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Aberrant methylation of tumor-suppressor gene promoter regions may play a causal role in the pre-neoplastic stage of cancer progression. In chronic myeloid leukemia, changes in the methylation status of the CpG-rich islands at several sites in the proximal ABL1 promoter (Pa) on the Philadelphia (Ph)-chromosome have been observed. It remains unclear if the Pa methylation precedes the translocation event (t9;22) that generates the Ph-chromosome or if Pa methylation is a stochastic event in a progenitor cell which will later acquire other mutations, namely t9;22. The present study was conducted to answer two questions: What is the methylation status of Pa in patients with Ph-negative myeloproliferative disorders (MPD)? Can the study of methylation in patients with Ph-negative MPD shed light on the initial events associated with the translocation? To probe CpG methylation, we used two methodologies; site-methylation-sensitive restriction enzyme assay and methylation-specific PCR analysis following modification of genomic DNA by bisulfite. Results showed that 22 of the 97 patients with Ph-negative MPD expressed BCR-ABL transcripts. Seven of the 97 patients possessed methylated Pa, but only 2 of them expressed BCR-ABL transcripts. In some of the patients, Pa methylation was a dynamic event. In conclusion, aberrant methylation in Ph-negative MPD could be an initial event triggering the occurrence of the t9;22 translocation and its clinical expression. These findings may shed light on the pathogenesis and progression of MPD.
Blood Cells Mol Dis
PMID:Detection of methylated ABL1 promoter in philadelphia-negative myeloproliferative disorders. 1266 92

Recent advances in molecular genetics impact the health care and outcome of patients with acute lymphoblastic leukemia (ALL). BCR-ABL, a common molecular defect in adult ALL, is a valuable tumor marker whose detection influences prognosis and clinical management decisions. Molecular methods such as fluorescence in situ hybridization (FISH), reverse-transcriptase polymerase chain reaction (rtPCR), and real-time quantitative rtPCR can be used to detect the chimeric BCR-ABL gene or its transcripts. These molecular assays improve our ability to measure residual disease and to estimate risk of relapse. On the horizon are gene expression profiles that will likely provide additional information beyond what is obtainable with current clinical and laboratory approaches.
J Mol Diagn 2003 May
PMID:Clinical applications of BCR-ABL molecular testing in acute leukemia. 1270 70

Treatment of acute lymphoblastic leukemia in adults focuses on the initial assessment of prognostic relevant genetic features as well as response-guided therapy based on molecular data. In at least half of adult acute lymphoblastic leukemia patients, clonal chromosomal abnormalities can be identified that deregulate candidate oncogenes or transcription factors by introducing a heterologous promoter or enhancer. Altered cell cycle progression or upregulated tyrosine kinase activity are other important mechanisms. Most of the translocations can lead to the generation of fusion genes that are translated into chimeric oncogeneic proteins, such as BCR-ABL, providing targets for novel therapeutic agents.
Expert Rev Mol Diagn 2003 May
PMID:Molecular genetic events in adult acute lymphoblastic leukemia. 1277 8

Diagnosis of chronic myeloid leukemia and acute lymphoblastic leukemia requires the investigation of the Philadelphia chromosome translocation t(9;22) or the molecular detection of BCR-ABL fusion transcripts. Determination of the type of fusion transcript is crucial for quantitative molecular monitoring the course of the disease during treatment. Histopathologists, who usually use formalin-fixed tissues, may be confronted with the need to investigate the BCR-ABL rearrangement when evaluating tumor forming infiltrates and bone marrow trephines from patients presenting with chronic myeloproliferative disorders. Therefore, we have established a one-tube multiplex RT-PCR for the detection of common BCR-ABL fusion transcripts (b2a2, b3a2, e1a2) in routinely processed tissues and bone marrow trephines with respect to the inevitable fragmentation of ribonucleic acids in these specimens. RT-PCR products allow distinct and unequivocal differentiation of the underlying fusion in either the Major- or minor-breakpoint cluster region. Detection of BCR-ABL fusion transcripts by multiplex RT-PCR in routinely processed and fixed tissues is a time- and cost-sparing tool for definite diagnosis of typical chronic myeloid leukemia and Philadelphia chromosome positive acute lymphoblastic leukemia.
Diagn Mol Pathol 2003 Sep
PMID:Multiplex RT-PCR for the detection of common BCR-ABL fusion transcripts in paraffin-embedded tissues from patients with chronic myeloid leukemia and acute lymphoblastic leukemia. 1296 Jun 92

The aim of this study was to validate the application of a commercially available multiplex reverse transcription polymerase chain reaction (RT-PCR) assay [Hemavision-7 System] for the seven most common leukemia translocations for routine molecular diagnostic hematopathology practice. A total of 98 samples, comprising four groups, were evaluated: Group 1, 16 diagnostic samples molecularly positive by our existing laboratory-developed assays for PML-RARalpha/t (15;17) or BCR-ABL/t (9;22); Group 2, 51 diagnostic samples negative by our laboratory-developed assays for PML-RARalpha/t (15;17) or BCR-ABL/t (9;22); Group 3, 21 prospectively analyzed diagnostic cases, without prior molecular studies; and Group 4, 10 minimal residual disease (MRD) samples. Analysis of the two previously studied cohorts (Groups 1 and 2) confirmed the diagnostic sensitivity and specificity of the multiplex assay with regard to these two translocations. Additionally, however, in the "negative" Group (Group 2) the assay revealed three unanticipated translocations (CBFbeta-MYH11, BCR-ABL, and MLL-AF4), two of which were confirmed on cytogenetics. Analysis of the prospective cohort demonstrated that the assay was cost-effective and amenable to standard laboratory practice, with an identically sensitive MRD detection rate to that of our laboratory-developed tests. Virtually all of the results obtained were consistent with the phenotype and karyotype by conventional methods. This study illustrates the utility of a kit-based multiplex RT-PCR assay for the molecular diagnosis and monitoring of leukemias and reinforces the complementary roles of molecular testing and cytogenetics in diagnostic hematopathology.
J Mol Diagn 2003 Nov
PMID:Multiplex RT-PCR for the detection of leukemia-associated translocations: validation and application to routine molecular diagnostic practice. 1457 82

Decreased Type 1 cytokine production has been observed in T cells of patients with untreated chronic myeloid leukemia (CML). The important role of T cells and T-cell cytokines in the long-term control of CML is well established, for example in allogeneic stem-cell graft recipients. This study examined whether or not molecularly targeted therapy with imatinib, an inhibitor of the BCR-ABL tyrosine kinase, improved endogenous T-cell function in patients resistant to or intolerant of previous IFN-alpha therapy. Intracellular cytokine staining and detection by flow cytometry was used to analyze the expression of the T1 cytokine IFN-gamma in T cells. To secure independence from changes in white blood cell counts during treatment, a constant number of T cells was purified from the peripheral blood before analysis of the proportion of IFN-gamma synthesizing T cells. Twenty-nine patients with CML were tested before and after a median follow-up of 3 month on imatinib. In addition, late follow-up (past the median time to best cytogenetic response) of 15 patients were obtained Twenty-nine age- and gender-matched individuals were used as healthy controls. The frequency of IFN-gamma producing T cells in CML patients resistant to or intolerant to previous IFN-alpha therapy was lower than in healthy individuals (p=0.0181, Mann-Whitney test). Imatinib therapy led to a significant increase over pre-treatment values (p<0.0001, Mann-Whitney test). Late follow-up indicated that the increase was sustained in patients not in major cytogenetic response. In contrast, in major responders levels returned towards values comparable to healthy individuals. In conclusion, treatment with imatinib achieves a significant increase in Type 1 (IFN-gamma) cytokine-producing T cells in patients with CML. This is consistent with the view that enhanced T-cell function is achievable in patients with CML, even in the absence of allo-mechanisms.
Cytokines Cell Mol Ther 2002
PMID:Increased IFN-gamma synthesis by T cells from patients on imatinib therapy for chronic myeloid leukemia. 1466 54

We examined the effects of interferon-alpha (IFN-alpha) treatment on the growth, cell cycle, proliferation, and apoptotic parameters as well as adhesive properties and proteome of chronic myelogenous leukemia (CML)-derived K562 cells. IFN-alpha treatment (200 to 600 U/ml, 24 to 72 h) suppressed growth and caused accumulation of K562 cells in the S-phase of cell cycle (increase in S-phase cells by up to 52% in comparison with the untreated controls) at the expenses of cells in G1-phase. No transition of cells to G0-phase occurred as followed from Ki-67 protein determination. Although the level of chimeric gene product, BCR-ABL mRNA coding for BCR-ABL protein with anti-apoptotic properties, decreased by 30%, apoptosis was not triggered as judged from Annexin-V, APO2.7, and TUNEL assays. Adhesion of K562 cells to fibronectin-coated surfaces increased by up to 52% as determined by calcein assay. The proteomic analysis (2-D electrophoresis in combination with mass spectrometry, MALDI-MS) revealed a single protein, ubiquitine cross-reactive protein (UBCR), whose level markedly increased due to IFN-alpha treatment. The ubiquitination-like directed degradation processes may thus play a role in the mechanism of IFN-alpha antiproliferative effects.
Blood Cells Mol Dis
PMID:Interferon-alpha suppresses proliferation of chronic myelogenous leukemia cells K562 by extending cell cycle S-phase without inducing apoptosis. 1475 43

The abnormal haemopoietic precursor cells of chronic myeloid leukaemia (CML) carry the cytogenetic abnormality [t(9;22)(q34;q11)]--a reciprocal translocation that results in the expression of a chimaeric protein derived from the fused BCR and ABL genes. This Bcr-Abl protein tyrosine kinase mediates an array of effects on signal transduction pathways affecting cell survival, proliferation, adhesion and genetic stability. The end-result of these abnormal signalling processes is a bi- or triphasic clinical disease. Initially, CML is characterised by the presence of an excess of myeloid progenitor cells and their mature progeny. This chronic phase of CML is followed, either directly or with an intervening 'accelerated phase', by a stage where primitive blast cells predominate (acute transformation). This review discusses the role of Bcr-Abl-mediated signalling events in cellular transformation, genetic instability and disease progression in CML, and describes current developments in CML treatment using a Bcr-Abl inhibitor.
Expert Rev Mol Med 2003 Nov 25
PMID:Molecular pathogenesis of chronic myeloid leukaemia. 1498 2

This chapter provides information on the application of flow cytometry for analysis of B-cell development, describing in detail the particular surface proteins that can serve as markers for recognizing distinct stages in this process. These cell fractions range from just prior to initial heavy chain rearrangement, the germline pro-B stage, through D-J rearranged pro-B and heavy chain expressing pre-B stages, to the maturing surface BCR positive B-cell stages. It also outlines assays for the characterization of these cells, including procedures for testing functional lineage restriction, determination of rearrangement status, analyses of gene expression at the ribonucleic acid (RNA) and protein level, and assessment of cell cycle state.
Methods Mol Biol 2004
PMID:Characterization of B lymphopoiesis in mouse bone marrow and spleen. 1514 9

Although GTPases of the Ras family have been implicated in many aspects of the regulation of cells, little is known about the roles of individual family members. Here, we analyzed the mechanisms of activation of H-Ras, N-Ras, K-Ras 4B, and M-Ras by two types of external stimuli, growth factors and ligation of the antigen receptors of B or T lymphocytes (BCRs and TCRs). The growth factors interleukin-3, colony-stimulating factor 1, and epidermal growth factor all preferentially activated M-Ras and K-Ras 4B over H-Ras or N-Ras. Preferential activation of M-Ras and K-Ras 4B depended on the presence of their polybasic carboxy termini, which directed them into high-buoyant-density membrane domains where the activated receptors, adapters, and mSos were also present. In contrast, ligation of the BCR or TCR resulted in activation of H-Ras, N-Ras, and K-Ras 4B, but not M-Ras. This pattern of activation was not influenced by localization of the Ras proteins to membrane domains. Activation of H-Ras, N-Ras, and K-Ras 4B instead depended on the presence of phospholipase C-gamma and RasGRP. Thus, the molecular mechanisms leading to activation of Ras proteins vary with the stimulus and can be influenced by either colocalization with activated receptors or differential sensitivity to the exchange factors activated by a stimulus.
Mol Cell Biol 2004 Jul
PMID:Distinct mechanisms determine the patterns of differential activation of H-Ras, N-Ras, K-Ras 4B, and M-Ras by receptors for growth factors or antigen. 1522 33


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