Deletions of CDKN1B and ETV6 in acute myeloid leukemia and myelodysplastic syndromes without cytogenetic evidence of 12p abnormalities

Andreasson, Patrik; Johansson, Bertil; Arheden, Kristina; Billström, Rolf; Mitelman, Felix; Höglund, Mattias

doi:10.1002/(sici)1098-2264(199706)19:2<77::aid-gcc2>3.0.co;2-x

Cited by 40 publications

(32 citation statements)

References 31 publications

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“…In addition, deletion of TEL can be observed without any associated 12p13 abnormality (unpublished results) (Andreasson et al, 1997). Furthermore, the association of t(12;21) translocation and inactivation of the untranslocated TEL allele also results in complete loss of TEL activity.…”

Section: Discussionmentioning

confidence: 88%

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Analysis of TEL proteins in human leukemias

et al. 1998

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Chromosomal translocations involving the human 12p13 band frequently a ect the TEL gene, usually resulting in gene fusion between TEL and genes encoding proteins of various types. The most frequent 12p13 translocation is the t(12;21)(p13;q22), which recombines TEL with the AML1 gene on chromosome 21 and is frequently associated with deletion of the untranslocated TEL allele. Using antisera against di erent parts of TEL and against the AML1 proteins, we undertook Western blot and immuno¯uorescence analyses of leukemic samples with and without 12p13 abnormalities. In t(12;21) samples, TEL-AML1 was detected as several protein species in the nuclei, whereas the AML1-TEL protein, was inconsistently expressed. AML1 was found to be expressed but no normal TEL proteins were detected. A survey of the TEL proteins in a panel of human leukemic samples without t(12;21) revealed a variation in the ratio of TEL protein isoforms. We also analysed a leukemic cell line bearing a t(12;22)(p13;q11) that was found to a ect the 5' untranslated (UT) region of TEL and to be associated with inactivation of the untranslocated TEL allele. No MN1-TEL fusion could be detected upon RT ± PCR analysis, in contrast to the previously investigated t(12;22). Strikingly, extremely low levels of apparently normal TEL proteins, expressed from the translocated allele, were detected by Western blot analysis. These results suggest that the level of TEL expression can be important for leukemogenesis.

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Section: Discussionmentioning

confidence: 88%

“…Rearrangement and/or deletion of TEL are, however, observed in malignant samples without obvious 12p chromosomal abnormality, in particular without t(12;21) (unpublished results) (Andreasson et al, 1997). This raises the possibility that the high frequency of t(12;21) could mask some less frequent events.…”

Section: Introductionmentioning

confidence: 97%

Analysis of TEL proteins in human leukemias

et al. 1998

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“…24 Moreover, FISH analysis is also a suitable technique to detect submicroscopic lesions, especially deletions, which are undetectable by conventional banding analysis. 25,26 We therefore studied by interphase FISH a large number of consecutive MDS patients with normal karyotype, using a panel of probes detecting the most frequent anomalies in MDS, in an attempt to define a possible role for FISH in risk assessment.…”

Section: Figurementioning

confidence: 99%

Clinical importance of interphase cytogenetics detecting occult chromosome lesions in myelodysplastic syndromes with normal karyotype

et al. 2001

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At diagnosis, approximately half of myelodysplastic (MDS) patients presents a normal karyotype by conventional cytogenetic analysis (CCA). Fluorescent in situ hybridization (FISH) is more sensitive than CCA allowing for the detection of minor clones and of submicroscopic lesions. We have analyzed by FISH 101 MDS patients with normal karyotype for the occurrence of the abnormalities which are most frequently observed in MDS (ie ؊5/5q؊, ؊7/7q؊, ؉8, 17p؊). In 18 patients, 15 to 32% of interphase cells were found to carry one FISH abnormality. Six patients presented trisomy 8, five had del(5)(q31), five del(7)(q31), one monosomy 7 and one del(17)(p13). FISH abnormalities were more frequently observed among patients with an increased percentage of bone marrow blasts (P ‫؍‬ 0.001). FISH abnormalities were also associated with a higher rate of progression into AML (13/18 vs 12/83, P Ͻ 0.001) and were predictive for a worse prognosis (P Ͻ 0.001). Multivariate analysis indicated that FISH positivity and IPSS risk group were independent predictors for a poor survival (P ‫؍‬ 0.0057 and 0.0123, respectively) and for leukemic transformation (P ‫؍‬

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“…24 Commercially available whole chromosome painting (wcp) probes were used to screen for rearrangements and duplications of chromosome 3 in the initial samples with normal karyotypes. Yeast artificial chromosome (YAC) probes (kindly provided by CEPH, Paris, France) close to the common cytogenetic breakpoint at 3q21 were chosen for mapping of the breakpoint (Figure 1).…”

Section: Fish and Prinsmentioning

confidence: 99%

Molecular characterization of jumping translocations reveals spatial and temporal breakpoint heterogeneity

et al. 1998

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Jumping translocations (JT) are characterized by the relocalization of the same part of a donor to several recipient chromosomes. Although JT occasionally are constitutional, most are associated with hematologic malignancies. In such cases, JT usually arise during disease progression and are associated with poor prognosis. Despite its clinical importance, this cytogenetic phenomenon has not been characterized at the molecular level. We have analyzed JT in a juvenile chronic myelomonocytic leukemia that subsequently transformed to an acute myeloid leukemia. Detailed fluorescence in situ hybridization (FISH) analyses showed that the cytogenetically identical donor breakpoint at 3q21 was highly heterogeneous. In fact, more than 10 distinct breakpoints, four of which mapped within YACs, were identified. Analyses of samples during disease progression showed that the breakpoint complexity decreased, indicating clonal selection. Hence, the 3q21 breakpoints displayed a spatial as well as a temporal heterogeneity, revealing that JT are highly unstable, showing great variation in the size of donor segment. The breaks at the recipient chromosomes were mapped within the subtelomeric regions. The general telomere length was not affected and an underlying replication error resulting in microsatellite instability was excluded. We conclude that the emergence of JT is unlikely to cause fusion genes or to affect the expression of genes located in the breakpoint regions. The identification of YACs spanning the breakpoints, ie, YACs 913c7, 937g5, 948c2 and 955g1, may facilitate the isolation of DNA sequences leading to a genetic instability associated with the origin of multiple translocations.

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Deletions of CDKN1B and ETV6 in acute myeloid leukemia and myelodysplastic syndromes without cytogenetic evidence of 12p abnormalities

Cited by 40 publications

References 31 publications

Analysis of TEL proteins in human leukemias

Analysis of TEL proteins in human leukemias

Clinical importance of interphase cytogenetics detecting occult chromosome lesions in myelodysplastic syndromes with normal karyotype

Molecular characterization of jumping translocations reveals spatial and temporal breakpoint heterogeneity

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