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)

Deletions of sequences centromeric to the p-arm breakpoint have been described in a subset of patients with inv(16) and acute myeloid leukemia (AML) and reported to be associated with a relatively good prognosis. We have investigated 16 p deletions in a cohort of 15 patients with AML and inv(16) or t(16;16) and compared non-deletion and deletion patients in terms of clinical course. Patients were studied by fluorescence in situ hybridization (FISH) using cosmid zit14 as a probe to detect the presence of 16 p deletions in metaphase chromosomes of leukemic cells. While seven patients (47%) revealed no evidence of a deletion, five patients (33%) presented 16 p deletions, thus bringing further support to the relatively frequent occurrence of this event in inv(16) patients. Remarkably, two patients with inv(16) and one patient with t(16;16) showed a mosaicism of deletion and non-deletion metaphases suggesting the presence of two distinct leukemic cell populations. Results let us assume that 16 p deletions are not restricted to inv(16) and may occur subsequently to inv(16) or t(16;16). The presence of a 16 p deletion in a case of inv(16) associated with CBFB-MYH11 transcript type E indicates that deletions are not limited to CBFB-MYH11 transcript type A rearrangements. Survival of deletion patients was compared with that of non-deletion and mosaic ones. No significant differences were observed. The advantage of FISH for enumerative and quantitative assessment of submicroscopic rearrangements of clinical significance is further emphasized.
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PMID:Detection of 16 p deletions by FISH in patients with inv(16) or t(16;16) and acute myeloid leukemia (AML). 920 76

In order to determine whether the polymerase chain reaction (PCR) is more suitable for the detection of inversion (16) as compared with standard cytogenetics, we prospectively investigated a total of 132 cases of de novo acute myeloid leukaemia (AML) (n = 121) and secondary AML after myelodysplastic syndromes (MDS) (n = 11) using a sensitive and nested PCR procedure to detect the fusion transcripts CBFbeta-MYH11. All patients were recruited within 10 months in an ongoing multicentre AML-trial. In addition, several cases from a retrospective molecular analysis were included. The data were compared with standard cytogenetics performed in a central laboratory. Of the 132 prospective AML cases, five patients (3.7%) harboured inv(16) upon conventional cytogenetics. In all cases fusion transcripts CBFbeta-MYH11 were detected using PCR. In addition in two patients fusion transcripts were detected, although cytogenetics revealed a normal karyotype. In the group of patients analysed retrospectively, four patients harboured fusion transcripts specific for CBFbeta-MYH11; cytogenetics were normal in one case, and could not be evaluated in two cases. These data show that PCR may be a better means to detect inv(16) in AML. Since inv(16) may have prognostic impact in AML, detection of this aberration seems important in the clinical management of AML patients.
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PMID:Underestimation of inversion (16) in acute myeloid leukaemia using standard cytogenetics as compared with polymerase chain reaction: results of a prospective investigation. 932 97

We evaluated the occurrence of the CBFbeta/MYH11 fusion transcripts by PCR analysis in 10 patients with inv(16)(p13;q22) acute myeloid leukemia (AML) who underwent allogeneic bone marrow transplantation (BMT) (n = 5), peripheral blood progenitor cell transplantation (PBPCT) (n = 3), or autologous transplantation (n = 2). In addition to the analysis of minimal residual disease (MRD), the chimerism status of patients after allogeneic transplant was studied by PCR. The CBFbeta/MYH11 fusion transcript was not detectable in six of seven patients who remained in remission after allogeneic BMT or PBPCT. Two of these patients in remission were monitored for 50 months and 64 months post-BMT. One patient in remission was PCR-positive for CBFbeta 3 months post-BMT in a single BM sample, but not in a simultaneously examined blood sample, suggesting that analyses from BM samples are more sensitive than those from blood samples. Sequential PCR assays performed 6 and 12 months post-BMT obtained from the same patient were negative. Another patient with a positive PCR assay 3 months post-allogeneic PBPCT, remained PCR positive for the CBFbeta/MYH11 fusion transcript when tested 6 months post-PBPCT. A chimerism analysis by PCR revealed a mixed chimerism status in this patient. He relapsed 7 months post-transplant. Before transplant, in all nine patients who were in complete remission of AML (eight patients in 1CR, one patient in 2CR), the CBFbeta/MYH11 transcript was detectable. In one patient in relapse, the fusion transcript was not only detectable in blood and bone marrow, but also in a cerebrospinal fluid sample prior to transplant. Two patients who received autologous BMT were monitored for CBFbeta/MYH11 transcripts 3 months after BMT. The CBFbeta/MYH11 was detected in these patients. Both patients subsequently relapsed 3 months and 23 months post-autologous BMT. The results study show that analysis of the CBFbeta/MYH11 fusion transcript by PCR seems to be a suitable method for monitoring minimal residual disease in AML patients with inv (16).
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PMID:Detection of CBFbeta/MYH11 fusion transcripts in patients with inv(16) acute myeloid leukemia after allogeneic bone marrow or peripheral blood progenitor cell transplantation. 948 33

The inv(16)(p13q22) and t(16;16)(p13;q22) cytogenetic abnormalities occur commonly in acute myeloid leukemia (AML), typically associated with French-American-British (FAB) AML-M4Eo subtype. Reverse transcriptase-polymerase chain reaction (RT-PCR) techniques have been recently developed to detect the presence of several variants of the resultant CBFB-MYH11 fusion gene that encodes a CBFbeta-smooth muscle myosin heavy chain (SMMHC) fusion protein. We have now determined the clinical use of a polyclonal antibody [anti-inv(16) Ab] directed against a junctional epitope of the most common type of CBFbeta-SMMHC fusion protein (type A), which is present in 90% of inv(16)/t(16;16) AML cases. Using flow cytometry, reproducible methods were developed for detection of CBFbeta-SMMHC proteins in permeabilized cells; flow cytometric results were then correlated with cytogenetics and RT-PCR detection methods. In an analysis of 42 leukemia cases with various cytogenetic abnormalities and several normal controls, the anti-inv(16) Ab specifically detected all 23 cases that were cytogenetically positive for inv(16) or t(16;16), including a single AML case that was RT-PCR-negative. In addition to detecting all type A fusions, the anti-inv(16) Ab also unexpectedly identified the type C and type D CBFbeta-SMMHC fusion proteins. Molecular characterization of one RT-PCR-positive and Ab-positive t(16;16) case with a non-type A product showed a novel previously unreported CBFB-MYH11 fusion (CBFB nt 455-MYH11 nt 1893). Flow cytometric results were analyzed using the Kolmogorov-Smirnov statistic D-value and the median value for positive samples was 0.65 (range, 0.35 to 0.77) versus 0.07 (range, -0.21 to 0.18) in the negative group (P < .0001). The overall concordance between cytogenetics and RT-PCR was 97%, whereas the concordance between flow cytometry and cytogenetics was 100%. Thus, using the anti-inv(16) Ab, all cytogenetically positive and RT-PCR-positive AML cases with inv(16) or t(16;16) could be rapidly identified. This study demonstrates the use of this antibody as an investigational tool in inv(16)/t(16;16) AML and suggests that the development of such reagents may have potential clinical diagnostic use.
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PMID:Characterization and use of an antibody detecting the CBFbeta-SMMHC fusion protein in inv(16)/t(16;16)-associated acute myeloid leukemias. 949 Jun 70

The inv(16)(p13q22) masked by different translocations was detected by fluorescence in situ hybridization (FISH) and confirmed by molecular analysis in three adult patients presenting with acute myeloid leukemia (AML)-M2 (cases 1 and 3) and M4Eo (case 2). Cytogenetic analysis revealed 47,XX,t(9;16)(p23;p13),+22 (case 1); 46,XX,t(1;16)(p32;p13) (case 2); and 46,XY,?del(16)(q22) (case 3). Using a panel of probes for chromosomes 1, 9, 16, and 20 as well as probes to detect inv(16), i.e., two cosmid contigs hybridizing proximally and distally to the 16p13 breakpoint, FISH demonstrated inv(16) involving the derivative 16 as well as reciprocal translocations between 16q22-qter and 9p24 (case 1), 1p32 (case 2), and 20q13 (case 3). In addition, a small interstitial del(16)(p13p13) proximal to the MYH11 breakpoint was detected in case 1. Reverse transcriptase-polymerase chain reaction (RT-PCR) and Southern blot analysis showed a CBFB-MYH11 fusion transcript and MYH11 rearrangement, respectively, in all three cases. We conclude that: 1) inv(16) can be masked by other structural abnormalities involving chromosome 16; 2) some of the so-called variant translocations not explored at the molecular level may in fact represent a masked inv(16); and 3) FISH, RT-PCR, and Southern blot analyses are reliable tools to detect masked inv(16) and should be applied in all AML cases with structural changes of chromosome 16.
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PMID:FISH identifies inv(16)(p13q22) masked by translocations in three cases of acute myeloid leukemia. 959 94

A case of acute myeloid leukemia (AML) M1 with bone marrow eosinophilia was characterized by cytogenetics and fluorescence in situ hybridization (FISH). A complex karyotype including a der(12)t(12;17)(p12-13;q11) and a der(16)t(16;20)(p13;p11) was found at diagnosis. FISH studies with probes for chromosome 16 and for the short arm of chromosome 12 showed even more complex rearrangements. Analysis with a panel of probes for 12p showed that D12S158 spanned the breakpoint on the der(12). Unexpectedly, FISH signals were found on the der(12) and on the der(6) at band p13, the site of juxtaposition between the short arm of chromosome 16 and chromosome 20. Moreover, both YAC 854E2, containing the MYH11 gene, and cosmid ZIT133, encompassing the MYH11 breakpoint in inv(16) and t(16;16) of AML-M4 with eosinophilia, demonstrated fluorescent signals on the normal 16, on the der(16), and on the der(12). These data clearly support a reciprocal exchange between D12S158 at 12p13.3 and the MYH11 gene at 16p13. In addition, experiments with two PAC clones for the CBFB gene at 16q22 excluded the presence of a masked inv(16). An interstitial deletion, independent from the translocation and flanked by VWF and KRAS2, was also detected on the der(12).
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PMID:Rearrangement between the MYH11 gene at 16p13 and D12S158 at 12p13 in a case of acute myeloid leukemia M1 (AML-M1). 971 91

Chromosomal translocations involving the genes encoding the alpha and beta subunits of the Pebp2/Cbf transcription factor have been associated with human acute myeloid leukemia and the preleukemic condition, myelodysplasia. Inv(16)(p13;q22) fuses the gene encoding the beta subunit of Pebp2 to the MYH11 gene encoding a smooth muscle myosin heavy chain (Smmhc). To examine the effect of the inv(16)(p13;q22) on myelopoiesis, we used the hMRP8 promoter element to generate transgenic mice expressing the Pebp2betaSmmhc chimeric fusion protein in myeloid cells. Neutrophil maturation was impaired in PEBP2betaMYH11 transgenic mice. Although the transgenic mice had normal numbers of circulating neutrophils, their bone marrow contained increased numbers of immature neutrophilic cells, which exhibited abnormal characteristics. In addition, PEBP2betaMYH11 inhibited neutrophilic differentiation in colonies derived from hematopoietic progenitors. Coexpression of both PEBP2betaMYH11 and activated NRAS induced a more severe phenotype characterized by abnormal nuclear morphology indicative of granulocytic dysplasia. These results show that PEBP2betaMYH11 can impair neutrophil development and provide evidence that alterations of Pebp2 can contribute to the genesis of myelodysplasia.
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PMID:The PEBP2betaMYH11 fusion created by Inv(16)(p13;q22) in myeloid leukemia impairs neutrophil maturation and contributes to granulocytic dysplasia. 975 56

The inv(16) and related t(16;16) are found in 10% of all cases with de novo acute myeloid leukemia. In these rearrangements the core binding factor beta (CBFB) gene on 16q22 is fused to the smooth muscle myosin heavy chain gene (MYH11) on 16p13. To gain insight into the mechanisms causing the inv(16) we have analysed 24 genomic CBFB-MYH11 breakpoints. All breakpoints in CBFB are located in a 15-Kb intron. More than 50% of the sequenced 6.2 Kb of this intron consists of human repetitive elements. Twenty-one of the 24 breakpoints in MYH11 are located in a 370-bp intron. The remaining three breakpoints in MYH11 are located more upstream. The localization of three breakpoints adjacent to a V(D)J recombinase signal sequence in MYH11 suggests a V(D)J recombinase-mediated rearrangement in these cases. V(D)J recombinase-associated characteristics (small nucleotide deletions and insertions of random nucleotides) were detected in six other cases. CBFB and MYH11 duplications were detected in four of six cases tested.
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PMID:Genomic acute myeloid leukemia-associated inv(16)(p13q22) breakpoints are tightly clustered. 992 11

Donor lymphocyte infusion (DLI) has been used successfully to induce remissions in relapse of acute myeloid leukaemia (AML) after bone marrow transplantation (BMT), but molecular eradication of leukaemia has rarely been documented. A patient with AML-M4Eo relapsed after HLA-identical sibling BMT in first complete remission (CR). Cytogenetic and molecular genetic investigations confirmed inv(16) and CBFbeta/MYH11 fusion characteristic of M4Eo. A second remission was obtained with chemotherapy. Full donor chimerism was demonstrated by fluorescence in situ hybridisation. However, molecular evidence of minimal residual disease still persisted, and donor lymphocyte infusion (DLI) was administered. This resulted in molecular eradication, and the patient remained in clinical and molecular remission 16 months from DLI. Our observations showed that, for AML relapse after BMT, molecular leukaemia eradication could be achieved by DLI so that, in cases where genetic markers are available, molecular monitoring should be performed to assess the efficacy of treatment.
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PMID:Donor lymphocyte infusion induced molecular remission in relapse of acute myeloid leukaemia after allogeneic bone marrow transplantation. 1038 62

The molecular characterization of childhood leukemias directly affects our treatment strategies. Acute lymphoblastic leukemia patients with the TEL-AML1 fusion have a favorable prognosis, whereas those with the E2A-PBX1 fusion require more intensive therapy to obtain a good outcome. Acute lymphoblastic leukemia patients whose leukemic lymphoblasts contain the MLL-AF4 or the BCR-ABL fusion are often candidates for allogeneic hematopoietic stem cell transplantation during first remission. Among acute myeloid leukemia patients, AML1-ETO and CBFbeta-MYH11 fusions are associated with a favorable response, especially when the chemotherapy regimen includes high-dose cytarabine. Patients with acute promyelocytic leukemia who carry the PML-RAR alpha fusion respond to all-trans retinoic acid and have an excellent outcome after treatment with all-trans retinoic acid in combination with anthracyclines. Several novel therapeutic agents targeted to molecular lesions of leukemic cells are under investigation.
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PMID:Molecular diagnostics in the treatment of leukemia. 1040 Mar 71


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