transduced antisense sequences. In this paper, we discuss the potential advantages and drawbacks of each approaches and report experimental evidences showing the feasibility of the second one in a murine lymphoid cell line (BaF3) expressing P210 upon retroviral transduction of the complete BCR-ABL cDNA. A retroviral vector was used to introduce selected antisense and sense sequences into this cell line, that P210 expression had rendered Interleukin-3 (IL3) independent. The antisense transcripts generated under the control of MoMLV promoter specifically killed BaF3 cells in the absence of IL3 and stably inhibited P210 expression. Retrovirally transduced antisense sequences can thus successfully achieve stable suppression of P210 and may be used to study further the mechanisms by which P210 is transforming cells. The effect on CML cell lines and fresh CML cells, in bone marrow cultures, remains to be investigated before considering this technique for in vitro selective suppression of Philadelphia-positive haematopoiesis.

Animals↗
PubMed2000

Chronic Myelogenous Leukemia: Disease Biology and Current and Future Therapeutic Strategies.

Over the last 2 decades, four major therapeutic approaches have drastically changed the prognosis in chronic myelogenous leukemia (CML): 1) allogeneic stem cell transplant (SCT); 2) interferon alpha (IFN-alpha) based regimens; 3) donor lymphocyte infusions (DLI); and 4) and the revolutionary BCR-ABL tyrosine kinase inhibitors such as STI571 (signal transduction inhibitor 571). Each modality has exploited and targeted different aspects of CML biology, and is associated with different risk-benefit ratios. In Section I of this review, Dr. Melo reviews the molecular pathophysiology of CML and potential new targets for therapy including anti-sense strategies to disrupt the BCR-ABL gene and inhibition of the BCR-ABL tyrosine kinase activity. In Section II, Dr. Tura, addresses important questions in the use of IFN-alpha for the treatment of CML, including the mechanism of action and the development of resistance, the optimal dose and duration of therapy and the prediction of response based on clinical features. An approach to the choice of therapy based on the predicted mortality is presented. In Section III Dr. Giralt presents an update on the results of unrelated donor transplantion, donor lymphocyte infusions (DLI) and non-ablative stem cell transplantation (NST) in CML. The roles of CD8-depletion, dose escalation and the transduction of suicide genes in treatment with DLI are addressed. Early results of NST in CML show that it is feasible and can result in long-term disease control. In Section IV Drs. Kantarjian and Talpaz review the results of IFN-alpha plus low-dose cytosine arabinoside and other promising modalities for CML including homoharringtonine, decitabine, and polyethylene glycol-interferon. In Section V they present an update on the recent experience with STI571. Objective but transient responses have been seen in 40% to 50% of patients in CML blastic phase. In accelerated phase, the response rate with STI571 exceeds 70%, and these responses are durable. In chronic phase CML, STI571 at 300 mg daily in patients who failed IFN-alpha produces a complete hematologic response (CHR) in over 90% of patients. Early results suggest cytogenetic response rates of approximately 50%, which may be major in approximately 30%. The maturing results with STI571 may soon change current recommendations regarding the relative roles of established modalities such as allogeneic SCT and IFN-alpha. Important questions include 1) whether STI571 therapy alone may be sufficient to induce long-term survival and event-free survival in CML, or whether it needs to be combined simultaneously or sequentially with IFN-alpha and cytosine arabinoside; and 2) what should the indications for frontline allogeneic SCT be in relation to STI571 therapy.

Journal Article↗
PubMed1999

Inhibition of bcr-abl oncogene expression by novel deoxyribozymes (DNAzymes).

Deoxyribozymes, or DNA enzymes (DNAzymes), are novel nucleic acids that have the ability to bind to specific sequences of RNA, and to cleave the target site catalytically. DNAzymes are smaller and more efficient enzymatically than ribozymes (RZs), which are catalytic nucleic acids synthesized from ribonucleotides. We have designed three DNAzymes that specifically target the two variants of the p210 bcr-abl gene (splice 1, b3a2; splice 2, b2a2) and the p190 variant (ela2). The cleavage sites for these DNAzymes are located 5 nucleotides (nt) 5' from the fusion site for b3a2, and only 1 nt 5' from the fusion sites for b2a2 and e1a2. We have shown in cell-free in vitro cleavage assays that these DNAzymes efficiently cleave their respective substrates. Mutated DNAzymes, in which only one critical base has been altered, do not cleave these targets. We have used a serum-resistant cytofectin (GS 2888; Gilead) to transfect the DNAzymes into target K562 cells, which express p210bcr-abl. In short-term transfection assays, the DNAzymes specifically inhibited p210bcr-abl protein expression by K562 cells by about 40%, and inhibited cell growth by more than 50% in a 6-day liquid culture assay. We have also transfected freshly isolated CD34+ bone marrow cells from patients with CML with the DNAzymes, which specifically inhibited the growth of bcr-abl-positive CFU-Mix colonies by 53-80%. The potential advantages of anti-bcr-abl DNAzymes over RZs include the following: DNAzymes are much less expensive to synthesize; they are more resistant to serum; and the anti-b2a2 DNAzyme cleaves at a site only 1 nt away from the fusion site, whereas its hammerhead RZ counterpart cleaves this target at a site 8 nt 3' to the fusion site, well within abl exon 2. DNAzymes are novel RNA-cleaving molecules that may significantly improve our ability to inhibit bcr-abl oncogene expression in Ph-positive target cells.

Alternative Splicing↗
PubMed2000

Ontogeny of natural killer cells and T cells by analysis of BCR-ABL rearrangement from patients with chronic myelogenous leukaemia.

Chronic myelogenous leukaemia (CML) is a haematological malignant disorder characterized by the Philadelphia chromosome (Ph) and BCR-ABL gene rearrangement. This abnormal fusion gene can be considered to serve as a marker for the transformed cell clone in CML and is found in all cells arising from the same malignant precursor cell. It has been detected in CML cells of the myeloid, monocytic, erythroid and B-lymphocytic lineages. However, it is still arguable as to whether T lymphocytes or natural killer (NK) cells carry this marker. Answering this question would clarify the ontogenic relationship between NK cells and T cells. We examined 12 CML patients and studied the expression of BCR-ABL rearrangement by fluorescence in situ hybridization (FISH) in both NK cells and T cells sorted by flow cytometry. The purity of T cells was 95.6-99.8% and that of NK cells was 95.3-99.3% after sorting. Neither NK cells nor T cells showed any positive BCR-ABL signal with the exception of one patient who recovered from a lymphoid blastic crisis. We speculate that T cells and NK cells originate from BCR-ABL-negative stem cells.

Adult↗
PubMed2004

Role of Dok-1 and Dok-2 in myeloid homeostasis and suppression of leukemia.

Dok-1 and Dok-2 are closely related rasGAP-associated docking proteins expressed preferentially in hematopoietic cells. Although they are phosphorylated upon activation of many protein tyrosine kinases (PTKs), including those coupled with cytokine receptors and oncogenic PTKs like Bcr-Abl, their physiological roles are largely unidentified. Here, we generated mice lacking Dok-1 and/or Dok-2, which included the double-deficient mice succumbed to myeloproliferative disease resembling human chronic myelogenous leukemia (CML) and chronic myelomonocytic leukemia. The double-deficient mice displayed medullary and extramedullary hyperplasia of granulocyte/macrophage progenitors with leukemic potential, and their myeloid cells showed hyperproliferation and hypo-apoptosis upon treatment and deprivation of cytokines, respectively. Consistently, the mutant myeloid cells showed enhanced Erk and Akt activation upon cytokine stimulation. Moreover, loss of Dok-1 and/or Dok-2 induced blastic transformation of chronic phase CML-like disease in mice carrying the bcr-abl gene, a cause of CML. These findings demonstrate that Dok-1 and Dok-2 are key negative regulators of cytokine responses and are essential for myeloid homeostasis and suppression of leukemia.

Adaptor Proteins, Signal Transducing↗
PubMed2003

[Oncogenes and leukemia: history and perspectives].

Oncogenes involved in the development of hematological malignancies were first discovered through the study of experimental leukemias induced in animals by retroviruses. The discovery that some of these genes were located at the breakpoints of chromosome rearrangements in human malignancies, such as the MYC gene in Burkitt's lymphoma and the ABL gene in chronic myeloid leukemia (CML) has suggested that chromosome abnormalities were causally implicated in the pathogenesis of human diseases. Numerous nonrandom somatically acquired chromosomal translocations or inversions have been identified in human leukemias. The molecular cloning of the genes located at the breakpoints of these rearrangements allowed to identify more than 100 new oncogenes, the products of which affect normal programs of cell proliferation, differentiation and survival. Chromosome translocations can lead to the deregulated expression of a normal gene product, but in most cases of leukemia, chromosome rearrangements result in the expression of a chimeric fusion protein. Oncogene products associated with acute leukemias are often transcription factors while tyrosine kinases and antiapoptotic proteins are more commonly activated or overexpressed in chronic leukemias and in lymphomas. Recent data indicated that gene rearrangements were not the sole gene alterations occurring in human leukemia since point mutations could also affect the function of transcription factors playing a key role in hematopoiesis such as C/EBP alpha, GATA1 and AML1. But the most exciting finding was the discovery of activating point mutations in tyrosine kinase receptors such as FLT3 and c-KIT in acute leukemia. Treatment of leukemia could therefore benefit from new therapeutic approaches targeting the function of specific oncogene products as already demonstrated for CML and acute promyelocytic leukemia.

Cytogenetics↗
PubMed2003

Innovations in the management of leukemia: role of biologic therapies.

Chronic myelogenous leukemia (CML) results from clonal proliferation of malignant hematologic progenitor cells and is responsible for 7% to 15% of all adult leukemias. The hallmark of CML is a genetic translocation between chromosomes 9 and 22 (the Philadelphia chromosome), which creates the abnormal bcr-abl gene and a continuously activated Bcr-Abl protein. Bcr-Abl tyrosine kinase activity leads to signal transduction and cell growth. Traditional therapies for CML include allogeneic stem cell transplantation, interferon alfa, and oral chemotherapeutic agents. However, because Bcr-Abl is the causative abnormality in CML, it represents an ideal target for rational biologic therapy. Imatinib mesylate is an orally available tyrosine kinase inhibitor that specifically blocks Bcr-Abl function. Clinical trials have demonstrated that imatinib mesylate produces rapid responses in patients with all stages of CML, including those who were resistant to interferon alfa therapy or intolerant of it. When imatinib mesylate therapy was initiated early in the course of CML, there was a complete hematologic response in 98% of the patients and a complete cytogenetic response in 72% of the patients. Although long-term safety and survival data are not yet available, imatinib mesylate is a promising new treatment option for CML that targets the molecular cause of the disease.

Antineoplastic Agents↗
PubMed2005

A cell-based screening strategy that predicts mutations in oncogenic tyrosine kinases: implications for clinical resistance in targeted cancer treatment.

The discovery of tyrosine kinases that, once deregulated, can cause malignancy, allowed the development of specifically acting anti-cancer compounds. In chronic myeloid leukaemia (CML), the Bcr-Abl kinase inhibitor imatinib (STI571, Gleevec) induces impressive response rates. However, resistance occurs especially in advanced phase CML and Ph+ ALL, primarily as a consequence of point mutations within the Bcr-Abl kinase domain that prevent imatinib from binding. To overcome imatinib resistance, alternative Abl kinase inhibitors are finding their way into clinical trials. However, it is likely that resistance to second-generation compounds will occur as well. Therefore, it will be critical to determine specific resistance profiles for each particular compound. We recently developed a cell-based screening strategy that allows one to predict the pattern and relative abundance of Bcr-Abl resistance mutations emerging in the presence of imatinib or an alternative Abl-kinase inhibitor. Using this strategy, the findings in inhibitor resistant sublines reflect observations made in CML patients with imatinib resistance, including Bcr-Abl mutations, amplification of the Bcr-Abl gene, and overexpression of the Bcr-Abl protein. We here provide a detailed methodological description, and discuss the implications of this strategy for different clinically relevant oncogenic tyrosine kinases.

Animals↗
PubMed2006

[Monitoring bcr-abl mRNA levels by real-time quantitative RT-PCR in chronic myeloid leukemia patients after hematopoietic stem cell transplantation].

OBJECTIVE: To evaluate the value of real time quantitative RT-PCR (Q-PCR) for monitoring bcr-abl mRNA levels in chronic myeloid leukemia (CML) patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: Quantification of bcr-abl mRNA was performed on 316 bone marrow samples from 112 patients with CML after HSCT by Q-PCR using the TaqMan probe system. The bcr-abl mRNA level was normalized by control gene abl. Cytogenetic response was evaluated with fluorescent in-situ hybridization (FISH). RESULTS: The reproducible sensitivity of Q-PCR was 5 copies. The coefficients C(T) of interassay and intraassay variation for abl and bcr-abl were all below 2.0%. 289 bone marrow samples were collected from 101 CML patients who achieved a sustained complete cytogenetic response (CCyR) one month post allo-HSCT in a period of 6 - 60 months (median 12 months) at different intervals. In general, the median bcr-abl levels gradually decreased with the prolongation of time after HSCT: the median bcr-abl levels were 0.035% (0 - 0.406%) at 1 month post allo-HSCT (+ 1 month), 0.006% (0 - 0.683%) at +3 month, 0% (0 - 0.225%) at +6 month and remained 0% till +24 months. The highest level in CCyR patients detected at + 6 month was 0.068%. The bcr-abl mRNA level was decreased by 3 log in sustained CCyR patients at + 1 month compared with the newly diagnosed CML-CP patients (33.0%, data unpublished). On the contrary, Q-PCR results ranged from 0.12% to 13.45% in 8 cytogenetic non-responders or relapsed patients post allo-HSCT. Among them, 5 patients' samples were collected 1 - 2 months before cytogenetic relapse, the results were ranged from 0.09% to 3.42%. If 0.09% was assumed 0.09% as a threshold, 9 sustained CCyR patients (8.9%) were tested once higher than that within 6 month after HSCT but decreased to 0% eventually. 2 blast crisis patients achieved CCyR within 1.6 and 3 months after HSCT, but hematological relapse occurred after 1 and 1.5 months, and their bcr-abl mRNA levels increased dramatically from 0% and 0.14% to 46.9% and 75.9% respectively. CONCLUSIONS: Q- PCR is a sensitive, precise and reliable technique, and can be used to monitor CML patients post allo-HSCT regularly. Patients in blast phase of CML should be monitored more frequently.

Adolescent↗
PubMed1993

Recent progress in understanding chronic myelogenous leukemia.

Several important issues in CML research are not covered in this brief review such as the structural or molecular basis of the translocation between ABL and BCR, the relationship between CML and ALL with an identical or related BCR/ABL abnormality, the biology of CML stem and progenitor cells and immunologic aspects of CML. These are discussed elsewhere in this volume. The data reviewed indicate considerable progress in understanding the molecular and cell biology of CML. More is known about what causes CML than any human cancer. However, many important unresolved issues are likely to provide a productive direction for future studies.

Animals↗
PubMed1993

Molecular defects associated with the acute phase CML.

Parts of the Bcr/Abl hybrid transcript supposed to be important for its transforming ability were sequenced in a series of CML blast crises, in order to evaluate the possible presence of alterations responsible for the disease transition from the chronic to the acute phase. In addition, the N- and Ki-ras as well as the p53 involvement was investigated by exploring their structure and expression in the same patients. We used traditional types of molecular analysis including Southern and Northern blot, together with methods that allow a rapid detection of point mutations and microdeletions, such as SSCP, single strand conformation polymorphism and direct sequencing. The results obtained may be summarized as follows: no alterations were found in the parts of the Bcr/Abl transcripts investigated in the present study (SH2, SH3 and the region surrounding codon 832); p53 alterations were observed in 5% and N- and Ki-RAS mutations in 5% of the cases examined. These molecular defects are therefore responsible for the clinical progression of the Ph1-positive CML only in a minority of cases.

Base Sequence↗