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)

The pericentric inversion on chromosome 16 [inv(16)(p13q22)] and related t(16;16)(p13;q22) are recurrent aberrations associated with acute myeloid leukemia (AML) M4 Eo. Both abberations result in a fusion of the core binding factor beta (CBFB) and smooth muscle myosin heavy chain gene (MYH11). A selected genomic 6.9-kb BamHl probe detects MYH11 DNA rearrangements in 18 of 19 inv(16)/t(16;16) patients tested using HindIII digested DNA. The rearranged fragments were not detectable after remission in two cases tested, while they were present after relapse in one of these two cases tested.
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PMID:Simple method for detection of MYH11 DNA rearrangements in patients with inv(16)(p13q22) and acute myeloid leukemia. 875 63

The inversion(16)(p13;q22) gives rise to chimeric transcripts CBFB-MYH11. To date however, no reports have described the full length coding sequence cloned from patient material or the protein product derived from transcripts. We describe here the cloning and sequencing of the coding region of the fusion gene (type A) from patient cells. The sequence is identical to the included portions of the normal constituent transcripts. We report the study of CBFB and CBFB-MYH11 protein using two anti-CBFB antisera. Twenty-two cases of inv(16) leukemia and a number of other cases of AML were examined. The predicted 70 kDa type A or 95 kDa type D CBFB-MYH11 peptide was detected in 20/22 cases of inv(16) AML. CBFB was expressed as a 21 kDa protein in all samples studied, including hematopoietic cell lines of all major lineages.
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PMID:The gene product of CBFB-MYH11. 875 66

An expressed gene formed by fusion between the CBFB transcription factor gene and the smooth muscle myosin heavy chain gene MYH11 is consistently detected by reverse transcription polymerase chain reaction (RT-PCR) in patients who have acute myeloid leukemia (AML) subtype M4Eo with an inversion of chromosome 16. We have previously shown that a CBFB-MYH11 cDNA construct can produce a chimeric protein and transform NIH 3T3 cells. However, the presence of the chimeric protein in patient cells has not been demonstrated previously. Here, we show that such chimeric proteins can be identified in vivo, primarily in the nuclei of the leukemic cells, by use of antibodies against the C-terminus of the smooth muscle myosin heavy chain and the fusion junction peptide. A very high molecular weight protein/DNA complex is generated when nuclear extracts from patient cells are used in electrophoretic mobility shift assays, as seen in NIH 3T3 cells transfected with the CBFB-MYH11 cDNA. Immunofluorescence staining shows that the proteins are organized in vivo into novel structures within cell nuclei. One isoform of the transcript of the CBFB-MYH11 fusion gene, containing the MHC204 C-terminus, was the predominant from in all five cases studied.
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PMID:Identification of the chimeric protein product of the CBFB-MYH11 fusion gene in inv(16) leukemia cells. 881 54

Multidrug resistance represents an important mechanism by which leukaemic and solid tumour cells escape cell death after exposure to anthracyclines and other natural products. Acute myeloid leukaemia (AML) associated with the inversion chromosome 16: inv(16)(p13q22) has a favourable prognosis and is known to be chemosensitive. The inversion chromosome is seen in a number of FAB subclasses but is most commonly associated with acute myelomonocytic leukaemia with abnormal eosinophils, M4Eo. It results in the creation of a fusion between the myosin heavy chain gene (MYH11) on the short arm and the gene for a transcription factor, core binding factor beta (CBFB) on the long arm. In a subset of these inv(16) AML patients, inversion also results in loss of the gene for the multidrug resistance protein (MRP) at the short arm breakpoint. This gene maps to 16p13.13, centromeric to the primary short arm breakpoint, separated from MYH11 by a distance of approximately 150kb. Deletion of the MRP gene has been demonstrated by in situ hybridisation, gene dosage studies and by loss of heterozygosity of a flanking microsatellite marker (D16S405). Twenty two patients with inv(16) leukaemia were analysed for deletion of the MRP gene. Deletion of the gene was detected in seven patients, fourteen patients showed retention of the gene and in one case the findings were indeterminate. Clinical data from 13 of these patients were analysed revealing deletion of the MRP gene to be significantly associated with longer time from diagnosis until failure (death or relapse from complete remission) in these patients (p = 0.007). From this work and the growing literature concerning MRP, it appears likely that the deletion of an MRP allele, may favourably affect the biology of inv(16) AML and may have important prognostic implications.
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PMID:The biological significance of the multidrug resistance gene MRP in inversion 16 leukemias. 883 90

The pericentric inversion of chromosome 16 (inv(16)(p12q22)) is a characteristic karyotypic abnormality associated with acute myeloid leukemia, most commonly of the M4Eo subtype. It is increasingly appreciated as both a favorable prognostic factor and important guide to therapy. The breakpoints of the inversion have been cloned and a fusion transcript can be identified by RT-PCR. We expand upon our prior abstract of a case of AML subtype M1 with abnormal eosinophils that expressed the inversion 16 fusion transcript CBFB/MYH11. During remission, the transcript could not be detected. The patient relapsed twice during the first year after attaining a complete remission. Morphologically, the relapsed specimens were identical to the appearance of his diagnostic specimen. However, the CBFB/MYH11 fusion transcript was not detected in the relapsed specimen. We conclude that CBFB/MYH11 fusion transcript detection, as a surrogate for the favorable prognosis and treatment planning implied by inv(16) in AML M4Eo, should not be exclusively relied upon in AML M1 in the absence of prospective study of this specific (M1) category of AML. RT-PCR analysis should be correlated with cytogenetics when available and if used alone should be interpreted cautiously in cases of AML with atypical morphological features.
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PMID:Clinical aspects of expression of inversion 16 chromosomal fusion transcript CBFB/MYH11 in acute myelogenous leukemia subtype M1 with abnormal bone marrow eosinophilia. 884 1

The fusion oncogene CBFB-MYH11 is generated by a chromosome 16 inversion in human acute myeloid leukemia subtype M4Eo. Mouse embryonic stem (ES) cells heterozygous for this oncogene were generated by inserting part of the human MYH11 cDNA into the mouse Cbfb gene through homologous recombination (knock-in). Chimeric mice were leukemia free, but the ES cells with the knocked-in Cbfb-MYH11 gene did not contribute to their hematopoietic tissues. Mouse embryos heterozygous for Cbfb-MYH11 lacked definitive hematopoiesis and developed multiple fatal hemorrhages around embryonic day 12.5. This phenotype is very similar to that resulting from homozygous deletions of either Cbfb or Cbfa2 (AML1), consistent with a dominant negative function of the Cbfb-MYH11 fusion oncogene. An impairment of primitive hematopoiesis was also observed, however, suggesting a possible additional function of Cbfb-MYH11.
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PMID:Failure of embryonic hematopoiesis and lethal hemorrhages in mouse embryos heterozygous for a knocked-in leukemia gene CBFB-MYH11. 892 37

We have developed a competitor-based RT-PCR technique which will detect and quantitate the CBFbeta/MYH11 transcripts associated with inv(16)(q22;p13) and have used it to study presentation and follow-up samples of acute myeloid leukaemia (AML). The levels of the leukaemia-specific transcripts are expressed as a ratio to a ubiquitously expressed mRNA species (Abl) which controls for RNA degradation. This technique has been applied to 75 consecutive patients presenting with either de novo AML or tMDS; 6/75 patients analysed were positive for the inv(16), all were confirmed by conventional cytogenetics. The inv(16) has a strong association with M4Eo, but we found only 2/6-positive patients to have this diagnosis (two patients with M2, one patient M1 and one patient had MDS). At presentation the levels of CBFbeta/MYH11 transcripts were 0.1-10/Abl transcript (mean 3.3/Abl transcript). Seventeen follow-up samples were available on 5/6 of these patients, and on two further patients in whom stored material was available. Following the first cycle of chemotherapy the level of transcripts was at least 10(-2) lower (0.1-10 x 10(-2)/abl transcript) than their presentation sample. Subsequent samples on these patients when in remission gave transcript levels in the range (1.0 x 10(-4) - 2 x 10(-3)/abl transcript), and three long-term follow-up samples were negative. We have developed a quantitative test which opens the possibility of predicting relapse by detecting changes in the numbers of leukaemia-specific transcripts.
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PMID:Detection and quantitation of the CBFbeta/MYH11 transcripts associated with the inv(16) in presentation and follow-up samples from patients with AML. 906 75

It has been established that cytogenetic findings at diagnosis of acute myeloid leukaemia (AML) are a powerful prognostic indicator. Patients who have the inv(16)(p13q22), closely associated with the FAB subtype M4Eo. are deemed to have good-risk disease. This subtle translocation may be difficult to detect in poor-quality metaphase preparations and if missed could lead to the incorrect assignment of risk group and influence further treatment strategies. We studied 321 patients with AML at diagnosis for the presence of inv(16)(p13q22) and CBF beta/MYH11 fusion transcripts by cytogenetic and RT-PCR techniques respectively. Karyotypic analysis detected 21 cases of inv(16) (p13q22), all of which were PCR positive. A further 12 cases were detected at the molecular level only, in FAB types other than M4Eo. The observed frequencies of CBF beta/MYH11 fusion transcripts in our study have been adjusted for the reported incidence of each FAB subtype and we calculate that 10.1% of all new cases of AMLs have molecular evidence of inv(16)(p13q22). only half of which are of the M4Eo subtype. We conclude that molecular screening for the presence of CBF beta/MYH11 fusion transcripts should be mandatory in all case of AML at diagnosis.
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PMID:Frequency of CBF beta/MYH11 fusion transcripts in patients entered into the U.K. MRC AML trials. The MRC Adult Leukaemia Working Party. 907 14

We report a 3-year-old girl with minimally differentiated acute myeloid leukemia and chromosome 16 inversion (inv 16). Inv 16 is generally associated with acute myelomonocytic leukemia with dysplastic eosinophils in the bone marrow (AML-M4Eo). Recently, molecular analysis showed that a fusion gene is generated by this inversion between the CBFB gene on the q arm and the MYH11 gene on the p arm. Using reverse transcriptase-polymerase chain reaction analysis, we tried to detect CBFB/MYH11 chimeric mRNA in blasts from our patients, however, were unable to detect any chimeric mRNA in the blasts: The absence of CBFB/MYH11 transcripts in this case suggests that rare chimeric products might be formed as a result of inv 16 that could not be detected by the primer sets used in this study. Another possibility is that different genes are rearranged on the chromosome 16 with the inv 16. More detailed molecular analysis of this case might be necessary in order to elucidate these possibility. Analyzing leukemias with inv 16 which do not have a typical CBFB/MYH11 chimeric mRNA might lead to understanding an alternative pathogenesis for acute leukemia with inv 16.
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PMID:Molecular analysis of minimally differentiated acute myeloid leukemia with chromosome 16 inversion. 915 61

Pericentric inversion of chromosome 16, translocation (16;16) and del(16q), resulting in a chimerical fusion of CBFbeta and MYH11 genes, are typically seen in the M4Eo French-American-British (FAB) classification subset of acute myelogenous leukemia (AML). In this study, we analyzed 70 cases of acute non-lymphoblastic leukemia, mainly of the M4 or M5 type. We report the very unusual presence of the t(16;16) and CBFbeta/MYH11 fusion transcript in an M7 patient. Ten M4Eo and four non-M4Eo patients presented an inv(16), t(16;16) or CBFbeta/MYH11 fusion transcript. In most cases, the common 'A-type' CBFbeta/MYH11 fusion transcript was detected. In addition to the eight different breakpoints and the three alternative splicing variants already described, evidence of a new CBFbeta/MYH11 fusion transcript was found which involves a 785-bp deletion of MYH11. Moreover, two patients had an unusual transcript, to our knowledge only observed once. Only one patient had abnormal eosinophilic differentiation without chromosome 16 cytogenetic abnormalities or detectable CBFbeta/MYH11 fusion. Conversely, only one patient presented CBFbeta/MYH11 fusion without abnormal eosinophilic differentiation. Altogether, our data suggest a correlation between the CBFbeta/MYH11 fusion transcript and characteristic abnormal eosinophilic differentiation, whatever the FAB subtype or the percentage of abnormal eosinophils
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PMID:Detection of CBFbeta/MYH11 fusion transcripts in acute myeloid leukemia: heterogeneity of cytological and molecular characteristics. 918 Feb 86


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