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 of chromosome 16 [inv(16)(p13q22)] and t(16;16)(p13;q22) are chromosomal rearrangements frequently associated with AML FAB type M4Eo resulting in the production of a fusion gene CBFB/MYH11. We studied 17 patients with a chromosome 16 abnormality (eight M4Eo, two M1, one M2, three M4 without abnormal eosinophils, three MDS) for the presence of CBFB/MYH11 transcripts using an RT-PCR technique. 10 AML patients with inv(16) tested RT-PCR positive (eight at presentation, one in remission, one in remission and relapse). Three of these patients were originally reported by cytogenetic analysis to have del(16q22) but the positive RT-PCR results prompted a cytogenetic re-examination, resulting in the correction of the reports to inv(16). We show that although inv(16) is closely associated with AML M4Eo, it can also be detected in cases of AML M4 without abnormal eosinophils. Three cases of MDS with inv(16) were also RT-PCR positive. Four patients with other chromosome 16 abnormalities were RT-PCR negative. Four AML patients with inv(16) were studied in remission. All were RT-PCR positive, including one patient in remission for 108 months and one 22 months post allogeneic bone marrow transplant. In the latter two remission patients, RT-PCR evaluation was positive in bone marrow (BM) but not in peripheral blood, suggesting that BM may be the more informative. We conclude that this technique is valuable in the accurate molecular classification of AML, particularly as treatment options may be influenced by such information. Though RT-PCR is highly sensitive in detecting CBFB/MYH11 fusion transcripts during remission, monitoring of minimal residual disease in patients with inv(16) remains to be established.
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PMID:Detection of CBFB/MYH11 transcripts in patients with inversion and other abnormalities of chromosome 16 at presentation and remission. 757 15

We have determined the structure of the human CBFB gene, which encodes the beta subunit of the heterodimeric transcription factor core binding factor (CBF). This gene becomes fused to the MYH11 gene encoding smooth muscle myosin heavy chain by an inversion of chromosome 16 that occurs in the M4Eo subtype of acute myeloid leukemia. The CBFB gene contains 6 exons and spans 50 kb. The gene is highly conserved in animal species as distant as Drosophila, and the exon boundaries are in locations identical to those of the murine Cbfb homologue. The CBFB promoter region has typical features of a housekeeping gene, including high G+C content, high frequency of CpG dinucleotides, and lack of canonical TATA and CCAAT boxes. This gene has a single transcriptional start site, 345 nucleotides upstream of the beginning of the coding region. The human and mouse CBFB promoters show conservation of several transcriptional regulatory sequence motifs, including binding sites for Sp1, Ets family members, and Myc, but do not contain any CBF binding sites. The 5' end of the human CBFB gene also contains a highly polymorphic, transcribed CGG repeat that is not present in the murine homologue.
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PMID:Structure of the leukemia-associated human CBFB gene. 906 79

Inv(16)(p13q22) is one of the most frequent chromosomal rearrangements found in acute myelogenous leukemia (AML), representing approximately 16% of documented karyotypic abnormalities. The inv(16) breakpoints have been cloned and shown to involve the non-DNA binding component of the AML-1 transcription factor complex termed core binding factor beta gene (CBF beta) on 16q and the smooth muscle myosin heavy chain gene (MYH11) on 16p. In this study, we analyzed 37 cases of inv(16)-containing AML and 4 cases with t(16;16)(p13;q22) for expression of the CBF beta/MYH11 chimeric message by reverse transcription-polymerase chain reaction (PCR) analysis. CBF beta/MYH11 chimeric messages were detected in 33 of 37 cases with the inv(16) and in the 4 t(16;16)-containing cases. Sequence analysis of PCR products showed extensive breakpoint heterogeneity in both CBF beta and MYH11. In addition to the previously described breakpoint in CBF beta at nucleotide (nt) 495 (amino acid 165), we have identified a second novel fusion point at nt 399 (amino acid 133) in 7% of the cases. Similarly, a unique breakpoint site was identified in MYH11 at nt 1098, as well as at three previously characterized sites at nts 994, 1201, and 1921. Of the 4 PCR-negative cases, 2 of 3 tested lacked CBF beta rearrangements by Southern blot analysis, suggesting the possible involvement of a different genomic locus in some cases with cytogenetic evidence of inv(16). To assess whether the portions of CBF-beta contained within the CBF beta/MYH11 chimeric products retain the ability to interact with their heterodimeric DNA-binding partner AML-1, we performed in vitro DNA-binding analysis. Recombinant CBF-beta polypeptides consisting of the N-terminal 165 amino acids retained their ability to interact with AML-1, whereas mutants containing only the N-terminal 133 amino acids interacted with AML-1 less efficiently. These data suggest that different CBF beta/MYH11 products may vary subtly in their biologic activities.
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PMID:Heterogeneity in CBF beta/MYH11 fusion messages encoded by the inv(16)(p13q22) and the t(16;16)(p13;q22) in acute myelogenous leukemia. 778 Jan 53

As acute nonlymphocytic leukemia (ANLL) with inv(16) (p13q22) or t(16;16)(p13;q22) has been shown to result from the fusion of transcription factor subunit core binding factor (CBFB) to a myosin heavy chain (MYH11), we sought to design methods to detect this rearrangement using reverse transcriptase-polymerase chain reaction (RT-PCR). In all of 27 inv(16)(p13q22) and four t(16;16)(p13;q22) cases tested, a chimeric CBFB-MYH11 transcript coding for an in-frame fusion protein was detected. In a more extensive RT-PCR analysis with different primer pairs, we detected a second new chimeric CBFB-MYH11 transcript in 10 of 11 patients tested. The CBFB-MYH11 reading frame of the second transcript was maintained in one patient but not in the others. We show that the different CBFB-MYH11 transcripts in one patient arise from alternative splicing. Translation of the transcript in which the CBFB-MYH11 reading frame is not maintained leads to a slightly truncated CBFB protein.
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PMID:RT-PCR diagnosis of patients with acute nonlymphocytic leukemia and inv(16)(p13q22) and identification of new alternative splicing in CBFB-MYH11 transcripts. 779 33

The inversion of chromosome 16 [inv(16)] in acute myeloid leukemia (AML) is associated with a p-arm deletion in a subset of patients. The inversion results in two fusion genes: 5'-CBFB/MYH11-3' on 16p and 5'-MYH11/CBFB-3' on 16q. We have studied cells from 42 patients with inv(16) (38 patients) or t(16;16) (four patients) to define the frequency and characteristics of the deletion further. Using fluorescence in situ hybridization (FISH) with probes from cosmids, cosmid contigs, and yeast artificial chromosomes (YACs), we found that six patients with inv(16) had a deletion of between 150 and 350 kb centromeric to the p-arm inversion breakpoint cluster region (p-ibc). This region was shown to contain the 5' portion of the myosin heavy chain (MYH11) gene. YACs containing the p-ibc, which had been useful as FISH probes in the diagnosis of inv(16), detected the inversion in deletion as well as nondeletion patient cells. Thus, the deleted region identified in patients is entirely contained within the human genomic content of the YACs. Southern blot experiments using probes flanking the p-ibc indicated that the deletion removes segments within 10 kb centromeric of the p-ibc. Reverse transcription-polymerase chain reaction (RT-PCR) using primers from the 5' region of CBFB and the 3' region of MYH11 (distal to the p-ibc) produced the 5'-CBFB/MYH11-3' chimeric transcript in inv(16)/del patients. These data confirm that the 5'-CBFB/MYH11-3' chimeric transcript, rather than the reciprocal 5'-MYH11/CBFB-3', is the critical product for chromosome 16-related leukemogenesis.
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PMID:Molecular characterization of 16p deletions associated with inversion 16 defines the critical fusion for leukemogenesis. 783 79

Karyotypic detection of chromosomal 16 abnormalities classically associated with AML M4Eo can be difficult. Characterization of the two genes involved in the inv(16)(p13q22), CBF beta and MYH11, has allowed the detection of fusion transcripts by reverse-transcriptase polymerase chain reaction (RT-PCR). We have analyzed CBF beta-MYH11 fusion transcripts by RT-PCR in myelomonocytic leukemias, with or without eosinophilia, to determine whether their presence correlates with morphology. Fifty-three cases (11 AML M4Eo; 1 AML M4 with atypical abnormal eosinophils (AML M4 "Eo"); 29 AML M4; 8 AML M5; 3 CMML; and 1 AML M2 with eosinophilia) were analyzed. All 11 typical AML M4Eo were CBF beta-MYH11 positive. The single case of AML M4 with distinctive eosinophil abnormalities was negative by karyotype, RT-PCR and fluorescent in situ hybridization (FISH). Three of 29 (10%) AML M4 without abnormal eosinophils were CBF beta-MYH11 positive, 1 of which did not show any apparent chromosome 16 abnormalities by classical metaphase analysis (2 not tested). Both cases tested also showed MYH11 genomic rearrangement. None of the other leukemias were RT-PCR positive. Follow-up of three patient showed residual positivity in apparent complete remission. These data show that CBF beta-MYH11 fusion transcripts occur not only in the vast majority of typical AML M4Eo, but also in approximately 10% of AML M4 without eosinophilic abnormalities, a much higher incidence than the sporadic reports of chromosome 16 abnormalities in AML M4 would suggest. Taken together with the detection of CBF beta-MYH11 transcripts in the absence of apparent chromosome 16 abnormalities by classical banding techniques, these data show that additional screening by either RT-PCR or FISH should be performed in all AML M4, regardless of morphologic features, to allow accurate evaluation of the prognostic importance of this fusion transcript.
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PMID:Detection of the chromosome 16 CBF beta-MYH11 fusion transcript in myelomonocytic leukemias. 785 61

Acute myelomonocytic leukemia with bone marrow eosinophilia (AML-M4Eo in the French-American-British FAB] classification) is frequently associated with pericentric inversion of chromosome 16, inv(16)(p13q22). Recently, the molecular cloning of teh breakpoints has led to the identification of the two fused genes, CBFB on 16q and MYH11 on 16p. We have analyzed 24 patients with AML-M4Eo at diagnosis and 47 patients with AML of other FAB subtypes, by a reverse-transcriptase polymerase chain reaction (RT-PCR) assay for the CBFB/MYH11 fusion mRNAs. Three types of fusion mRNAs were detected in 22 samples of AML-M4Eo (type A, n = 20; type C, n = 1; and type D, n = 1). Among these 22 positive samples, inv(16) was found in the 20 cytogenetically studied cases. No fusion transcript was detected in two patients with AML-M4Eo and in patients with other types of AML. These results confirm that CBFB/MYH11 transcripts (with a predominant type A form) are present in most cases of inv(16) AML. Moreover, detection of the hybrid transcript is closely associated with the finding of abnormal bone marrow (BM) eosinophils in AML-M4Eo as it is not found in other, FAB subtypes of AML, including AML-M4. To assess the presence of type A CBFB/MYH11 fusion transcripts in five AML-M4Eo patients in remission, we designed a sensitive assay combining nested PCR and allele-specific amplification (NPASA). Residual leukemia cells were detected in four patients who were in remission from 4 to 22 months, but not in one patient in long-term remission (5 years). The clinical relevance of persistent CBFB/MYH11 fusion transcripts in remission remains to be established by studying a large prospective series of patients. NPASA provides a useful and sensitive tool for the detection of minimal residual disease in inv(16) AML and, potentially, in other leukemias associated with translocations that result in a predominant fusion transcript.
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PMID:Detection of minimal residual disease in acute myelomonocytic leukemia with abnormal marrow eosinophils by nested polymerase chain reaction with allele specific amplification. 791 48

Pericentric inversion of chromosome 16 [inv(16)(p13q22)] and the related t(16;16)(p13;q22) are seen in a subset of acute myelogenous leukemia (AML) phenotypically and prognostically differing from other cases. We have recently shown that inv(16) results in fusion of CBFB/PEBP2B, a gene encoded at 16q22 to MYH11, a smooth muscle myosin heavy chain gene encoded at 16p13. Chimeric transcripts consisting of upstream CBFB fused to downstream MYH11 coding sequences result from this fusion. In this study we have examined a series of 37 of these cases using reverse transcriptase-polymerase chain reaction (RT-PCR) to detect expression of a hybrid CBFB/MYH11 transcript. Chimeric cDNAs were detected in all but 1 of 37 leukemias with typical inv(16) or t(16;16). Such chimeric products were not seen in a case with inv(16)(p13q24) (ie, a variant q arm breakpoint) or any of 10 cases of AML without these chromosomal changes. Four different chimeric transcripts were found, representing differing fusion points within MYH11 spliced to position 495 of CBFB. Primer sets are described for efficient amplification of these different cDNA forms. Amplification of cDNA showed that all but 17 codons of the CBFB coding sequence are included in the abnormal transcripts. RT-PCR was shown to be highly sensitive and potentially useful for detection of leukemic cells during morphologic remission.
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PMID:Detection of fusion transcripts generated by the inversion 16 chromosome in acute myelogenous leukemia. 814 42

The pericentric inversion of chromosome 16 [inv(16)(p13q22)] is a characteristic karyotypic abnormality associated with acute myeloid leukemia, most commonly of the M4Eo subtype. The 16p and 16q breakpoints were pinpointed by yeast artificial chromosome and cosmid cloning, and the two genes involved in this inversion were identified. On 16q the inversion occurred near the end of the coding region for CBF beta, also known as PEBP2 beta, a subunit of a heterodimeric transcription factor regulating genes expressed in T cells; on 16p a smooth muscle myosin heavy chain (SMMHC) gene (MYH11) was interrupted. In six of six inv(16) patient samples tested, an in-frame fusion messenger RNA was demonstrated that connected the first 165 amino acids of CBF beta with the tail region of SMMHC. The repeated coiled coil of SMMHC may result in dimerization of the CBF beta fusion protein, which in turn would lead to alterations in transcriptional regulation and contribute to leukemic transformation.
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PMID:Fusion between transcription factor CBF beta/PEBP2 beta and a myosin heavy chain in acute myeloid leukemia. 835 18

Pericentric inversion of chromosome 16 [inv(16)(p13q22)] is seen in patients with acute myelomonocytic leukemia with bone marrow eosinophilia. This inversion juxtaposes the MYH11 gene on p13 and the CBFB gene on q22, resulting in the formation of a chimeric mRNA transcript. We describe a patient with acute myelogenous leukemia (M1), with del(16)(q22), who expressed the chimeric transcript. Reverse transcriptase polymerase chain reaction and the sequencing of its product showed fusion of 5'CBFB at position 495 to 3'MYH11 at position 1201. To our knowledge, this is the first report of an AML (M1) case with del(16) and CBFB/MYH11 rearrangement.
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PMID:CBFB/MYH11 fusion transcripts in a case of acute myelogenous leukemia (M1) with partial deletion of the long arm of chromosome 16. 873 92


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