Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The BCR/ABL oncogene in chronic myelogenous leukemia produces an activated tyrosine kinase fusion protein (p210). Like other tyrosine kinase oncogenes, BCR/ABL can abrogate the interleukin-3 (IL-3) dependence of lymphoid cell lines. To investigate the ability of BCR/ABL to generate growth factor independence in myeloid cells, the IL-3 dependent myeloid cell line NFS/N1.H7 (H7) was transfected with the p210BCR/ABL-containing plasmid, pGD210. Stable clones A54 and A74 were capable of IL-3 independent growth and tumor formation in syngeneic mice. Relief of growth factor dependence was not mediated by autocrine release of IL-3. The baseline proliferation rate of the BCR/ABL transformed cells was greater than that of the parental H7 cells maximally stimulated by IL-3. Abundant constitutive expression of c-myc, c-jun, and c-fos was observed in the p210BCR/ABL transfectants even in low serum conditions. In contrast, c-myc expression in H7 cells was dependent upon IL-3 stimulation, and neither c-jun nor c-fos was highly expressed following IL-3 stimulation in H7 cells. Thus, BCR/ABL transformation and relief of IL-3 dependence involve not only pathways that can substitute for IL-3 induced growth via tyrosine kinase mediated signals, but also pathways that recruit constitutive c-jun and c-fos expression.
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PMID:BCR/ABL confers growth factor independence upon a murine myeloid cell line. 137 13

Chromosomal translocation within B and T cell malignancies has proven a rich source for proto-oncogenes. The obligate DNA breaks within immunoglobulin (Ig) and T cell receptor (TCR) loci are frequently the sites of recurrent translocations. Burkitt's lymphoma established the paradigm by introducing the myc oncogene from chromosome segment 8q24 into the Ig heavy chain gene locus at 14q32. Molecular cloning of an aberrant Ig rearrangement in follicular lymphoma revealed Bcl-2. Bcl-2 constitutes the first member of a new category of oncogenes: regulators of programmed cell death. Bcl-2 blocks apoptosis and maintains long-term immune responsiveness including B-cell memory. The PRAD1 gene of parathyroid adenomas appears to be the elusive Bcl-1 gene of t(11;14)(q13;q32) bearing lymphomas. It proves to be a novel G1 cyclin. Acute lymphoblastic leukemias (ALL) pre-B phenotype produce a E2A/PBX fusion protein that possesses the leucine zipper of E2A with the homeodomain of PBX. Two molecular forms of the BCR/ABL fusion protein are produced by the Philadelphia chromosome. A deregulated p210 tyrosine kinase is found in chronic myelogenous leukemia, while a p190 form predominates in Ph+ ALL. In contrast, T-cell ALLs introduce a potpourri of genes into their T cell receptor loci. However, a common theme is emerging. These oncogenes (Ttg1, Ttg2, SCL, LylI, H0X11) all belong to classic families of transcription factors, possessing LIM domains, helix-loop-helix motifs, or homeodomains. Provocatively, these transcription factors are normally intended for lineages other than T cells. These genes have widened the horizons of both oncogenesis and normal development.
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PMID:Chromosomal translocations in lymphoid malignancies reveal novel proto-oncogenes. 159 Oct 3

We investigated the significance of p210 and p190 molecular abnormalities in 32 adults with Philadelphia chromosome (Ph)-positive acute leukemia. p210 was detected in 15 patients (47%), p190 in 16 (50%), and both in one (3%). p210 was noted in 11 of 24 patients (46%) with acute lymphocytic leukemia, and in four of eight patients (50%) with acute myelogenous or undifferentiated leukemia. Among 29 patients with untreated disease (p210, 14 patients; p190, 15 patients), no significant differences in the two molecularly distinct groups were observed by pretreatment characteristics including age, degree of organomegaly, anemia, leukocytosis, thrombocytopenia, occurrence of karyotypic abnormalities in addition to Ph, or residual diploid metaphases. Complete response (CR) rates were also similar. Although the remission duration tended to be longer with p190 (P = .08), the differences were minor (median duration 29 v 20 weeks) and not paralleled by differences in survival rate. In 10 patients studied by karyotypic analysis in remission, two of four patients with p190 and two of six patients with p210 showed 100% normal metaphases. One of the seven patients (14%) with p210 who achieved CR manifested a morphologic picture of second chronic-phase chronic myelogenous leukemia lasting for 1 month. We conclude that the molecular studies in Ph-positive acute leukemia are not associated with significantly different clinico-laboratory, karyotypic, or prognostic implications.
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PMID:Significance of the P210 versus P190 molecular abnormalities in adults with Philadelphia chromosome-positive acute leukemia. 193 53

The translocation between chromosome 9 and chromosome 22 which creates the Philadelphia chromosome moves the ABL oncogene from its normal location on chromosome 9 and fuses it with a portion of the BCR gene on chromosome 22. This new BCR/ABL fusion gene generates a unique 8.7 kilobase (kb) RNA which codes for a new 210 kilodalton (kd, p210) protein which has a protein tyrosine kinase activity that is greatly increased in comparison to the normal ABL protein. The human K562 cell line was derived from a patient with CML, and serves as one model for the regulation of expression of the ABL and BCR/ABL genes. This study examines the expression of the BCR/ABL fusion gene and the normal ABL gene in relation to differentiation and changes in proliferative state. The expression of both the normal ABL transcripts and the BCR/ABL fusion transcript decrease approximately ten-fold when the cells are induced to differentiate with hemin. In contrast, expression of the MYC oncogene is unaffected by hemin-induced differentiation. The results suggest that both ABL and BCR/ABL expression vary in proportion to the differentiation of the cells, but minimally if at all as a function of the cells' proliferative state.
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PMID:ABL oncogene expression during erythroleukemia cell differentiation. 199 45

The presence of Philadelphia chromosome t(9:22) is a hallmark of 95% of clinical cases of chronic myelogenous leukemia (CML) as well as 20% of adult acute lymphoblastic leukemia (ALL) and 5% of acute myeloid leukemia (AML). The product of t(9;22) is a fusion protein BCR-ABL. The fusion proteins of CML, ALL and AML have increased tyrosine kinase activity and show a transforming potential in vitro and in animal models. The shorter p190 protein is associated almost only with ALL and AML, while the protein p210 is present in both chronic phase and blast crisis of CML and also in 50% of Philadelphia-positive (Ph1+) ALL. In CML the transition from chronic phase to blast crisis is usually accompanied by additional genetic events, e.g. additional chromosomal abnormalities, and oncogene activation(s). The detailed understanding of molecular basis of CML, and Ph1+ ALL and AML provides highly sensitive molecular and serological methods to complement classical cytogenetics. The advantages and limitations of these techniques are described and discussed below.
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PMID:Molecular pathology of chronic myelogenous leukemia. 224 53

Human chronic myelogenous leukemia is characterized by a reciprocal translocation between chromosomes 9 and 22. This results in the transfer of the c-abl protooncogene from chromosome 9 into the bcr gene on chromosome 22. The purpose of this study was to characterize the bcr and related gene products. Antibodies were raised against a fused trpE-bcr protein induced in a bacterial expression vector. Immunoprecipitation with the monoclonal and polyclonal antibodies of metabolically [35S]methionine labeled leukemic cell lines shows a 210, 160 and 130 Kda protein in Philadelphia positive cells containing the bcr-abl fused transcript. Only the 160 and 130 Kda were present in the Philadelphia negative cells. In vitro kinase assay shows that the 130 Kda protein is a phosphoprotein mainly phosphorylated on serine. Partial proteolysis indicates that the p210 and p130 share common domains. In subcellular fractionation experiments, the p130 is colocalized with the p210 bcr-abl in the cytoplasmic fraction. Together with the mapping of 4 distinct bcr related loci our data suggest that the 130 Kda phosphoprotein belongs to a wider family of bcr related gene products.
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PMID:Identification of a 130 Kda bcr related gene product. 249 32

Despite the major breakthrough in the knowledge of the molecular events underlying the t(9;22) translocation, still no consistent data have been found on the evolution of Ph1 positive CML from the chronic to the accelerated or blastic phase of the disease. In most patients in fact the bcr/abl rearrangements are identical both in chronic phase and in blast crisis, and overall differences in chronic phase duration, related to different location of breakpoints inside the bcr region, were found to be marginal. We approached this problem by studying the molecular features of the bcr/abl abnormality in rare CML patients with very long, atypical chronic phase. The three patients studied, whose chronic phase duration is 17, 19, and 21 years, respectively, have typical genomic bcr rearrangements, and two of them show, hybridizing Northern blots to c-abl, the 8.5 kb mRNA, as that typically present in CML. It seems that genomic alterations within bcr and abl cannot account, alone, for the duration of the chronic phase of Ph1 positive CML and those quantitative and/or qualitative alterations of the p210 bcr/abl protein, unluckily awkward to prove, might be responsible for the atypical clinical features of these CML long survivors.
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PMID:Philadelphia-positive chronic myelogenous leukemia with typical bcr/abl molecular features and atypical, prolonged survival. 273 55

The aberrant abl protein product of a chronic myelogenous leukemia (CML) blast crisis cell line (K562) and of five Philadelphia chromosome-positive CML patients in blast crisis were analyzed by an immune complex kinase assay using two antipeptide sera generated against the hydrophilic domain of v-abl and a region within the third exon of the breakpoint cluster region (bcr) respectively. Both the anti-abl and anti-bcr sera detected a 210 kd band in extracts derived from K562 cells and from two CML patients with myeloid blast crisis. p210 was detected by the anti-abl but not the anti-bcr sera in three CML patients with myeloid (one patient) and lymphoid (two patients) blast crisis, indicating the absence of bcr exon 3 in this protein. Southern blot analysis on DNA derived from one of the patients in the latter group was consistent with the break on chromosome 22 occurring 5' to bcr exon 3. Our observations demonstrate that the Philadelphia translocation results in the generation of a chimeric bcr-abl protein with at least two molecular variants, both of which are enzymatically active as protein kinases.
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PMID:Identification of molecular variants of p210bcr-abl in chronic myelogenous leukemia. 288 48

Philadelphia (Ph1) chromosome breakpoints in acute lymphoblastic leukemia (ALL) are of two kinds: those within the breakpoint cluster region (bcr+), as in chronic myeloid leukemia (CML), and those outside it (bcr-). These encode different c-abl messenger RNAs (mRNAs), p210 and p190, respectively. It has been suggested that one class of Ph+ ALL (bcr+) may be a variant of CML arising in a multipotent stem cell, the other (bcr-) de novo ALL initiated in a lymphoid-committed progenitor. Thirty-two cases of ALL (12 Ph1+, ten chromosomally normal, and ten non-mitotic cases) were investigated for bcr involvement. Breakpoints were found within five Ph1+ and in one normal case. There was no difference in clinical features, common ALL antigen (CALLA) positivity, cytogenetics, or response to treatment between the 6 bcr+ and 7 Ph1+ bcr- patients. Myeloid antigen expression was found in 2 bcr+ cases. Bcr rearrangement appeared to be restricted to the lymphoblastic component of marrow or blood in at least four bcr+ cases. In one case, separated myeloid and lymphoid cell fractions were both bcr+. Potential heterogeneity of the Ph1+ target cell, as seen in this study, may be more important in determining disease outcome than the precise location of the Ph breakpoint.
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PMID:Variable Philadelphia breakpoints and potential lineage restriction of bcr rearrangement in acute lymphoblastic leukemia. 316 1

The chromosome 22 derivative, the Philadelphia (Ph) chromosome, results from a reciprocal translocation t(9;22) (q34;q11) and is associated with chronic myeloid leukemia (CML). The translocation can be identified at the DNA level in Ph-positive CML by using a probe to the breakpoint cluster region (bcr). In addition, as a result of this translocation an abl-related 210-kd protein with protein tyrosine kinase (PTK) activity is produced. We analyzed 28 cases of Ph-negative CML for rearrangement of the chromosome 22 sequences and found that eight of the 28 show rearrangement of the bcr. When 12 of the Ph-negative cases were independently reviewed, five were indistinguishable from Ph-positive CML on the basis of morphology, peripheral blood film and clinical details. These five also showed bcr rearrangement. The other seven were reclassified as six atypical CML (aCML) and one chronic myelomonocytic leukemia (CMML). None of these seven showed bcr rearrangement. In addition 11 cases of bcr- CML were assayed for abl-related PTK, and no detectable activity was present, whereas p210 phl/abl PTK was observed both in Ph-positive (three cases examined) and Ph-negative, bcr + (four cases examined) CML. Therefore, bcr + CML, whether or not the Ph chromosome is cytogenetically apparent, involves a similar molecular alteration and produces the 210-kd protein with enhanced PTK activity. Furthermore, these cases can be distinguished from Ph-negative bcr- CML by careful evaluation of clinical and hematologic data.
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PMID:The correlation of breakpoint cluster region rearrangement and p210 phl/abl expression with morphological analysis of Ph-negative chronic myeloid leukemia and other myeloproliferative diseases. 327 62


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