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)

One hundred patients with Ph1-chromosome-positive chronic myelogenous leukemia (CML) with t(9;22) are included in the present investigation. The position of the Ph1 chromosome in relation to the normal as well as the abnormal chromosomes 9 was localized at metaphase in 1,000 bone-marrow cells. Our study suggests that the rearranged chromosomes, i.e., Ph1 and t(9;22), are closer together than their normal homologues. This impression is based on extensive statistical analysis. The intimate relationship may be due to the fact that they carry reciprocal genetic material responsible for a power of attraction between them. Alternatively, it is tempting to hypothesize that there may be a DNA sequence homology in the bands of chromosomes 9q and 22q involved in the reciprocal translocation perpetuating this relationship in subsequently generating cells during mitotic cell divisions. Furthermore, c-abl and bcr genes might play some role in maintaining the spatial relationship.
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PMID:Spatial relationship of chromosomes 9 and 22 at metaphase in patients with chronic myelogenous leukemia (CML). 316 80

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

Tumor-specific alterations in oncogenes are thought to play a central role in the development of cancer. An example is the consistent fusion of the bcr gene to the c-abl oncogene on the Ph chromosome in CML. The Ph chromosome can also be observed in ALL. About 50% of Ph+ ALL cases, in contrast to CML, do not exhibit chromosomal breakpoints in the major cluster region or mcr (Ph+ mcr- ALL). These cases may have a novel bcr-abl fusion gene instead. We tested this hypothesis in eight Ph+ mcr- ALL patients by amplifying the putative hybrid part of the bcr-abl cDNA, using the polymerase chain reaction method. All cases examined showed the same joining of the first exon of the bcr gene to the c-abl oncogene. Thus, the novel bcr-abl fusion in Ph+ mcr- ALL is the result of a molecularly distinct Ph chromosome. This allows the definition of Ph+ leukemias by their respective bcr-abl oncogene activation. Moreover, the cDNA amplification method we use is a clinically useful tool to screen for bcr-abl oncogene activations in leukemia patients.
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PMID:bcr-abl oncogene activation in Philadelphia chromosome-positive acute lymphoblastic leukemia. 317 39

The case of a 62-year-old Japanese male with a myelodysplastic syndrome and a Philadelphia (Ph)-like chromosome, which probably involved bands 11q23 and 22q11, is presented. Cytogenetic analysis of bone marrow cells revealed a Ph chromosome as well as -5, -7, +8, +11, -16, and an extra Ph. Some of the cells had a normal karyotype. Molecular analysis using breakpoint cluster region probes (5' bcr and 3' bcr) did not detect a rearrangement within the bcr DNA sequences, indicating that the breakpoint at 22q11 occurred outside the bcr. Furthermore, the bone marrow cells from this patient did not express an 8.5-kb c-abl mRNA. Thus, the Ph chromosome in this case differs from that of Ph-positive chronic myelogenous leukemia, and the present case suggests that we should retain the term of "Ph-like chromosome" in such cases.
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PMID:Myelodysplastic syndrome with Philadelphia-like chromosome without bcr rearrangement. 318 18

Philadelphia (Ph) chromosome negative chronic myeloid leukemia (CML) can be distinguished from clinically similar disorders on the basis of the presence of rearrangement of the breakpoint cluster region (bcr) of chromosome 22. We have identified six patients with Ph-negative CML, each with bcr rearrangement. Apparently normal karyotypes were observed in two cases, and a third contained a rearrangement that did not appear to involve chromosomes 9 or 22. The other three cases had translocations involving chromosome band 9q34 but no case contained the common derivative chromosome 9pter----9q34::22q11----22qter. One case appeared to contain either a deletion of an unrearranged bcr locus in approximately 50% of cells or duplication of rearranged bcr, both 5' and 3' of the chromosome 22 breakpoint. Considerable complexity exists in the types of genetic changes that can juxtapose bcr and the c-abl oncogene in CML. Based on the molecular and cytogenetic analyses of these and other cases described in the literature, we conclude that most cases of true Ph-negative CML arise from submicroscopic genetic exchanges rather than masking of simple t(9;22)(q34;q11) translocations by secondary rearrangements.
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PMID:The karyotype of Philadelphia chromosome-negative, bcr rearrangement-positive chronic myeloid leukemia. 318 23

DNA of peripheral blood or bone marrow leukocytes from 8 normal subjects, 7 cases of acute lymphocytic leukemia (ALL), 2 of acute myelogenous leukemia (AML) and 1 of chronic myelogenous leukemia (CML), having been digested by endonuclease Eco RI or Pst I separately, was hybridized with the probes of 3' fragment (Pst I/Hind III) or 5' fragment (Hinc II/Pst I) of Abelson murine leukemia virus (A-MuLV) oncogene v-abl. The proto-oncogene c-abl, which is homologous to v-abl, was found amplified in 4 ALL, 1 CML and 1 AML. In one of these 4 ALL, c-abl was amplified even over 100 times. A new c-abl BamH I fragment with 6.7 kilobase pairs (kb) in length was observed in 2 ALL and 1 CML out of these 6 cases with amplification, but none of this fragment was found in the normal subjects or other leukemia patients. These 3 patients with the presence of 6.7 kb fragment were high risk ones and 2 of them had died, suggesting that 6.7 kb fragment be the index of poor prognosis. The amplification and rearrangement of c-abl imply the activation of proto-oncogene in leukemogenesis.
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PMID:[Amplification and rearrangement of proto-oncogene c-abl in human leukemia cells]. 321 75

We report a case of acute leukemia in which studies at presentation showed both myeloid and lymphoid cell surface markers. At relapse membrane markers studies were consistent with a leukemia of B-lymphoid lineage. However, immunoglobulin (Ig) and T cell receptor (TCR) beta chain genes were both found in a rearranged configuration. The majority of metaphases from the leukemic cells at presentation showed the Philadelphia chromosome, t(9;22)(q34;q11), whereas a minority were normal. At relapse both Ph-positive and -negative metaphases were still present in the bone marrow but some of the Ph-negative metaphases had acquired an additional chromosome #19 [47,XY, + 19]. Southern analysis of DNA from leukemic bone marrow cells at diagnosis showed no rearrangement of breakpoint cluster region (bcr). There was no bcr-abl chimeric mRNA typical of Ph-positive chronic myeloid leukemia (CML). However, the cells expressed an abl-related protein of Mr 190 kd with enhanced tyrosine kinase activity. Leukemic cell metaphases were studied by the technique of in situ hybridization with probes for C-lambda, sis, abl, and 5' bcr. The c-abl probe mapped to chromosome 22q11 in Ph-positive metaphases. The 5' bcr probe mapped to 9q+ in the Ph-positive metaphases and the C-lambda gene mapped to the Ph chromosome. Thus, the genomic breakpoint in this patient must lie upstream of the BCR defined by study of Ph-positive CML and downstream of the C-lambda gene locus. We speculate that the Ph-negative cells in this patient may represent a leukemic proliferation susceptible to acquisition of specific chromosomal changes.
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PMID:The genomic breakpoint in a patient with Philadelphia-positive acute leukemia is 5' of the breakpoint cluster region. 325 55

In this review we have described molecular consequences of the t(9;22) translocation typical of CML and some cases of ALL. This data indicates an important role for abl and bcr and suggest some common mechanisms of activation of c-abl related tyrosine kinase activity. This data also provides insight into the relationship between Ph1 positive, Ph1 negative CML and Ph1 positive ALL. Although this data answers some questions, they raise others; eg, what is the molecular basis of the t(9;22) translocation? How does increased abl related kinase activity eventuate in CML? Finally, this data reviewed suggests that factors other than abl and bcr must play a role in CML. Definition of these factors will be important in the future.
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PMID:Molecular biology of chronic myelogenous leukemia. 327 14

Two types of Philadelphia (Ph') chromosome positive acute lymphoblastic leukemias (ALL) have been described. One shows rearrangements within the 5.8 kb breakpoint cluster region (bcr), which forms the mid-portion of the bcr gene, on chromosome 22, while the other carries rearrangements involving a more proximal region on chromosome 22. To understand the nature of the breakpoints on chromosome 22 in bcr rearrangement negative, Ph'-positive ALLs, we have cloned and sequenced the cDNA of the c-abl oncogene in such ALL cells. The 5' ends of the cDNA clones correspond to the normal sequences of the bcr gene first exon with two of the clones extending beyond the GCCATGG consensus sequence for the initiation of translation. The bcr sequence stops at nucleotide 1813 of the coding sequence of the bcr gene, while the c-abl sequence starts at the beginning of the second c-abl exon (nucleotide 227). Thus the joining point between bcr and c-abl is at the boundary between two exons, suggesting intronic fusion and the occurrence of a splicing event. Our current observations indicate that the Ph' translocation in bcr negative ALL involves bcr gene sequences, albeit only a proximal portion of those involved in CML. These genomic differences may be important factors in the pathogenesis of the distinct phenotypes of ALL and CML.
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PMID:Fusion of the bcr and the c-abl genes in Ph'-positive acute lymphocytic leukemia with no rearrangement in the breakpoint cluster region. 328 53

In chronic myelocytic leukemia, the human c-abl oncogene is translocated from chromosome 9 to a region on chromosome 22 designated as the breakpoint cluster region (bcr) (A. de Klein, A. Guerts van Kessel, G. Grosveld, C. R. Bartram, A. Hagemeyer, D. Bootsma, N. K. Spurr, N. Heisterkamp, J. Groffen, and J. R. Stephenson, Nature (London) 300:765-767, 1982; J. Groffen, J. R. Stephenson, N. Heisterkamp, A. de Klein, C. R. Bartram, and G. Grosveld, Cell 36:93-99.) Abnormal c-abl homologous mRNA and protein have been detected in the leukemic cells of patients with chronic myelocytic leukemia (E. Canaani, D. Stein-Saltz, E. Aghai, R. P. Gale, A. Berrebi, and E. Januszewicz, Lancet 1:593-595, 1984; S. J. Collins and M. T. Groudine, Proc. Natl. Acad. Sci. USA 80:4813-4817, 1983; R. P. Gale and E. Canaani, Proc. Natl. Acad. Sci. USA 81:5648-5652, 1984; J. B. Konopka, S. M. Watanabe, J. W. Singer, S. J. Collins, and O. N. Witte, Proc. Natl. Acad. Sci. USA 82:1810-1814, 1985). The abnormal mRNA represents a chimeric transcript consisting of 5' bcr and 3' c-abl sequences (G. Grosveld, J. Verwoerd, T. van Agthoven, A. de Klein, K. L. Ramachandran, N. Heisterkamp, K. Stam, and J. Groffen, Mol. Cell. Biol. 6:607-616, 1986; E. Shtivelman, B. Lifshitz, R. B. Gale, and E. Canaani, Nature (London) 315:550-554, 1985; K. Stam, N. Heisterkamp, G. Grosveld, A. de Klein, R. S. Verma, M. Coleman, H. Dosik, and J. Groffen, N. Engl. J. Med. 313:1429-1433, 1985). In the present study, we demonstrated that the abnormal c-abl protein is a fusion protein. In addition, the normal gene encompassing bcr sequences was shown to encode a 160,000-dalton phosphoprotein with an associated serine or threonine kinase activity. We propose that this gene be designated phl, reserving the term bcr for the region within the phl gene encompassing the Ph' translocation breakpoints.
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PMID:Evidence that the phl gene encodes a 160,000-dalton phosphoprotein with associated kinase activity. 329 55


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