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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overwhelming evidence indicates a role for the deregulated ABL protein tyrosine kinase in the aetiology of CML and Ph-positive acute leukaemia. These disorders are characterized by the generation of BCR/ABL fusion proteins with elevated tyrosine kinase activity. Although much is known concerning the transforming potential of ABL proteins in various systems, very little is understood of the normal function and mode of regulation of ABL activity. The mechanism of oncogenic activation is therefore also obscure. In spite of this, our understanding of the molecular details of these chromosomal translocations allows the design of therapies directed against their unique, leukaemia-specific proteins and RNA products.
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PMID:Philadelphia chromosome-positive leukaemia: the translocated genes and their gene products. 130 69

The negative impact of donor marrow T lymphocyte depletion on relapse of chronic myeloid leukaemia (CML) following bone marrow transplantation strongly suggests that the leukaemia is particularly susceptible to immune regulation. The immune response to CML may be mediated by major histocompatibility (MHC) locus unrestricted natural killer and lymphokine activated killer cells, or by MHC-restricted CD4 and CD8 lymphocytes. Interaction with the leukaemia is both by direct cell-contact cytotoxicity, and indirectly via cytokines and growth factors. T4 and T8 lymphocytes recognize a spectrum of minor histocompatibility antigens on the leukaemia cell which may be non-specific, leading to graft-versus-leukaemia and graft-versus-host reactions, or present only on myeloid cells leading to a tissue restricted response. The possibility that the P210 protein derived from the BCR/ABL fusion gene on chromosome 22 leads to the presentation via MHC molecules of leukaemia-specific peptide antigens is currently under investigation. Developments in understanding the immune response to CML open up the possibility of developing leukaemia-specific immunotherapy strategies.
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PMID:Immune responses to chronic myeloid leukaemia. 161 13

There is increasing evidence for a relationship between specific genomic alterations and the distinctive features of leukemia, including the course and the response to treatment. In Philadelphia (Ph) positive chronic myeloid leukemia (CML) the BCR/ABL fusion genes can be transcribed in at least two different mRNAs that can either include (a2b3) or exclude (a2b2) the exon 3 of the major breakpoint cluster region in chromosome 22. We identified by polymerase chain reaction the transcript type in 146 patients with Ph+ CML who were enrolled in a prospective study of treatment with alpha-interferon (alpha-IFN) for at least 1 year, and were followed for 39 to 84 months (median 60 months). The transcript was a2b3 in 84 cases (57%) and a2b2 in 62 cases (43%). A trend in favor of a2b3 cases was observed, as to the karyotypic response after 1 year of alpha-IFN treatment (39% in the a2b3 cases vs 24% in the a2b2 cases) and 5-year survival rate, that was 71% (95% CI 59-82) in a2b3 cases vs 57% (95% CI 41-73) in a2b2 cases. However, these differences were not significant, and we conclude that the identification of the transcript type by current methodology does not predict for response to alpha-IFN and for prognosis. Further studies may be required to confirm that conclusion, or to detect a true smaller difference.
Leukemia 1995 Oct
PMID:Chronic myeloid leukemia, BCR/ABL transcript, response to alpha-interferon and survival. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. 756 4

A strong association between the Philadelphia chromosome (Ph1) and chronic myelogenous leukemia (CML) suggests that the Ph1 translocation plays a significant role in pathogenesis of CML. For this reason, Ph1-positive leukemias have been well studied from the molecular, clinical and cell biological perspective. In this review article, intracellular signalling events involving BCR/ABL fusion gene products are discussed in the context of the role of the Ph1 chromosome in human leukemia.
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PMID:BCR/ABL signal transduction. 759 21

We describe a patient with a t(7;11)(p15;p15) acute myeloid leukemia who was subsequently found to harbor the Philadelphia (Ph) translocation, in addition to the t(7;11), at the second relapse. A BCR/ABL transcript was detected at the second relapse by reverse transcription-polymerase chain reaction assay; the leukemic cells had a BCR/ABL fusion gene involving the minor breakpoint cluster region (minor-BCR; situated in intron 1 of the BCR gene). Although the Ph translocation is commonly detected in de novo acute leukemia and chronic myeloid leukemia as the primary leukemia-specific chromosomal translocation, our case suggests that this cytogenetic change might occur as an additional chromosomal change in neoplastic cells. Moreover, minor-BCR/ABL rearrangements may also occur as a late appearance of Ph translocation.
Leukemia 1995 Apr
PMID:Late appearance of a Philadelphia translocation with minor-BCR/ABL transcript in a t(7;11)(p15;p15) acute myeloid leukemia. 772 98

We report cases with a variant BCR/ABL mRNA expression lacking ABL exon a2 sequences. Two of these cases showed major breakpoint cluster region (BCR) exon 3 (b3) and ABL exon 3 (a3) junction (b3/a3), while the other case showed minor BCR exon 1 (e1) and a3 junction (e1/a3). One of the two cases with b3/a3 junction and the case with e1/a3 junction were diagnosed as acute lymphoblastic leukemia, and the remaining case with b3/a3 junction was chronic myeloid leukemia. Two of these cases, however, were found to have a breakpoint in the ABL gene outside of the intron between exons a2 and a3, probably 5' upstream of exon a2, suggesting that the BCR exon was spliced to ABL exon a3. These findings differ from those previously reported, in which the breakpoints in the ABL gene were between exons a2 and a3, and indicate a novel mechanism for the deletion of ABL exon a2 sequences in the formation of a variant BCR/ABL fusion transcript. The significance of the finding that a part of the SH3 region of ABL protein is missing in some Philadelphia chromosome-positive leukemias is discussed in reference to the cases reported previously.
Leukemia 1994 Oct
PMID:Heterogeneity of the breakpoint in the ABL gene in cases with BCR/ABL transcript lacking ABL exon a2. 793 65

The E2A/PBX1 and the BCR/ABL fusion genes result from the t(1;19)(q23;p13) and the t(9;22)(q34;q11), respectively, and encode oncoproteins which are thought to play an important role in the development of acute lymphoblastic leukemia (ALL) subtypes associated with adverse prognosis. The use of the polymerase chain reaction (PCR) for the detection of these genetic rearrangements may offer advantages over cytogenetic techniques which are often unsatisfactory in patients with ALL and, furthermore, provide a useful tool for monitoring of residual disease. However, it has not yet been evaluated whether the employment of PCR at the time of diagnosis improves the detection rate of these clinically relevant genetic anomalies. We have developed a multiprimer-PCR protocol which facilitates the detection of each of the four chimeric E2A/PBX1 and BCR/ABL mRNAs in a single reaction. This protocol was used for the evaluation of bone-marrow or blood samples from 251 children with ALL in whom cytogenetic analyses had been performed. Of the 251 patients, 221 had a B-cell precursor immunophenotype. In this group, 21 patients (9.5%) carrying the E2A/PBX1 rearrangement and three patients (1.4%) with BCR/ABL transcripts were detected by PCR. Twelve of these cases had escaped the detection by conventional cytogenetic analysis. In two of 12 patients with a typical t(1;19)(q23;p13), no E2A/PBX1 transcripts were identified by PCR, thus suggesting the presence of different molecular rearrangements. Residual leukemic cells were detected by PCR in five of eight patients who were followed during complete clinical remission. The frontline use of PCR has an important impact on the timely diagnosis, therapeutic decisions, and monitoring of high-risk patients with B-cell precursor leukemia who carry the E2A/PBX1 or BCR/ABL fusion genes.
Leukemia 1993 May
PMID:Detection and clinical relevance of genetic abnormalities in pediatric acute lymphoblastic leukemia: a comparison between cytogenetic and polymerase chain reaction analyses. 848 19

We have developed an in vivo model of human chronic myeloid leukemia (CML). A peripheral blood (PB) sample of Philadelphia (Ph) chromosome-positive CML cells in lymphoid blast crisis was transplanted intravenously (IV) into sublethally irradiated severe combined immunodeficient (SCID) mice, and this resulted in engraftment with systemic proliferation. Growth of leukemia was monitored by PB cell morphology and by flow cytometric analysis of murine PB cells labelled with an anti-human leukocyte antigen (HLA) monoclonal antibody. Human cells were first detected in the PB at 4 weeks and comprised a mean of 57% of the total nucleated cells in the PB of these mice by 15 weeks. The Ph chromosome was retained and the population has been successfully passaged. BCR/ABL fusion gene expression was detected in a subsequent passage. Experiments are underway to use this in vivo model to assess the antileukemic activity of BCR/ABL antisense oligonucleotides.
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PMID:Human Philadelphia chromosome-positive chronic myeloid leukemia: a potential model for antisense therapy. 850 May 81

A variant form of BCR/ABL junction was identified in a patient with chronic myelogenous leukaemia (CML). The BCR/ABL fusion mRNA of this patient showed in-frame junction between BCR exon c3 and ABL exon 2. Although the diagnosis of CML was made, the patient showed clinical features of essential thrombocythaemia (ET) rather than that of typical CML. Treatment with interferon-alpha showed no cytogenetic response. The c3-a2 type of BCR/ABL junction seems to be associated with elevated platelet count and thus could form a novel clinical entity different from typical CML.
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PMID:Elevated platelet count features the variant type of BCR/ABL junction in chronic myelogenous leukaemia. 875 98

Of 144 adult Eastern Cooperative Oncology Group (ECOG) patients with acute lymphoblastic leukemia (ALL) entered on study E2993 at the time of analysis, 104 had informative immunophenotypes and molecular analysis by polymerase chain reaction for BCR/ABL fusion transcripts. In 23 patients (22%), BCR/ABL transcripts were detected: the ALL-typical e1a2 alone in 12, e1a2 + b2a2/b3a2 in five, and b2a2 and/or b3a2 in six. Of BCR/ABL-positive patients, 83% had early pre-B ALL, one patient had pre-T ALL, while half of the BCR/ABL-negative patients had early pre-B ALL, 18% had CD10-negative pro-B ALL and 21% were pre-T. When antibodies to both the interleukin-2 receptor alpha (CD25) and beta chain (CD122) were tested, CD25 was expressed significantly more frequently in BCR/ABL-positive (median 23% positive blast cells, range 1-84%) than BCR/ABL-negative patients (median 3%, range 0-69%) (P = 0.00006). There was no corelation with CD122 expression. Therefore, CD25 expression may serve as a surrogate marker for BCR/ABL positivity (Philadelphia chromosome), the major poor prognostic parameter in adult ALL.
Leukemia 1997 Nov
PMID:Expression of CD25 (interleukin-2 receptor alpha chain) in adult acute lymphoblastic leukemia predicts for the presence of BCR/ABL fusion transcripts: results of a preliminary laboratory analysis of ECOG/MRC Intergroup Study E2993. Eastern Cooperative Oncology Group/Medical Research Council. 936 22


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