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)

Therapy-associated myelodysplastic syndromes and acute myeloid leukaemia (t-AML/MDS) following high dose chemotherapy are significant problems, with a cumulative incidence of 20% or more in myeloablative treatment regimen. Retrospective findings indicated that t-AML/MDS associated genetic aberrations can be observed directly after exposure to chemotherapy and can precede t-AML by several months. To determine the incidence of post-therapeutic aberrations and their predictive value, we prospectively investigated 316 samples of 95 patients with non-Hodgkin lymphoma (NHL) who were treated with intermediate and high dose chemotherapy (Arm A and B of the megaCHOEP (cyclophosphamide, doxorubicin, etoposide, vincristine, prednisolone) trial of the German High Grade NHL study group). Molecular aberrations (RUNX1/RUNX1T1, PML-RARA, CBFB-MYH11, MLL-MLLT1, BCR-ABL1) were observed in 33.3% (Arm A) and 55.4% (Arm B) of patients and in 14.9% and 28.7% of respective samples. Cytogenetic analysis of 53 NHL patients after high dose therapy showed frequent chromosomal breakage. Clonal aberrations were found in three patients. None of these patients developed a t-AML/MDS during a 3-year clinical follow up period. We concluded that the high incidence of genetic aberrations reflected a dose-dependent, transient therapy-induced genetic damage which is not predictive of a t-AML/MDS.
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PMID:Therapy-associated genetic aberrations in patients treated for non-Hodgkin lymphoma. 1832 66

The acute myeloid leukemia (AML) subtype M4Eo occurs in 5% of all AML cases and is usually associated with either an inv(16)(p13.1q22) or a t(16;16)(p13.1;q22) chromosomal abnormality. At the molecular level, these abnormalities generate a CBFB-MYH11 fusion gene. Patients with this genetic alteration are usually assigned to a low-risk group and thus receive standard chemotherapy. AML-M4Eo is rarely found in infants. We describe clinical, conventional banding, and molecular cytogenetic data for a 12-month-old baby with AML-M4Eo and a chimeric CBFB-MYH11 fusion gene masked by a novel rearrangement between chromosomes 1 and 16. This rearrangement characterizes a new type of inv(16)(p13.1q22) masked by a chromosome translocation.
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PMID:Banding and molecular cytogenetic studies detected a CBFB-MYH11 fusion gene that appeared as abnormal chromosomes 1 and 16 in a baby with acute myeloid leukemia FAB M4-Eo. 1832 53

TP73 encodes for two proteins: full-length TAp73 and DeltaNp73, which have little transcriptional activity and exert dominant-negative function towards TP53 and TAp73. We compared TATP73 and DeltaNTP73 expression in acute myeloid leukaemia (AML) samples and normal CD34(+) progenitors. Both forms were more highly expressed in leukaemic cells. Amongst AML blasts, TATP73 was more expressed in AML harbouring the recurrent genetic abnormalities (RGA): PML-RARA, RUNX1-RUNX1T1 and CBFB-MYH11, whereas higher DeltaNTP73 expression was detected in non-RGA cases. TP53 expression did not vary according to DeltaNTP73/TATP73 expression ratio. Leukaemic cells with higher DeltaNTP73/TATP73 ratios were significantly more resistant to cytarabine-induced apoptosis.
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PMID:The expression of DeltaNTP73, TATP73 and TP53 genes in acute myeloid leukaemia is associated with recurrent cytogenetic abnormalities and in vitro susceptibility to cytarabine cytotoxicity. 1842 93

We report a novel three-way translocation involving inversion 16 and chromosome 12 at bands 16p13, 16q22, and 12q24 in a patient with therapy-related acute myeloid leukemia (AML)-M4eo. Conventional G-banding of bone marrow cells at diagnosis was suggestive of inv(16)(p13q22) and a translocation of chromosomes 12 and 16. The presence of inv(16) was confirmed by reverse-transcription polymerase chain reaction (RT-PCR) analysis, which corresponded to the type A CBFB-MYH11 chimeric transcript. Spectral karyotyping (SKY) analysis clearly identified a reciprocal translocation between chromosomes 12 and 16. In addition, dual-color fluorescence in situ hybridization (FISH) analysis revealed a fusion signal for the CBFB and MYH11 probes and a signal for the MYH11 probe on the der(16) chromosome, as well as a signal for the CBFB probe on the der(12) chromosome. Thus, the karyotype was refined to 46,XX,der(12)t(12;16)(q24;q22),der(16)inv(16)(p13q22)t(12;16). Although we could not establish that this complex chromosomal aberration occurred either as a one-step, three-way event, or a sequential event with inv(16)(p13q22) followed by t(12;16)(q24;q22), SKY in combination with FISH and RT-PCR analyses successfully detected this complex chromosome abnormality in the patient.
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PMID:Spectral karyotyping and fluorescence in situ hybridization analyses identified a novel three-way translocation involving inversion 16 in therapy-related acute myeloid leukemia M4eo. 1861 61

Acquired genetic alterations such as balanced and unbalanced chromosome aberrations and submicroscopic gene mutations and changes in gene expression strongly affect pretreatment features and prognosis of adults with acute myeloid leukemia (AML). The most frequent chromosome/molecular rearrangements, that is, t(8;21)(q22;q22)/RUNX1-RUNX1T1 and inv(16)(p13q22)/t(16;16)(p13;q22)/CBFB-MYH11 characteristic of core-binding factor (CBF) AML and t(15;17)(q22;q12-21)/PML-RARA characteristic of acute promyelocytic leukemia (APL), confer favorable clinical outcome when patients receive optimal treatment, that is, regimens that include high-dose cytarabine for CBF AML and all-trans-retinoic acid and/or arsenic trioxide for APL. Recently, mutations in such genes as KIT in CBF AML and FLT3 in APL have been correlated with clinical features and/or outcome of patients with these AML subtypes, and microarray gene expression profiling has been successfully used for diagnostic purposes and to provide biologic insights. These data underscore the value of genetic testing for common translocations for diagnosis, prognostication, and, increasingly, selecting therapy in acute leukemia.
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PMID:Clinical significance of the most common chromosome translocations in adult acute myeloid leukemia. 1864 4

Nonrandom gene rearrangements have been demonstrated in leukemic cells at diagnosis. These genetic abnormalities are associated with specific types, clinical characteristics, and prognosis of acute leukemia. Common fusion transcripts in childhood acute lymphoblastic leukemia (ALL) are TEL-AML1, E2A-PBX, MLL-AF4, and BCR-ABL (p190) and in acute nonlymphoblastic leukemia (ANLL) are AML-ETO, PML-RARA, and CBFB-MYH11. Reverse transcription-polymerase chain reaction (RT-PCR) for detection of each individual fusion transcript is impractical and time consuming. The purpose of this study was to develop simple RT-PCR methods to identify common fusion transcripts of newly diagnosed acute leukemia in children. Total RNA was extracted from bone marrow samples of children diagnosed with acute leukemia. Multiplex RT-PCR panel A (ALL) included primers for TEL-AML1, E2A-PBX, MLL-AF4, and BCR-ABL (p190) whereas panel B (ANLL) composed of primers for AML-ETO, PML-RARA, and CBFB-MYH11. Known leukemic cell lines were used to serve as positive controls. Eighty three children diagnosed with ALL (n = 63) and ANLL (n = 20) were included in this study. Fusion transcripts could be identified using multiplex RT-PCR panel A for ALL and panel B for ANLL in 26/83 (31.3%) cases. In ALL samples, we found TEL-AML1 = 16/63 (25.4%), E2A-PBX = 3/63 (4.8%), MLL-AF4 = 1/63 (1.6%), and BCR-ABL = 1/63 (1.6%). Four cases of AML1-ETO (20%) and one PML-RARA (5%) were found in ANLL samples. In conclusion, our simple multiplex RT-PCR for detection of fusion transcripts in childhood acute leukemia was found to be a rapid, accurate, and effective method.
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PMID:Simple multiplex RT-PCR for identifying common fusion transcripts in childhood acute leukemia. 1866 25

Apoptotic protease activating factor 1 (APAF-1) has a critical role in the regulation of apoptosis. In the present study, the mRNA expression analysis of different APAF-1 transcripts (APAF-1S, APAF-1LC, APAF-1LN, and APAF-1XL) was analyzed in bone marrow samples from 37 patients with acute myeloid leukemia (newly diagnosed, with no previous treatment). APAF-1XL and APAF-1LN transcripts (with and without an extra WD-40 repeat region, respectively) were detected in all samples, although the major form expressed was APAF-1XL in 65% of the samples (group 1), while 35% of the samples expressed primarily APAF-1LN (group 2). Only 46% of the patients presented complete remission in response to remission induction therapy (represented by less than 5% marrow blasts and hematological recovery), all but 2 cases being from group 1, 21.6% did not attain complete remission (only 1 case from group 1), and 32.4% of the patients died early. Lower expression of APAF-1XL (APAF-1XL/APAF-1LN ratio <1.2) was associated with a poor response to therapy (P = 0.0005, Fisher exact test). Both groups showed similar characteristics regarding white blood cell counts, cytogenetic data or presence of gene rearrangements associated with good prognosis as AML1-ETO, CBFB-MYH11 and PML/RARA. Since it has been shown that only the isoforms with the extra WD-40 repeat region activate procaspase-9, we suggest that low procaspase-9 activation may also be involved in the deregulation of apoptosis and chemotherapy resistance in acute myeloid leukemia.
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PMID:Low expression of APAF-1XL in acute myeloid leukemia may be associated with the failure of remission induction therapy. 1871 38

MicroRNAs (miRNAs) are postulated to be important regulators in cancers. Here, we report a genome-wide miRNA expression analysis in 52 acute myeloid leukemia (AML) samples with common translocations, including t(8;21)/AML1(RUNX1)-ETO(RUNX1T1), inv(16)/CBFB-MYH11, t(15;17)/PML-RARA, and MLL rearrangements. Distinct miRNA expression patterns were observed for t(15;17), MLL rearrangements, and core-binding factor (CBF) AMLs including both t(8;21) and inv(16) samples. Expression signatures of a minimum of two (i.e., miR-126/126*), three (i.e., miR-224, miR-368, and miR-382), and seven (miR-17-5p and miR-20a, plus the aforementioned five) miRNAs could accurately discriminate CBF, t(15;17), and MLL-rearrangement AMLs, respectively, from each other. We further showed that the elevated expression of miR-126/126* in CBF AMLs was associated with promoter demethylation but not with amplification or mutation of the genomic locus. Our gain- and loss-of-function experiments showed that miR-126/126* inhibited apoptosis and increased the viability of AML cells and enhanced the colony-forming ability of mouse normal bone marrow progenitor cells alone and particularly, in cooperation with AML1-ETO, likely through targeting Polo-like kinase 2 (PLK2), a tumor suppressor. Our results demonstrate that specific alterations in miRNA expression distinguish AMLs with common translocations and imply that the deregulation of specific miRNAs may play a role in the development of leukemia with these associated genetic rearrangements.
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PMID:Distinct microRNA expression profiles in acute myeloid leukemia with common translocations. 1883 81

We report on a 20-year-old man with acute myeloid leukemia (AML) showing a distinct novel CBFB/MYH11 variant fusion transcript. Initial results of bone marrow, chromosome, and flow cytometric analyses were not in accordance with the diagnosis of acute myelomonocytic leukemia with eosinophilia (AML-M4Eo) or AML with a CBFB/MYH11 rearrangement. However, results from 2 commercially available multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) tests repeatedly showed an unusual PCR product from his bone marrow specimen. Not only does this case show a partial insertion of exon 6 of the CBFB (ENSG00000067955) gene, but it also involves novel breakpoints within both exon 6 of the CBFB gene and exon 28 (previously exon 7) of the MYH11 (ENSG00000133392) gene, which is regarded as a previously non-reported, new type (K-type) of CBFB/MYH11 fusion transcript. In addition, our study result was in agreement with the recent report of Schnittger et al. that rare fusion transcripts of CBFB/MYH11 are correlated with an atypical cytomorphology and other aberrant characteristics. Therefore, multiplex RT-PCR and sequence analysis of these atypical products should be performed to diagnose atypical AML with CBFB/MYH11 rearrangement, to predict prognosis of these patients as well as to elucidate the molecular mechanism.
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PMID:Detection of a novel CBFB/MYH11 variant fusion transcript (K-type) showing partial insertion of exon 6 of CBFB gene using two commercially available multiplex RT-PCR kits. 1921 88

Minimal residual disease may help to establish clinical decisions in patients with AML. WT1 offers the possibility to analyze those cases without currently known underlying genetic abnormalities. To compare the value of chimeric specific quantitative PCR with WT1 PCR in CBF acute leukemia, 445 samples from 96 AML (49 AML1-ETO+ and 47 CBFB-MYH11+) cases were included in the study. For each sample AML1-ETO or CBFB-MYH11 levels obtained using the conditions of the BIOMED group were compared with the results of WT1 levels using sensitive primers and conditions. Simultaneously, normal range expression of WT1 was established using RNA obtained from eight healthy donors. WT1 mutations were also investigated both at RNA and at the genomic level. The majority of CBF samples showed rises in WT1 levels (88.7%) at diagnosis. However, 18% of AML1-ETO showed WT1 levels below 250 copies in contrast with 5% CBFB-MYH11 cases. WT1 mutation was not detected in any case (70 diagnostic samples). We found correlation between WT1 levels at diagnosis and the CD34 blast population estimated by flow cytometry in CBFB-MYH11+ cases. We found no association between WT1 levels and clinical outcome. There was a high concordance between chimeric transcript analysis and WT1 levels in CR patients. Concordance was also high in relapsed patients (78% in AML1-ETO and 98% in CBFB-MYH11+ cases). Both WT1 and specific chimeric transcript identified and rescued false negative results of the other test. Additional studies are needed to determine whether the rare discrepancies are a reflection of the cooperative nature of WT1 overexpression or a consequence of the uneven distribution in the leukemic population. WT1 is a powerful MRD tool even in cases with currently available molecular targets.
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PMID:WT1 monitoring in core binding factor AML: comparison with specific chimeric products. 1942 34


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