Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report the molecular cytogenetic analysis of a case of Philadelphia (Ph)-negative, BCR-positive chronic myeloid leukemia (CML) which appeared by conventional cytogenetics to have a t(6;9)(p23;q34) as the sole cytogenetic abnormality. Neither conventional nor pulse-field Southern blots detected any rearrangement of the DEK or CAN genes which are often fused in acute myeloid leukemia (AML) with t(6;9)(p23;q34). However, rearrangements of both BCR and ABL genes were detected. The breakpoint in BCR was located in the major translocation cluster region between exons b1 and b3. ABL rearrangements were detected with an ABL exon 1B probe and with a probe located 5' of the entire ABL gene. Comigration between the rearranged fragments obtained with M-bcr-5' and ABL exon 1B probes was observed, implying that the entire ABL gene was fused to the 5' part of the BCR gene. Fluorescence in situ hybridization (FISH) analyses using BCR and ABL probes showed that in 20% of metaphases BCR and ABL signals were present on one chromosome 6 at 6p23, whilst in 80% of metaphases BCR and ABL signals were identified on both copies of chromosome 6. Furthermore, FISH analysis with a whole-chromosome 22 paint demonstrated that chromosome 22 material was present on both copies of chromosome 6. These data indicate a complex Philadelphia translocation involving chromosome band 6p23 and duplication of the whole aberrant chromosome. The nature of the gene locus on 6p23, involved in this rearrangement, remains unknown. A similar translocation has been previously reported in a case of CML, which also lacked DEK and CAN gene rearrangements implying that abnormalities of 6p23 involving genes other than DEK may be a recurrent abnormality in CML.
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PMID:Molecular cytogenetics of chronic myeloid leukemia with atypical t(6;9) (p23;q34) translocation. 759 89

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.
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PMID:Late appearance of a Philadelphia translocation with minor-BCR/ABL transcript in a t(7;11)(p15;p15) acute myeloid leukemia. 772 98

This report describes a patient presenting with acute myeloid leukaemia (AML-FAB classification M2). Phenotypic markers were positive for cells of the myeloid lineage, but negative for monocyte/macrophage, megakaryocyte, and T-cell lineages. The occasional blast was positive for CALLA. All blasts carried the Philadelphia chromosome (Ph+), with 20% also harbouring a monosomy 7 (a cytogenetic marker for AML). Reverse transcriptase polymerase chain reaction (RT-PCR) analysis revealed the presence of two BCR/Abl mRNA transcripts; b2a2, the CML-type and E1a2, the ALL-type. Immunoglobulin (Ig) gene analysis demonstrated the presence of a small population of cells containing rearranged Ig genes. After a short remission, the patient relapsed. At relapse the leukaemia had undergone a major phenotypic switch from AML to ALL, with blasts bearing B-cell markers. Ig gene analysis confirmed a monoclonal population of B-cells. The Ph+ persisted, but the monosomy 7 had disappeared. The same two BCR/Abl mRNA transcripts were found at relapse as at presentation. To our knowledge, this is the first report of an AML simultaneously expressing BCR/Abl transcripts from both the minor and major BCR. The possible mechanisms of this dual expression are discussed.
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PMID:A Ph+ acute myeloid leukaemia expressing both CML-type and ALL-type BCR/ABL mRNA transcripts. 795 Sep 25

The detection of BCR-ABL transcripts by polymerase chain reaction and hybridization protection assay was investigated in 59 adults with acute leukemia in whom the Philadelphia chromosome (Ph) abnormality was not documented by cytogenetic analysis. These included 35 patients with acute lymphocytic leukemia (ALL) and 24 with acute myelogenous leukemia (AML). Overall, three patients were found to have Ph-related molecular abnormalities; one had p190 and two had p210 disease. All three patients had ALL and were among 16 patients with insufficient metaphases by cytogenetic analysis, yielding an incidence of 19% in the latter category. Based on a 32% incidence of insufficient metaphases in our adult ALL population, we project an additional detection rate of 6% Ph-positive ALL by molecular studies and an overall incidence of 20% (14% + 6%) Ph-positive or BCR-ABL-positive ALL. None of the remaining patients with ALL and none of the 24 patients with AML investigated had BCR-ABL-positive disease. We conclude that molecular studies are useful in detecting BCR-ABL-positive disease in a subset of patients with Ph-positive ALL who are not identified by cytogenetic analysis because of insufficient metaphases.
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PMID:What is the contribution of molecular studies to the diagnosis of BCR-ABL-positive disease in adult acute leukemia? 810 97

The translocation (6;9) in acute nonlymphocytic leukemia results in the formation of a dek-can fusion gene. In a case of acute undifferentiated leukemia, the oncogene can is fused to a different gene, named set, instead of dek and is assumed to be activated. Transcripts of set encode a putative SET protein with a predicted molecular mass of 32 kDa. We identified SET as a 39-kDa protein by immunoprecipitation with rabbit antiserum against each of three synthetic peptides predicted from the open reading frame of the set gene. We confirmed this identification of SET by protein sequencing. We also observed that SET is expressed ubiquitously in various human cell lines. SET is phosphorylated on serine residue(s) in cultured cells and is localized predominantly in nuclei. Although the function(s) of SET and SET-CAN is not known, we propose that SET plays a key role in the mechanism of leukemogenesis in acute undifferentiated leukemia, perhaps by activating CAN in nuclei and stimulating the transformation potential of SET-CAN. This proposed role would therefore be similar to the roles observed for BCR and DEK of the chimeric oncoproteins BCR-ABL and DEK-CAN in acute myeloid leukemia and acute nonlymphocytic leukemia, respectively.
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PMID:Identification and characterization of SET, a nuclear phosphoprotein encoded by the translocation break point in acute undifferentiated leukemia. 829 83

We report two cases of Philadelphia chromosome (Ph)-positive acute leukemia with definite myeloid markers. Ph was the sole chromosomal abnormality at presentation, and neither eosinophilia, basophilia, thrombocytosis nor hepatosplenomegaly was present. In both cases, Ph+ myeloblasts showed positive stain for myeloperoxidase and naphthol ASD chloroacetate esterase, which fulfilled the FAB criteria of acute myelogenous leukemia (AML). Ph+ myeloblasts co-expressed myeloid and B-lymphoid antigens (CD10, CD13, CD19 and CD33). In case 1, myeloblasts rearranged M-BCR, and the expression of M-BCR/ABL chimeric RNA was demonstrated by using the reverse transcription polymerase chain reaction (RT-PCR). They also clonally rearranged IGH. Ph clone disappeared on cytogenetic analysis in remission, and granulocytes in remission did not have rearranged M-BCR. In case 2, morphocytochemically distinct myeloid and lymphoid blast populations were seen. Myeloblasts and lymphoblasts were enriched > 96% as CD19-/CD33+ and CD19+/CD33- populations, respectively. Both of them possessed the identical rearrangement of IGH and M-BCR, indicating a common leukemic progenitor cell origin. Furthermore, m-BCR/ABL was detected in addition to M-BCR/ABL on RT-PCR. Accordingly, both cases were diagnosed as de novo Ph+ acute leukemia rather than as chronic myelogenous leukemia in blastic crisis. Their mixed B-lymphoid/myeloid characteristics strongly suggest that so-called 'Ph+ AML' is derived from Ph+ myeloid/B-lymphoid stem cells.
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PMID:B-lymphoid/myeloid stem cell origin in Ph-positive acute leukemia with myeloid markers. 832 35

The Philadelphia (Ph) translocation [t(9;22)(q34;q11)] is the most common genetic abnormality in human leukemia; a transposition of the ABL gene to the major-breakpoint cluster region (M-BCR) is associated with the pathogenesis in Ph+ chronic myelogenous leukemia (Ph+ CML) and in some cases of Ph+ acute leukemia (Ph+ AL). Our current understanding of the methylation of human genomes allows us to consider the association between the epigenetic phenomenon and the control of differentiation and proliferation in mammalian cells. In order to determine whether the methylation status of the M-BCR is associated with breakpoint-localization in this region and with the lineage of hematopoietic cells, we have examined 28 patients with Ph+ leukemias, including nine with Ph+ AL, six patients with acute myeloblastic leukemia without Ph (Ph- AML), and five patients with Ph- acute lymphoblastic leukemia (Ph- ALL); using the restriction endonuclease isochizomers, MspI and HpaII. In CML patients in the chronic phase, the hypomethylated status within the normal M-BCR allele is heterogeneous. In contrast, patients with Ph+ CML in the lymphoid blast crisis phase exhibited a 2.5/2.7 kb band with a complete disappearance of the germline M-BCR fragment (type L). This pattern is consistently noted in Ph- ALL cells, and the pattern is quite different from that found in myeloid blast crisis or Ph- AML (type M). In patients with M-BCR-nonrearranged Ph+ ALL, it is suggested that the M-BCR methylation patterns are cell-lineage specific but some Ph+ ALL cells had a hypomethylation pattern that was identical to that observed in Ph- AML, suggesting a distinction of genetic diversity of leukemia cells with the Ph chromosome, especially Ph+ AL.
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PMID:The methylation status of the major breakpoint cluster region in human leukemia cells, including Philadelphia chromosome-positive cells, is linked to the lineage of hematopoietic cells. 850 75

Blastic transformation of chronic myelogenous leukemia (CML) is characterized by the presence of nonrandom, secondary genetic abnormalities in the majority of Philadelphia1 clones, and loss of p53 tumor suppressor gene function is a consistent finding in 25-30% of CML blast crisis patients. To test whether the functional loss of p53 plays a direct role in the transition of chronic phase to blast crisis, bone marrow cells from p53+/+ or p53-/- mice were infected with a retrovirus carrying either the wild-type BCR/ABL or the inactive kinase-deficient mutant, and were assessed for colony-forming ability. Infection of p53-/- marrow cells with wild-type BCR/ABL, but not with the kinase-deficient mutant, enhanced formation of hematopoietic colonies and induced growth factor independence at high frequency, as compared with p53+/+ marrow cells. These effects were suppressed when p53-/- marrow cells were coinfected with BCR/ ABL and wild-type p53. p53-deficient BCR/ABL-infected marrow cells had a proliferative advantage, as reflected by an increase in the fraction of S+G2 phase cells and a decrease in the number of apoptotic cells. Immunophenotyping and morphological analysis revealed that BCR/ABL-positive p53-/- cells were much less differentiated than their BCR/ABL-positive p53+/+ counterparts. Injection of immunodeficient mice with BCR/ABL-positive p53-/- cells produced a transplantable, highly aggressive, poorly differentiated acute myelogenous leukemia. In marked contrast, the disease process in mice injected with BCR/ABL-positive p53+/+ marrow cells was characterized by cell infiltrates with a more differentiated phenotype and was significantly retarded, as indicated by a much longer survival of leukemic mice. Together, these findings directly demonstrate that loss of p53 function plays an important role in blast transformation in CML.
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PMID:Blastic transformation of p53-deficient bone marrow cells by p210bcr/abl tyrosine kinase. 891 57

This report describes a precise molecular analysis of a rare case of Philadelphia chromosome (Ph) positive acute myeloid leukemia (AML) (FAB classification M2). Phenotypic markers were positive for cells of the myeloid lineage, but negative for B cell and T cell lineage. The leukemic cells carried a Philadelphia chromosome. Major breakpoint cluster region (M-BCR) rearrangement was detected by the Southern blot analysis. Reverse transcriptase polymerase chain reaction analysis revealed the presence of b3a2 BCR/ABL mRNA transcripts. The patient achieved complete remission by conventional remission induction therapy for acute myeloid leukemia. M-BCR rearrangement could not be detected during complete remission. After hematological remission of an 8-month duration, the patient relapsed and died of respiratory distress due to pneumonia. Our case indicate Ph-positive AML with M-BCR rearrangement actually exists. Ph-positive AML carries either M-BCR rearrangement expressing the P210 BCR-ABL or minor breakpoint cluster region (m-BCR) rearrangement producing the P190 BCR-ABL. Therefore, additional other factor (s) apart from the Ph chromosome must be responsible for the acute malignant transformation.
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PMID:Molecular analysis of a case of Philadelphia chromosome-positive acute myeloid leukemia. 906 90

We performed fluorescence in situ hybridization (FISH) upon 9;22 and 15;17 translocation-positive bone marrow cells to monitor the clinical course of 46 patients with chronic myelocytic leukemia (CML) and nine with acute promyelocytic leukemia (AML M3) who received chemotherapy and/or bone marrow transplantation (BMT). M-BCR-ABL and PML-RAR alpha probes were used to detect translocations of t(9;22) and t(15;17), respectively. Signals from CML patients treated with interferon (17 patients) or BMT (29 patients) were 0.5-15% positive for the 9;22 translocation. Among nine M3 patients who received extensive chemotherapy or BMT, 1-5% were positive for the 15;17 translocation. A highly sensitive FISH procedure using both translocation probes and a whole chromosome Y probe was established and applied to eight sex-mismatched BMT patients (seven CML and one AML M3), in which 0.1-0.6% of signals positive for the specific translocations were detected. These results suggested that interphase FISH is powerful enough to identify minor cell populations of 9;22 or 15;17 translocations after therapy, as well as to detect specific chromosome abnormalities at diagnosis.
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PMID:Application of fluorescence in situ hybridization to detect residual leukemic cells with 9;22 and 15;17 translocations. 906 86


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