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 describe two cases of acute myelomonocytic leukemia with eosinophilia (AML-M4Eo) that were diagnosed with an inv(16)(p13q22) based on conventional cytogenetics (CC) and fluorescence in situ hybridization (FISH) technique using a chromosome 16p arm specific paint probe. Additional FISH analysis with a dual-color CBFB DNA probe showed that the 3' portion of the CBFB gene was translocated to chromosome 10p13 in the first patient and 1p36 in the other. These two cases indicate that some inv(16)(p13q22) identified by CC and FISH with chromosome arm-specific painting probe may represent cases of inversion-associated translocation. We suggest that all cases with inv(16)(p13q22) should be investigated by FISH with appropriate probes for a possible translocation of 16q22-->qter to another chromosome.
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PMID:Chromosome 16 inversion-associated translocations in acute myeloid leukemia elucidated using a dual-color CBFB DNA probe. 1203 28

We have designed a real-time CBFB-MYH11 reverse transcription polymerase chain reaction (RT-PCR) assay to quantify minimal residual disease (MRD) in patients with inv(16)-positive acute myeloid leukaemia (AML). Six patients were followed for a median of 17.5 months after diagnosis during which 120 evaluable samples were analysed. The CBFB-MYH11 expression at diagnosis varied only fourfold between the six patients and was virtually identical to that observed in the CBFB-MYH11-positive cell line ME-1. For two cases, a patient-specific real-time PCR for CBFB-MYH11 quantification at genomic DNA level was designed. Similar disease levels were found at the RNA and genomic DNA level during and after treatment, indicating that CBFB-MYH11 gene expression was unaltered during treatment and that the percentage of malignant cells can be accurately quantified at the RNA level. Following successive courses of chemotherapy, the reduction of malignant cells was found to be significantly more pronounced (80-250-fold greater) in peripheral blood compared with bone marrow in five out of six cases tested. Treatment with gemtuzumab ozogamicin as sole agent at relapse did not result in a selective decrease of tumour cells in three cases analysed. We conclude that real-time PCR is a powerful method of monitoring MRD levels and quantifying the antileukaemic effect of separate (experimental) courses of chemotherapy.
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PMID:Minimal residual disease quantification in patients with acute myeloid leukaemia and inv(16)/CBFB-MYH11 gene fusion. 1213 24

Core-binding factor beta (CBFbeta) and CBFalpha2 form a heterodimeric transcription factor that plays an important role in hematopoiesis. The genes encoding either CBFbeta or CBFalpha2 are involved in chromosomal rearrangements in more than 30% of cases of acute myeloid leukemia (AML), suggesting that CBFbeta and CBFalpha2 play important roles in leukemogenesis. Inv(16)(p13;q22) is found in almost all cases of AML M4Eo and results in the fusion of CBFB with MYH11, the gene encoding smooth muscle myosin heavy chain. Mouse embryos heterozygous for a Cbfb-MYH11 knock-in gene lack definitive hematopoiesis, a phenotype shared by Cbfb(-/-) embryos. In this study we generated a Cbfb-GFP knock-in mouse model to characterize the normal expression pattern of Cbfbeta in hematopoietic cells. In midgestation embryos, Cbfbeta was expressed in populations enriched for hematopoietic stem cells and progenitors. This population of stem cells and progenitors was not present in mouse embryos heterozygous for the Cbfb-MYH11 knock-in gene. Together, these data suggest that Cbfb-MYH11 blocks embryonic hematopoiesis at the stem-progenitor cell level and that Cbfb is essential for the generation of hematopoietic stem and progenitor cells. In adult mice, Cbfbeta was expressed in stem and progenitor cells, as well as mature myeloid and lymphoid cells. Although it was expressed in erythroid progenitors, Cbfbeta was not expressed during the terminal stages of erythropoiesis. Our data indicate that Cbfb is required for myeloid and lymphoid differentiation; but does not play a critical role in erythroid differentiation.
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PMID:Role of Cbfb in hematopoiesis and perturbations resulting from expression of the leukemogenic fusion gene Cbfb-MYH11. 1223 55

To evaluate the prognostic significance of quantitative PML-RARA, AML1-ETO, and CBFB-MYH11 fusion transcript expression, real-time polymerase chain reaction was used to analyze bone marrow samples of 349 such patients at diagnosis and 522 samples of 142 patients also during therapy (total analyses, n = 859; median number of follow-up samples, 4/patient; median duration of assessment, 12 months). Lower expression levels at diagnosis correlated with better overall and event-free survival in all 3 leukemia subtypes. By combining the median expression ratio after consolidation therapy and the 75th percentile of the expression ratio at diagnosis, a new score was established that separates a group with 100% EFS from a significantly worse group (P <.0001) in each of the 3 acute myeloid leukemia subgroups. Eight patients showed increasing levels of expression during follow-up and all had relapse. In conclusion, patients at high risk for treatment failure can be identified by high levels of fusion gene expression at diagnosis or less than 3 logs of tumor reduction during the first 3 to 4 months of therapy. By combining the transcription ratios at these 2 checkpoints, a new powerful prognostic score has been established.
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PMID:New score predicting for prognosis in PML-RARA+, AML1-ETO+, or CBFBMYH11+ acute myeloid leukemia based on quantification of fusion transcripts. 1284 88

Acute myeloid leukemia subtype M4 with eosinophilia is associated with a chromosome 16 inversion that creates a fusion gene CBFB-MYH11. We have previously shown that CBFB-MYH11 is necessary but not sufficient for leukemogenesis. Here, we report the identification of genes that specifically cooperate with CBFB-MYH11 in leukemogenesis. Neonatal injection of Cbfb-MYH11 knock-in chimeric mice with retrovirus 4070A led to the development of acute myeloid leukemia in 2-5 months. Each leukemia sample contained one or a few viral insertions, suggesting that alteration of one gene could be sufficient to synergize with Cbfb-MYH11. The chromosomal position of 67 independent retroviral insertion sites (RISs) was determined, and 90% of the RISs mapped within 10 kb of a flanking gene. In total, 54 candidate genes were identified; six of them were common insertion sites (CISs). CIS genes included members of a zinc finger transcription factors family, Plag1 and Plagl2, with eight and two independent insertions, respectively. CIS genes also included Runx2, Myb, H2T24, and D6Mm5e. Comparison of the remaining 48 genes with single insertion sites with known leukemia-associated RISs indicated that 18 coincide with known RISs. To our knowledge, this retroviral genetic screen is the first to identify genes that cooperate with a fusion gene important for human myeloid leukemia.
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PMID:Identification of genes that synergize with Cbfb-MYH11 in the pathogenesis of acute myeloid leukemia. 1504 90

The Runt domain transcription factor, PEBP2/CBF, is a heterodimer composed of 2 subunits. The DNA-binding alpha subunit, or RUNX protein, interacts with a partner PEBP2beta/CBFbeta through the evolutionarily conserved Runt domain. Each of the genes encoding RUNX1 and PEBP2beta/CBFbeta is frequently involved in acute myeloid leukemia. The chimeric protein, CBFbeta(PEBP2beta)/SMMHC, is generated as a result of inversion of chromosome 16 in such a way to retain the heterodimerization domain of PEBP2beta at the amino-terminal side fused to the C-terminal coiled-coil region of smooth muscle myosin heavy chain (SMMHC). Here we show that, in the chimeric protein, the second heterodimerization domain is created by the fusion junction, enabling the chimeric protein to interact with RUNX1 at far greater affinity than PEBP2beta and inactivate the RUNX1/AML1 function. To explain why and how heterozygous CBFB/MYH11 can inactivate homozygous RUNX1 near to completion, we propose a new model for this chimeric protein that consists of a Y-shaped dimer with unpaired N-terminal halves followed by a coiled-coil for the C-terminal region.
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PMID:Molecular basis for a dominant inactivation of RUNX1/AML1 by the leukemogenic inversion 16 chimera. 1507 Jul 3

Inv(16)(p13q22) is associated with acute myeloid leukemia subtype M4Eo that is characterized by the presence of myelomonocytic blasts and atypical eosinophils. This chromosomal rearrangement results in the fusion of CBFB and MYH11 genes. CBF beta normally interacts with RUNX1 to form a transcriptionally active nuclear complex. The MYH11 gene encodes the smooth muscle myosin heavy chain. The CBF beta-SMMHC fusion protein is capable of binding to RUNX1 and form dimers and multimers through its myosin tail. Previous results from transgenic mouse models show that Cbfb-MYH11 is able to inhibit dominantly Runx1 function in hematopoiesis, and is a key player in the pathogenesis of leukemia. In recent years, molecular and cellular biological studies have led to the proposal of several models to explain the function of CBF beta-SMMHC. In this review, we will first focus our attention on the molecular mechanisms proposed in the recent publications. We will next examine recent gene expression profiling studies on inv(16) leukemia cells. Finally, we will describe a recent study from one of our labs on the identification of cooperating genes for leukemogenesis with CBFB-MYH11.
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PMID:Mechanism of leukemogenesis by the inv(16) chimeric gene CBFB/PEBP2B-MHY11. 1515 86

We describe a case of a 38-year old male with inv(16)(p13q22) positive acute myeloid leukaemia (AML) with eosinophilia, relapsing after a molecular remission of almost three years. Remarkably, the leukaemia at relapse was identified as a precursor-B-cell acute lymphoblastic leukaemia (B-ALL) by cytology and immunophenotyping, but was inv(16)(p13q22) positive as revealed by interphase FISH, FICTION analysis, and real-time quantitative PCR. Analysis of immunoglobulin and T-cell receptor genes showed a bi-allelic DH2-JH rearrangement at relapse, but not at diagnosis. These findings indicate a myeloid to lymphoid lineage switch from an inv(16)(p13q22) positive leukaemia and show that IGH gene rearrangements can occur in the presence of CBFB-MYH11 fusion transcripts.
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PMID:An inv(16)(p13q22) positive acute myeloid leukaemia relapsing as acute precursor B-cell lymphoblastic leukaemia. 1533 97

Acute myelomonocytic leukemia with bone marrow eosinophilia (AML M4Eo) is a subtype of AML with distinct morphological features. Inversion (16)(p13.1q22), t(16;16)(p13.1;q22), and del(16)(q22) are nonrandom abnormalities associated with AML M4Eo and a favorable prognosis, compared with the standard risk group for AML. Deletions of the proximal region of the MYH11 gene located at 16p13.1 have been detected in about 20% of patients with inv(16), with an undetermined effect on patient survival. We present the case of a patient with AML M4Eo and inversion 16 with a distal deletion of the CBFB gene at 16q22 detected with fluorescence in situ hybridization. To our knowledge, only one previous report of a similar deletion has appeared in the literature.
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PMID:Deletion of CBFB in a patient with acute myelomonocytic leukemia (AML M4Eo) and inversion 16. 1538 74

Recurrent chromosomal rearrangements are associated with the development of acute myeloid leukemia (AML). The frequent inversion of chromosome 16 creates the CBFB-MYH11 fusion gene that encodes the fusion protein CBFbeta-SMMHC. This fusion protein inhibits the core-binding factor (CBF), resulting in a block of hematopoietic differentiation, and induces leukemia upon the acquisition of additional mutations. A recent genetic screen identified Plag1 and Plagl2 as CBF beta-SMMHC candidate cooperating proteins. In this study, we demonstrate that Plag1 and Plagl2 independently cooperate with CBF beta-SMMHC in vivo to efficiently trigger leukemia with short latency in the mouse. In addition, Plag1 and Plagl2 increased proliferation by inducing G1 to S transition that resulted in the expansion of hematopoietic progenitors and increased cell renewal in vitro. Finally, PLAG1 and PLAGL2 expression was increased in 20% of human AML samples. Interestingly, PLAGL2 was preferentially increased in samples with chromosome 16 inversion, suggesting that PLAG1 and PLAGL2 may also contribute to human AML. Overall, this study shows that Plag1 and Plagl2 are novel leukemia oncogenes that act by expanding hematopoietic progenitors expressing CbF beta-SMMHC.
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PMID:Plag1 and Plagl2 are oncogenes that induce acute myeloid leukemia in cooperation with Cbfb-MYH11. 1558 52


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