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

In chronic myeloid leukemia (CML) the proto-oncogene c-abl from chromosome 9 q34 is translocated to the breakpoint cluster region (bcr) gene on chromosome 22 q11. This translocation results in a BCR-ABL fusion gene, which encodes chimeric fusion oncoproteins p210BCR-ABL. Here we demonstrate that a peptide with joining region sequence ATGFKQSSKALQRPVAS (eight amino acids (aa) encoded by BCR exon 3; one novel lysine, encoded by the fusion codon; eight aa encoded by ABL exon 2) is immunogenic to human T cells. Primary immune response induction with this peptide resulted in a HLA DR2(DRB1*1501) restricted CD4+ BCR-ABL peptide specific T cell line P1. Responses of P1 were negatively affected by individual aa replacement by alanine at eight aa positions within the 17mer peptide (F4, K5, Q6, K9, L11, Q12, R13, P14). These findings were supported by experiments with a panel of overlapping 11mer b3a2 peptides. Only two of these peptides with an aa sequence encompassing all residues which could not be replaced by alanine induced P1 proliferation. Since presentation of cytosolic oncoproteins as peptides by DR molecules has been observed, the present findings provide a possible explanation for post interferon-alpha persisting remissions in spite of the presence of BCR-ABL PCR positive progenitors.
Leukemia 1995 Aug
PMID:Recognition of peptides corresponding to the joining region of p210BCR-ABL protein by human T cells. 764 23

We investigated the use of donor leukocytes for the treatment of Epstein-Barr virus (EBV) lymphoproliferative disease following T cell-depleted bone marrow transplantation (BMT) for chronic myeloid leukemia (CML). We wanted to determine whether donor leukocyte treatment would result in altered biological responses with respect to anti-EBV lymphoma activity, donor-host chimerism and graft-versus-leukemia (GVL) responses. Three patients with CML in cytogenetic remission received < 10(6)/kg donor leukocytes for treatment of EBV lymphoproliferative disease. Lineage specific chimerism and residual leukemia detection were assessed using sensitive PCR methodologies. Following donor leukocyte treatment 1 patient had no recurrence and the other 2 had responsive EBV lymphoma. The 2 patients who were mixed T cell chimeras before treatment, remained so after treatment. Two were BCR-ABL positive by PCR before and after treatment and both developed hematologic relapse. None of the 3 patients developed acute graft-versus-host disease (GVHD) with 1 patient developing limited chronic GVHD. These data suggest that small numbers of donor T cells can eradicate EBV lymphoproliferative disease but may not alter donor-host chimerism or mediate GVL responses.
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PMID:Adoptive immunotherapy using donor leukocytes following bone marrow transplantation for chronic myeloid leukemia: is T cell dose important in determining biological response? 765 86

Experiments were performed to elucidate the mechanism through which p210 BCR-ABL, by its downstream signals, regulates c-myc messenger RNA expression in hematopoietic cells. We studied a model system in which stable expression of p210 BCR-ABL in interleukin-3 (IL-3) dependent murine myeloid cell lines led to growth factor independent transformation. Active c-myc transcription was observed in p210 BCR-ABL transformed cells by nuclear run-on assay, and in heterologous reporter assays performed with the 5' regulatory region of murine c-myc linked to firefly luciferase. Transcription initiation occurred primarily from the P2 promoter in p210 BCR-ABL transformed cells. Cis and trans elements responsible for transcription initiation from the c-myc P2 promoter were studied. Expression of E2F1 protein in p210 BCR-ABL transformed cells accounted, in part, for binding to the E2F site of the P2 c-myc promoter. The functional importance of E2F1 expression in p210 BCR-ABL transformed cells toward c-myc transcription was established in reporter assays performed with the P2 c-myc promoter containing either wild-type or mutant E2F sites. Mutation of the E2F motif of P2 5' c-myc reduced activity of the promoter by 50%. By gel mobility shift, E2F1 was found in P2 c-myc band shift complexes along with the cyclin-dependent kinase 2. Therefore, coupling of E2F to components of the retinoblastoma-cyclin pathway defines a route from p210 BCR-ABL to c-myc transcription, which is required for p210 BCR-ABL transformation.
Leukemia 1995 Sep
PMID:Role for E2F1 in p210 BCR-ABL downstream regulation of c-myc transcription initiation. Studies in murine myeloid cells. 765 19

Available evidence suggests a double-pathway two-staged genetic alteration in the pathogenesis of Chronic Myeloid Leukaemia (CML). The regular Ph' defect results in BCR-ABL gene chimaerism on the one hand and suppressed synthesis of the protein responsible for Zn absorption on the other. The resulting Zn deficiency leads, through its metalloenzymes, to a low NAP activity and depressed DNA & RNA polymerase activities: the latter necessitates an adaptive mechanism to sustain cell division despite low zinc. This adaptation is in the form of another gene alteration; a point mutation in the BCR-ABL chimaeric gene, now an oncogene, whose onco-proteins are zinc-independent and stimulate cell division more efficiently (though abnormally also) than the polymerases while defying the usual mechanisms regulating DNA synthesis and cell division. Thus it seems possible that assisted transcellular zinc transport could prevent development of CML in Ph'-positive individuals and the enhanced (abnormal) cellular proliferation might be specifically inhibited.
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PMID:Possible significance of Ph, zinc and BCR-ABL chimaerism in the pathogenesis of chronic myeloid leukaemia. 766 34

It has previously been shown that a cluster of HpaII sites with the potential to be methylated exist around exon b3 of the M-bcr region involved in the formation of the Philadelphia chromosome in chronic myeloid leukemia (CML). The degree of hypermethylation of these sites can be directly correlated with the percentage of immature cells, whilst progressive hypomethylation occurs during the maturation of the granulocyte lineage. We have examined samples obtained from CML patients at diagnosis, during chronic phase, and blast crisis to examine the degree of methylation of this region in the non-rearranged BCR gene and the rearranged BCR-ABL gene. A low degree of methylation of the non-rearranged gene, similar to that observed in normal individuals, was observed in diagnosis and chronic phase samples. Increased methylation was observed during blast crisis indicative of the presence of immature cells in the samples. In contrast, a significantly lower degree of methylation was observed in the rearranged BCR-ABL gene at the onset of blast crisis. Division of the samples into those patients who had lost exon b3 during the formation of the BCR/ABL gene and those that had retained exon b3 produced differing patterns of methylation during disease progression. The former group, who also expressed a b2-a2 mRNA, showed an increase in methylation of the non-rearranged BCR gene prior to and during blast crisis, with a inverse decrease in the methylation of the BCR/ABL gene. Those patients who had retained exon b3, and expressed a b3-a2 mRNA, showed no change in the extent of methylation of the BCR/ABL gene but did exhibit an increase in methylation of the BCR gene during blast crisis. The consequence of the differing degree of methylation during disease progression could affect, to some extent, the specificity of protein binding or RNA expression.
Leukemia 1993 May
PMID:Methylation of the major breakpoint cluster region (M-bcr) in Philadelphia-positive CML. 768 49

A newly established human leukemia cell line, OM9;22, is reported, with B-precursor immunophenotype (CD10+ CD19+ CD22+ HLA- DR+ C mu-) and CD13 antigen, originated from a 19-year-old female patient with Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (ALL). The OM9;22 cells carry a Philadelphia (Ph) translocation and hybrid message detected by a minor-breakpoint cluster region (BCR) exon 1/ABL exon 2 junctional probe using reverse transcriptase polymerase chain reaction. The genetic alterations are consistent with those observed in the donor's leukemia cells, allowing us to conclude that this cell line is a minor-BCR rearranged Ph-positive ALL (Ph+ ALL). Colony formation of the OM9;22 cells in methylcellulose culture is enhanced by the addition of human interleukin 7 (IL-7). In liquid culture, more than 80% of IL-7-treated OM9;22 cells express CD20 antigen but fail to express surface immunoglobulins or cytoplasmic mu-chain, indicating that the cells have a potential of limited maturation by IL-7. By contrast, IL-4 suppresses the colony formation of the OM9;22 cells. These findings suggest that this cell line might be a model of B-precursor human leukemia with proliferative capability by IL-7.
Leukemia 1993 Jul
PMID:Interleukin-7 enhances colony growth and induces CD20 antigen of a Ph+ acute lymphoblastic leukemia cell line, OM9;22. 768 4

Genomic imprinting has recently been associated with the reciprocal t(9;22) chromosome translocation of chronic myeloid leukaemia (CML). This translocation gives rise to a 22q-, or Philadelphia (Ph), chromosome and a derivative 9q+. Based on heterochromatin polymorphisms, it was reported that the former is of maternal and the latter of paternal origin in every case of CML. This parental bias led to the hypothesis that the genes disrupted by the translocation, BCR and ABL, were themselves imprinted, and that in CML the BCR-ABL gene was formed by BCR sequences of maternal and ABL sequences of paternal origin. We have identified a BstNl restriction fragment length polymorphism in the ABL coding sequence which enabled us to investigate directly the expression and inheritance of the two ABL alleles in heterozygous CML patients. Amplification of the specific BCR-ABL and normal ABL mRNA messages by reverse transcriptase-polymerase chain reaction in these patients showed that the ABL moiety of the BCR-ABL gene has an even chance of being the paternal or the maternal copy. We conclude therefore that there is no parental bias in the origin of the translocated ABL gene and no evidence for genomic imprinting of ABL in CML.
Leukemia 1995 Apr
PMID:Balanced parental contribution to the ABL component of the BCR-ABL gene in chronic myeloid leukemia. 772 12

The apparent nonrandom contribution of the paternally-derived chromosome 9 and the maternally-derived chromosome 22 to the leukemia-specific translocation t(9;22)(q34;q11) obtained by cytogenetic analysis suggested that the two genes affected by this rearrangement, namely ABL and BCR, are imprinted. The results of recent molecular genetic studies have challenged this notion, since it was shown that both the paternal as well as the maternal BCR- and ABL-alleles may be affected by the translocation event and that both genes may be expressed from both alleles. This paper offers possible explanations for the apparent contradictory results obtained through cytogenetic and molecular genetic means. Based on the few available data concerning their allelic methylation pattern, replication behavior and expression status, as well as by referring to similar problems encountered in other genes whose imprinting status had also remained elusive for a long time, I argue that it still remains likely that ABL and BCR are imprinted.
Leukemia 1995 Apr
PMID:Are ABL and BCR imprinted? No definitive answers, but more questions. 772 13

Cytogenetic studies of Ph-positive leukemic patients and their parents have indicated that chromosome 22 involved in the formation of the t(9;22) is of maternal origin, whereas chromosome 9 is preferentially of paternal origin. These data have suggested that the two genes BCR and ABL, which become fused through the translocation, might be imprinted, ie expressed in a parental-specific manner. Recent molecular genetic studies however, have shown that BCR and ABL are expressed on both alleles and that the maternal and paternal ABL genes contribute equally often to the BCR-ABL fusion messenger. The findings make imprinting of these genes unlikely as an explanatory model and necessitate a combined cytogenetic and molecular genetic study.
Leukemia 1995 Apr
PMID:Standpoint on imprinting of BCR and ABL. 772 14

Among the contents of chromosome 9 the author mentions locuses for Friedreich's ataxia (FRDA), familial malignant melanoma (MLM), acute hepatic porphyria caused by deficiency of delta-aminolevulinate dehydrogenase (ALAD) and locus XPAC, the defective alleles of which condition disorders of nucleic acid reparative systems. By transcription and translation of the ABL oncogene attached to gene BCR and belonging to the 22nd chromosome a fusion protein with a high kinase activity is formed which is typical for the pathological clone of haematopoietic cells in chronic leukaemia.
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PMID:[The human genome--chromosome 9]. 775 88


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