| 1. |
- Andreasson, Patrik, et al.
(författare)
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BCR/ABL-negative chronic myeloid leukemia with ETV6/ABL fusion
- 1997
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Ingår i: Genes, Chromosomes and Cancer. - 1045-2257. ; 20:3, s. 299-304
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Tidskriftsartikel (refereegranskat)abstract
- A BCR/ABL-negative chronic myeloid leukemia (CML) with t(12;14) (p12;q11-13) as the sole chromosomal abnormality was investigated by fluorescence in situ hybridization (FISH), which disclosed a cryptic insertion of ETV6 (previously called TEL), located at 12p12, into ABL at chromosome band 9q34. ETV6/ABL fusion was confirmed by RT-PCR, revealing that the first five exons of ETV6 were fused in frame with ABL at exon 2. Wild-type ETV6 was expressed, in accordance with the FISH results showing no deletion of the second ETV6 allele. ETV6/ABL chimeric transcripts have previously been reported in acute leukemias, but never before in CML. The present case suggests that ETV6/ABL positivity may constitute a new genetic subgroup of BCR-negative CML.
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| 2. |
- Billstrom, R, et al.
(författare)
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Poor survival in t(8;21) (q22;q22)-associated acute myeloid leukaemia with leukocytosis
- 1997
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Ingår i: European Journal of Haematology. - 1600-0609. ; 59:1, s. 47-52
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Tidskriftsartikel (refereegranskat)abstract
- Twenty-nine consecutive cases with a t(8;21)(q22;q22) in the bone marrow (BM) karyotype were retrospectively studied concerning clinical, morphological and cytogenetic data. All had been diagnosed as acute myeloid leukaemia (AML), 27 FAB subtype M2 and two M1, comprising 5% of all cytogenetically analysed AML during 18 yr. Auer rods were the most consistent t(8;21)-associated morphological finding and were demonstrated in 92% of the reviewed BM specimens, whereas BM eosinophilia was seen in only 24%. The median age was 53 yr, and 30% of the patients were > 60 yr old. Twenty-four patients had received induction chemotherapy; 22 of these (91%) entered a complete remission (CR). The median survival time in treated patients was 18 months. Leukocytosis at diagnosis (> or = 20 x 10(9)/1) was significantly (p = 0.01) associated with shorter survival time. All four children are still in first CR after 9-80 months. Seven cases (25%) developed granulocytic sarcomas, discovered either at diagnosis (n = 4) or at first relapse (n = 3). Secondary chromosome abnormalities were found in 62% of the cases, most often loss of a sex chromosome. The presence of such secondary aberrations did not correlate with any morphological or clinical characteristics, including survival. This first Scandinavian study of AML with t(8;21) corroborates the previous findings that these AMLs are characterized by distinct morphological features, a high frequency of CR and a striking tendency to develop extramedullary leukaemic manifestations. Leukocytosis at diagnosis indicates a less favourable prognosis.
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| 3. |
- Fioretos, Thoas, et al.
(författare)
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Isochromosome 17q in blast crisis of chronic myeloid leukemia and in other hematologic malignancies is the result of clustered breakpoints in 17p11 and is not associated with coding TP53 mutations
- 1999
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Ingår i: Blood. - 1528-0020. ; 94:1, s. 225-232
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Tidskriftsartikel (refereegranskat)abstract
- An isochromosome of the long arm of chromosome 17, i(17q), is the most frequent genetic abnormality observed during the disease progression of Philadelphia chromosome-positive chronic myeloid leukemia (CML), and has been described as the sole anomaly in various other hematologic malignancies. The i(17q) hence plays a presumably important pathogenetic role both in leukemia development and progression. This notwithstanding, the molecular consequences of this abnormality have not been investigated in detail. We have analyzed 21 hematologic malignancies (8 CML in blast crisis, 8 myelodysplastic syndromes [MDS], 2 acute myeloid leukemias, 2 chronic lymphocytic leukemias, and 1 acute lymphoblastic leukemia) with i(17q) by fluorescence in situ hybridization (FISH). Using a yeast artificial chromosome (YAC) contig, derived from the short arm of chromosome 17, all cases were shown to have a breakpoint in 17p. In 12 cases, the breaks occurred within the Smith-Magenis Syndrome (SMS) common deletion region in 17p11, a gene-rich region which is genetically unstable. In 10 of these 12 cases, we were able to further map the breakpoints to specific markers localized within a single YAC clone. Six other cases showed breakpoints located proximally to the SMS common deletion region, but still within 17p11, and yet another case had a breakpoint distal to this region. Furthermore, using chromosome 17 centromere-specific probes, it could be shown that the majority of the i(17q) chromosomes (11 of 15 investigated cases) were dicentric, ie, they contained two centromeres, strongly suggesting that i(17q) is formed through an intrachromosomal recombination event, and also implicating that the i(17q), in a formal sense, should be designated idic(17)(p11). Because i(17q) formation results in loss of 17p material, potentially uncovering the effect of a tumor suppressor on the remaining 17p, the occurrence of TP53 mutations was studied in 17 cases by sequencing the entire coding region. In 16 cases, no TP53 mutations were found, whereas one MDS displayed a homozygous deletion of TP53. Thus, our data suggest that there is no association between i(17q) and coding TP53 mutations, and that another tumor suppressor gene(s), located in proximity of the SMS common deletion region, or in a more distal location, is of pathogenetic importance in i(17q)-associated leukemia.
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| 4. |
- Gisselsson Nord, David, et al.
(författare)
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The structure and dynamics of ring chromosomes in human neoplastic and non-neoplastic cells
- 1999
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 1432-1203 .- 0340-6717. ; 104:4, s. 315-325
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Tidskriftsartikel (refereegranskat)abstract
- Acquired ring chromosomes have been found in most types of human neoplasia, with a frequency approaching 10% in malignant mesenchymal tumours. In this study, the composition and dynamics of ring chromosomes were analysed in eight cases of acute myelogenous leukaemia, 17 solid tumours, and five cases with constitutional rings. Chromosomal banding and fluorescence in situ hybridisation were performed to determine the content and the structural heterogeneity of the rings. Telomeric repeats were detected using peptide nucleic acid probes or primed in situ labelling, whereas centromeric activity was evaluated by detection of kinetochore proteins. Mitotic instability was assessed by the frequency of anaphase bridges. The results suggest that human ring chromosomes can be structurally and functionally divided into two categories. In the first of these, size variation is minimal and rearrangement at cell division is uncommon. The majority of such rings contain subtelomeric sequences. Constitutional ring chromosomes and most rings in leukaemias belong to this group, whereas only a few mesenchymal tumours exhibit rings of this type. The second category consists of rings with amplified sequences, primarily from chromosome 12, characteristically occurring in atypical lipomatous tumours and other subtypes of low or borderline malignant mesenchymal neoplasms. Variation in size and number is extensive, and breakage-fusion-bridge events occur at a high frequency. Abnormalities in pericentromeric sequences are common and, in some cases, kinetochores assemble in the absence of alphoid DNA. We conclude that it is not only the ring structure per se or the neoplastic nature of the host cell that determines ring instability, but probably also the functional role of the genes carried in the ring.
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| 5. |
- Jerkeman, Mats, et al.
(författare)
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Prognostic implications of cytogenetic aberrations in diffuse large B-cell lymphomas
- 1999
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Ingår i: European Journal of Haematology. - 1600-0609. ; 62:3, s. 184-190
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Tidskriftsartikel (refereegranskat)abstract
- A single institution series of 81 consecutive, cytogenetically analyzed, diffuse large B-cell lymphomas (DLBL), the majority of which treated with anthracycline-containing combination chemotherapy, were reviewed retrospectively to investigate whether the karyotypic pattern or certain abnormalities correlate with survival. Clonal chromosome changes were found in 79 of the 81 cases. The prognostic impact of the following aberrations, all suggested in previous studies to be associated with either shorter or longer survival, were tested: 1q21-23 breakpoints, +2/dup(2p), +3/dup(3p), +5, +6, 6q21-25 breakpoints, monosomy 7/der(7p)/i(7q), trisomy 7, 14q11-12 breakpoints, monosomy 17/der(17p)/i(17q), trisomy 18, > 4 marker chromosomes, > 4 breakpoints, and > or = 10 abnormalities. Univariate analysis showed that a breakpoint at 1q21-23 or trisomy 6 was associated with a shorter survival. However, when adjusted for age, stage, performance status and lactate dehydrogenase level, none of the cytogenetic aberrations had an independent prognostic value. Thus, the present investigation provides no support for any of the above-mentioned abnormalities being of prognostic importance in DLBL.
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| 6. |
- Johansson, B, et al.
(författare)
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Abberant cytogenetic evolution pattern of Philadelphia-positive chronic myeloid leukemia treated with interferon-alpha
- 1996
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Ingår i: Leukemia. - 1476-5551. ; 10:7, s. 1134-1138
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Tidskriftsartikel (refereegranskat)abstract
- The cytogenetic evolution of 32 Philadelphia (Ph)-positive chronic myeloid leukemias (CML) receiving interferon-alpha (IFN-alpha) therapy was compared to the patterns in untreated CML and cases treated with busulfan (Bu), hydroxyurea (Hy), and allogeneic bone marrow transplantation (BMT). Half of the CML receiving IFN-alpha had at least one of the well-known major or minor route aberrations whereas 16 cases displayed unusual secondary abnormalities, of which only del(7p) and del(13q) were recurrent; a frequency significantly higher than in CML without therapy or after Bu and Hy treatment (P < 0.001) but similar to the one found post-BMT. The incidence of cases with cytogenetically divergent subclones, ie cell populations with unrelated aberrations in addition to the t(9;22), was also higher in the IFN-alpha group compared to the untreated, Bu and Hy groups (P < 0.01) but similar to the post-BMT group. Finally, 14 of the 32 IFN-alpha-treated CML displayed cytogenetic evolution already during the chronic phase; again a higher incidence than in the untreated, Bu and Hy groups (P < 0.001) but not different from the post-BMT group. These findings strongly indicate that IFN-alpha, directly or indirectly, can induce clones with aberrant chromosomal evolution patterns to evolve and proliferate, but the mechanisms underlying these cytogenetic peculiarities remain to be elucidated.
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| 7. |
- Johansson, Bertil, et al.
(författare)
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Cytogenetic polyclonality in hematologic malignancies
- 1999
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Ingår i: Genes, Chromosomes and Cancer. - 1045-2257. ; 24:3, s. 222-229
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Tidskriftsartikel (refereegranskat)abstract
- The present study was undertaken to ascertain the frequency of cytogenetic polyclonality in various hematologic malignancies and to investigate whether morphologic subgroup, age, gender, or previous genotoxic exposure influences the incidence. Among 2,243 cytogenetically investigated hematologic malignancies, 10 acute myeloid leukemias (AML), 5 myelodysplastic syndromes (MDS), 2 acute lymphoblastic leukemias (ALL), 1 acute undifferentiated leukemia (AUL), 1 atypical Philadelphia chromosome-negative (Ph-) chronic myeloid leukemia (CML), 1 chronic myeloproliferative disorder (CMD), and 1 chronic lymphoproliferative disorder (CLD) with karyotypically unrelated clones were identified, constituting 2.6% of AML, 1.6% of MDS, 0.8% of ALL, 13% of AUL, 9.1% of Ph- CML, 1.5% of CMD, and 2.8% of CLD with chromosomal abnormalities. In contrast to the cytogenetic features, the X-inactivation pattern was monoclonal in the two informative female patients that could be investigated. Among 17,733 karyotypically aberrant published cases surveyed, significant frequency differences (P < 0.001) were discerned: 1.7% of 6,526 AML, 3.4% of 2,391 MDS, 0.4% of 1,920 Ph+ CML, 2.9% of 856 CMD, 0.9% of 4,226 ALL, and 5.8% of 1,814 CLD displayed unrelated clones. The incidence of cytogenetic polyclonality did not differ significantly among the MDS, CMD, or ALL subgroups, between males and females, between children (< 16 years) and adults, or between B- and T-cell ALL, whereas the frequencies varied among the AML FAB types (P < 0.05), among the different CLD entities (P < 0.001), and between B- and T-cell CLD (P < 0.001). Furthermore, the incidence was higher in therapy-related AML and MDS than in de novo AML and MDS (P < 0.001 and P < 0.01, respectively).
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| 8. |
- Johansson, Bertil, et al.
(författare)
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t(3;21)(q26;q22) with AML1 rearrangement in a de novo childhood acute monoblastic leukaemia
- 1996
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 92:2, s. 429-431
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Tidskriftsartikel (refereegranskat)abstract
- t(3;21)(q26;q22) is a recurrent chromosomal abnormality in Philadelphia-positive chronic myeloid leukaemia in blast crisis and in treatment-related myelodysplastic syndrome and acute myeloid leukaemia. The molecular consequences of the t(3;21) are presently being unravelled; various transcripts between the AML1 gene in 21q22 and several unrelated genes, i.e. EAP, EVI1 and MDS1, in 3q26 are generated, resulting in the formation of a chimaeric transcription factor. The t(3;21) has only rarely been described in de novo leukaemias and never before in an acute leukaemia in a child. We here present the clinical, cytogenetic and molecular genetic findings in a boy with a de novo acute monoblastic leukaemia with t(3;21)(q26;q22) and AML1 rearrangement.
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| 9. |
- Mauritzson, Nils, et al.
(författare)
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A single-center population-based consecutive series of 1500 cytogenetically investigated adult hematological malignancies: karyotypic features in relation to morphology, age and gender
- 1999
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Ingår i: European Journal of Haematology. - 1600-0609. ; 62:2, s. 95-102
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Tidskriftsartikel (refereegranskat)abstract
- During the 18-yr period 1976-93, a population-based series of 1586 adults with suspected or confirmed hematological malignancies were successfully cytogenetically investigated at a single center. Eighty-six cases were excluded due to unretrievable medical records or if analyzed only in remission or at relapse. The remaining 1500 medical records were reviewed regarding morphology and clinical parameters in order to investigate possible associations between karyotypic pattern (normal, 1, 2 or complex anomalies; specific abnormalities) and gender, age and morphological subgroups. The impact of time-period, i.e. 1976-87 vs. 1988-93, and referring center on cytogenetic findings was also studied. A total of 372 acute myeloid leukemias (AML), 389 myelodysplastic syndromes (MDS), 64 acute lymphoblastic leukemias (ALL) and 262 chronic myeloid leukemias (CML) were identified, altogether 1087 cases. Patients with other (n=261) or no hematological malignancies (n = 152) were excluded from the present analysis. Cytogenetic abnormalities were detected in 52% AML, 51 % MDS, 68% ALL and 97% CML, frequencies that did not differ significantly between the 2 time periods or referring centers. No significant age- or gender-related differences in karyotypic patterns were discerned in AML, MDS, ALL or CML, whereas the karyotypic patterns varied among the FAB groups in both AML (p= 0.001) and MDS (p < 0.001). The specific abnormalities t(8;21), t(15;17) and inv(16) were more common (p < 0.001) in younger AML patients and 5q- was more frequent in females with MDS (p<0.001). These findings indicate, in contrast to previous series, that neoplasia-associated karyotypic aberrations are not more common among older patients or in males.
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| 10. |
- Mitelman, Felix, et al.
(författare)
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A breakpoint map of recurrent chromosomal rearrangements in human neoplasia
- 1997
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 15:4, s. 417-474
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Tidskriftsartikel (refereegranskat)abstract
- Cytogenetic studies over the past few decades have revealed clonal chromosomal aberrations in almost 27,000 human neoplasms. Many of these neoplasia-associated chromosomal abnormalities have been characterised at the molecular level, revealing previously unknown genes that are closely associated with the tumorigenic process. Information on chromosome changes in neoplasia is growing rapidly, making it difficult to identify all recurrent chromosomal aberrations. We have developed a computer program to ascertain, for the first time, all recurrent structural abnormalities in all haematological malignancies and solid tumours published up to June 1996. Out of 26,523 cases, a total of 215 balanced and 1,588 unbalanced recurrent aberrations were identified among 75 different neoplastic disorders. Our compilation of all recurrent balanced and unbalanced neoplasia-associated rearrangements should help in directing future efforts aimed at identifying the molecular mechanisms involved in tumorigenesis.
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