ETV6 (TEL) gene amplification in a myelodysplastic syndrome with excess of blasts.
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Aged↗
Biomedical subjects
F Brizard
Publications and source records attributed to F Brizard.
Quantitative HOX expression in chromosomally defined subsets of acute myelogenous leukemia.
We used a degenerate RT-PCR screen and subsequent real-time quantitative RT-PCR assays to examine the expression of HOX and TALE-family genes in 34 cases of chromosomally defined AML for which outcome data were available. AMLs with favorable cytogenetic features were associated with low overall HOX gene expression whereas poor prognostic cases had high levels. Characteristically, multiple HOXA family members including HOXA3-HOXA10 were jointly overexpressed in conjunction with HOXB3, HOXB6, MEIS1 and PBX3. Higher levels of expression were also observed in the FAB subtype, AML-M1. Spearmann correlation coefficients indicated that the expression levels for many of these genes were highly inter-related. While we did not detect any significant correlations between HOX expression and complete response rates or age in this limited set of patients, there was a significant correlation between event-free survival and HOXA7 with a trend toward significance for HoxA9, HoxA4 and HoxA5. While patients with elevated HOX expression did worse, there were notable exceptions. Thus, although HOX overexpression and clinical resistance to chemotherapy often coincide, they are not inextricably linked. Our results indicate that quantitative HOX analysis has the potential to add new information to the management of patients with AML, especially where characteristic chromosomal alterations are lacking.
Acute Disease↗
A complex pattern of recurrent chromosomal losses and gains in T-cell prolymphocytic leukemia.
T-cell prolymphocytic leukemia (T-PLL) is a rare malignant proliferation of lymphoid cells with a postthymic phenotype. Previous cytogenetic and molecular studies reported complex karyotypes with recurrent chromosomal abnormalities, including translocations involving either TCL1 at 14q32.1 or MTCP1 at Xq28, inactivation of the ATM gene by deletion and/or mutation, and isochromosomes 8. For extensive study of chromosomal imbalances in T-PLL, we analyzed 22 tumoral DNAs using comparative genomic hybridization (CGH). Abnormal CGH profiles were detected in all cases, demonstrating highly recurrent gains and losses and largely extending the abnormalities previously established. Only a few nonrecurrent abnormalities were observed, in contrast to the genetic instability anticipated from ATM inactivation. Nine recurrent regions of loss were identified at 8p (frequency 86%), 11q (68%), 22q11 (45%), 13q (41%), 6q (36%), 9p (27%), 12p (23%), 11p11-p14 (23%), and 17p (23%), as well as four regions of gain at 8q (82%), 14q32 (50%), 22q21-qter (41%), and 6p (23%). Several recurrent chromosomal abnormalities were simultaneously present in each case (mean, 5.7; up to 10), none being mutually exclusive of another. Fluorescence in situ hybridization analysis confirmed and extended 22q11 and 13q losses, giving final frequencies of 55% and 45%, respectively. Analysis of one case over a 7-year period confirmed the overall genetic stability of T-PLL and showed that tumor progression was associated with the onset of a few chromosomal abnormalities. This study establishes a complex pattern of highly recurrent chromosomal abnormalities in T-PLL, including some, such as chromosome 13 deletion, commonly found in other lymphoid malignancies.
Chromosome Aberrations↗
Human LPP gene is fused to MLL in a secondary acute leukemia with a t(3;11) (q28;q23).
The mixed lineage leukemia, MLL, gene is frequently rearranged in patients with secondary leukemia following treatment with DNA topoisomerase II inhibitors. By FISH and Southern blot analyses we identified a rearrangement in the MLL gene due to a novel t(3;11)(q28;q23) chromosomal translocation in a patient who developed AML-M5 3 years after treatment for a follicular lymphoma. Through inverse PCR, the LPP (lipoma preferred partner) gene on 3q28 was identified as the MLL fusion partner. LPP contains substantial identity to the focal adhesion protein, zyxin, and is frequently fused to HMGIC in lipomas. The breakpoint occurred in intron 8 of MLL and LPP. Two in-frame MLL-LPP transcripts, which fuse MLL exon 8 to LPP exon 9, were detected by RT-PCR, although the smaller of these contained a deletion of 120 bp from the MLL sequence. The predicted MLL-LPP fusion protein includes the A/T hook motifs and methyltransferase domain of MLL joined to the two last LIM domains of LPP. A reciprocal LPP-MLL transcript, predicted to include the proline-rich and leucine zipper motifs, and the first LIM domain of LPP were also detected by RT-PCR. In summary, LPP is a newly identified MLL fusion partner in secondary leukemia resulting from topoisomerase inhibitors. The MLL-LPP and LPP-MLL predicted proteins contain many of the features present in other MLL rearrangements.
Adult↗
Ovarian sarcoma and acute myelogenous leukaemia.
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Antineoplastic Combined Chemotherapy Protocols↗
Bile Salt Anion Sorption by Polymeric Resins: Comparison of a Functionalized Polyacrylamide Resin with Cholestyramine.
Cholestyramine and a cross-linked polyacrylamide resin with lateral alkyl quaternary ammonium groups (QPDA12) were used to study their ability to bind several bile salt anions (including the cholate, glycocholate, taurocholate, and chenodeoxycholate), individually and competitively, from phosphate buffer solutions at room temperature. The latter resin showed high affinities for all the bile salt anions examined, while cholestyramine exhibited a high affinity only for the more hydrophobic chenodeoxycholate. However, for the binding with cholestyramine, cooperative effects were more pronounced, leading to the enhancement of sorption at higher concentrations. The Langmuir equation and its modified versions were used in the interpretation of both individual and competitive binding of bile salts. The data from competitive binding studies indicated that the presence of the tightly bound chenodeoxycholate did not significantly diminish the ability of QPDA12 resin to bind cholate. However, for cholestyramine, the sorption of chenodeoxycholate increased the relative binding affinity for the more hydrophilic cholate, revealing a novel "cooperative" effect involving different bile salt anions. The latter results suggest that the observed higher affinity of QPDA12 is brought about predominantly through the hydrophobic interactions with the pendant alkyl groups rather than with the resin backbone. Copyright 2000 Academic Press.
Journal Article↗
Persistence of BCR-ABL genomic rearrangement in chronic myeloid leukemia patients in complete and sustained cytogenetic remission after interferon-alpha therapy or allogeneic bone marrow transplantation.
In recent years, the prognosis of chronic myeloid leukemia (CML) has been greatly improved either with interferon-alpha (IFN-alpha) therapy or allogeneic bone marrow transplantation (BMT). In the present study, minimal residual disease was evaluated in 21 patients in complete cytogenetic response (CCR) after such treatments. Samples from bone marrow aspirates or peripheral blood or both were analyzed by conventional cytogenetics, Southern blot, interphase fluorescent in situ hybridization (FISH), and quantitative reverse transcription-polymerase chain reaction (Q-RT-PCR). In all patients, FISH detected 1% to 12% nuclei with a BCR-ABL fusion gene, whereas Q-RT-PCR experiments were negative or weakly positive. Based on these results, we hypothesize that the BCR-ABL genomic rearrangement persists unexpressed in nonproliferating cells whatever the treatment (IFN-alpha or BMT). These data point to the need for follow-up of CML patients in CCR over an extensive period at the DNA level (FISH) to evaluate the residual disease and at the RNA level (Q-RT-PCR) to estimate the risk of relapse. (Blood. 2000;95:404-408)
Adult↗
Interstitial telomere repeats in translocations of hematopoietic disorders.
Cytogenetic and fluorescence in situ hybridization studies have shown the presence of telomeric repeats in translocation present in three patients with hematopoietic malignancies. One had jumping translocations, involving 1q12 and 2q, 16p, and 19q. These sequences were detected by FISH only in derivative chromosomes t(1;16) and t(1;19) in the first patient, and t(1;7) in the second. They were not seen in derivative t(1;2) and t(7;8), respectively. Interstitial telomeric sequences were observed in der(2)t(1;2) in about half of the metaphases in the third patient. The instability of interstitial telomeric DNA repeats in translocations is shown by the present findings. Moreover it supports the hypothesis that the presence of interstitial telomere repeats is not sufficient to make it functional.
Aged↗
Genomic organization of the human and mouse stau genes.
Mammalian Staufen is a double-stranded RNA-binding protein potentially involved in mRNA transport and localization. Recently, we reported that the human gene is located on chromosome 20, region q13.1. We now report the genomic organization of both the human and mouse stau genes. Amplification of genomic DNA and sequencing of the resulting PCR products indicated that the human and mouse genes are fragmented into 15 and 12 exons, distributed over at least 65 and 17 kb of genomic DNA, respectively. The three additional exons found in the human gene are subjected to differential splicing, generating four different transcripts. Corresponding exons have not been found in mouse transcripts. Apart from those three exons, the overall organization of the stau gene is similar in the two species, and the positions of the exon-intron junctions are perfectly conserved. Even an alternative choice between two splicing acceptor sites, which causes an insertion of 18 nucleotides in exon 5, is conserved in both humans and mice. An extremely G+C-rich region lacking canonical TATA and CAAT boxes was found upstream of the most 5' RACE sequence, suggesting that a housekeeping-like promoter drives the broad expression of Staufen in mammalian cells. This work represents the first step toward production of knockout mice and the elucidation of putative Staufen-linked hereditary diseases in humans.
Alternative Splicing↗
Fluorescence in situ hybridization analysis of chromosome 1 abnormalities in hematopoietic disorders: rearrangements of DNA satellite II and new recurrent translocations.
Using fluorescence in situ hybridization analysis, breakpoints involving the long arm of chromosome 1 (1q) were localized in 36 patients with various hematopoietic disorders and rearrangements of the proximal part of 1q, as ascertained with banding techniques. The breakpoint was localized within the satellite II (sat II) domain in 14 patients with various abnormalities, between the sat II domain and the BCL9 locus in eight, between the BCL9 and ARNT loci in two, between sat II and ARNT in two others, and distal to ARNT in seven. A dicentric chromosome 1 was present in two patients. A high incidence of heterochromatin heteromorphism of chromosome 1 was present in this series. Two recurrent translocations were identified, t(1;2)(q12;q37) in three patients suffering from three different acute leukemia subtypes, and t(1;16)(q12;q24) in two patients with different diseases. Two patients had jumping translocations. Most of the rearrangements of 1q were secondary abnormalities, included in complex karyotypes. The roles of methylation, interactions with the proteins interfering with heterochromatin and possible gene silencing due to heterochromatin rearrangements are discussed.
Adolescent↗
Aml1/ETO and Pml/RARA rearrangements in a case of AML-M2 acute myeloblastic leukemia with t(15;17).
We report a case of acute myeloid leukemia FAB-type 2 with a translocation t(15;17)(q22;q12) On the basis of the cytological findings, a translocation t(8;21)(q22;q22) was suspected. FISH analyses using specific probes for t(15;17) and t(8;21) detected both PML/RARalpha and AML1/ETO rearrangements in a few percentage of cells. This case demonstrates the complexities that may occur between cytology and cytogenetic findings and the usefulness of FISH methods to detect an AML1/ETO rearrangement only suspected by cytological examination of bone marrow smears.
Adult↗
Abnormalities of the short arm of chromosome 12 in T cell prolymphocytic leukemia.
Abnormalities of the short arm of chromosome 12 are nonrandom events in T cell prolymphocytic leukemia (T-PLL). Fluorescence in situ hybridization (FISH) studies were performed in three patients with T-PLL and one patient with T cell peripheral lymphoma and rearrangement of 12p. Whereas the rearrangements of 12p were different in the four patients, a breakpoint centromeric to the ETV6 gene was present in the three T-PLL patients. In addition, loss of heterozygosity for a chromosomal segment telomeric to ETV6 with loss of the RAD52 locus was also shown by FISH studies. In contrast, the breakpoint was telomeric to ETV6 in the patient with peripheral lymphoma.
Aged↗
Does BCR-ABL genomic rearrangement persist in CML patients in complete remission after interferon alpha therapy?
Cytogenetic, interphase fluorescent in situ hybridization (FISH) and RT-PCR methods were used to study minimal residual disease in peripheral blood stem cells collected for autografting in three chronic myeloid leukemia (CML) patients in sustained complete cytogenetic remission after treatment with interferon alpha (IFNalpha). Karyotypic analysis failed to reveal Ph-positive metaphases. FISH detected 9-16% nuclei with a BCR-ABL fusion gene, contrasting with RT-PCR, performed in two cases, which was negative in one case and weakly positive in the other. RT-PCR was also subsequently weakly positive in the third patient. This discrepancy suggests that the BCR-ABL genomic rearrangement persists unexpressed in quiescent cells. These preliminary results, which need to be confirmed in larger series, suggest that monitoring residual disease in CML should be performed both at DNA and RNA levels. Moreover, autografting following IFNalpha therapy should be considered with caution because of the persistence of the BCR-ABL genomic rearrangement in a sizeable proportion of the cells.
Adult↗
t(3;17)(q21;q25) in Epstein-Barr virus associated peripheral T-cell lymphoma: a paediatric case.
We describe an immunocompetent 8-year-old boy with a serological profile indicating chronic infection by Epstein-Barr virus (EBV) who developed subcutaneous and pulmonary lesions related to a peripheral T-cell proliferation. No clonal rearrangement of T-cell receptor or immunoglobulin genes was seen. However, the finding of a t(3;17)(q21;q25) in 44 metaphases from one skin lesion demonstrated a clonal origin. We also showed that the proliferative T cells contained EBV genome leading to the diagnosis of EBV-associated peripheral T-cell lymphoma. Further cytogenetic and molecular studies are needed to identify genes implicated in the pathogenesis of this haematological malignancy.
Child↗
Multiple chromosomal mechanisms generate an EWS/FLI1 or an EWS/ERG fusion gene in Ewing tumors.
The t(11;22)(q24;q12) translocation is found in about 85% of Ewing tumors and leads in all cases to an EWS/FLI1 fusion gene. In a few instances, complex translocations, involving chromosomes 11, 22 and a third chromosome or other variant translocations not involving chromosome 11 also have been reported. These rearrangements generate an active fusion gene between the EWS gene and either the human FLI1 gene or other members of the ETS gene family: the ERG gene localized in band 21q22.2, the ETV1 gene localized in band 7p22, or the E1AF gene localized in band 17q12. Using fluorescence in situ hybridization (FISH) on interphase nuclei or metaphases, we report here the characterization of particular karyotypes in Ewing tumors, namely a complex t(2;11;22) translocation, a variant t(12;22) translocation, and one Ewing tumor without specific rearrangements but with an EWS/ERG fusion gene demonstrated by molecular analysis. These molecular cytogenetic methods allowed us (1) to precisely localize the genomic breakpoints within-EWSR1 and EWSR2 and to identify the chromosome carrying the fusion gene; (2) to determine the nature of events generating the fusion genes; (3) to demonstrate that some variant translocations represent masked complex translocations; and (4) to show that the generation of an EWS/ERG fusion gene cannot be obtained through a simple balanced translocation.
Chromosome Aberrations↗
11q13 rearrangement in B cell chronic lymphocytic leukemia.
Translocation t(11;14)(q13;q32) and/or 11q13 rearrangements have been reported in various B cell immunoproliferative disorders. They appear to be frequent in mantle cell zone lymphoma (MZL) and rare in B-cell chronic lymphocytic leukemia (B-CLL). Discrimination between MZL and B-CLL is sometimes uncertain on the basis of morphology and immunophenotype. To evaluate the incidence of 11q13 rearrangements in B-CLL, purified B cells from 59 untreated patients were studied by cytogenetic methods after short term stimulated culture. Abnormalities at band 11q13 were found in 2 cases only. Fluorescent in situ hybridization (FISH) study confirmed del(11)(q13) in one case and showed translocation t(11;13) in another one. Thus this rearrangement appears to be very rare in B-CLL and its finding should lead to a careful search for the characteristic features of MZL, namely, morphology, the expression of CD5 without CD23, high density monotypic SIg, together with t(11;14) and/or bcl-1/IgH rearrangement.
Aged↗
Trisomy 8q due to i(8q) or der(8) t(8;8) is a frequent lesion in T-prolymphocytic leukaemia: four new cases and a review of the literature.
Cytogenetic abnormalities found in four cases of T-cell prolymphocytic leukaemia (T-PLL) are described. An isochromosome 8q was found in three patients and a t(8;8) in one. In the four cases, karyotypes were complex and showed a high degree of instability. In addition, we reviewed 27 published cases of cytogenetically studied T-PLL. On the whole, the most frequently recurring anomalies in T-PLL are 14q lesions with nonrandom breakpoints, inversion (14)(q11q32) or tandem translocations (14;14) (not seen in any of our cases) and trisomy for 8q. mainly due to i(8q), found in more than 40% of patients each. Similar structural anomalies were found almost as frequently among the 23 cytogenetically studied cases of so-called T-chronic lymphocytic leukaemia (T-CLL) reported prior to 1989. It is now accepted that the T-cell counterpart of B-CLL either does not exist or is exceedingly rare and thus previously reported cases of T-CLL sharing the chromosomal characteristics of T-PLL may well have been misdiagnosed examples of T-PLL. Isochromosomes 8q are exceptionally found in other types of haematological malignancies. However, i(8q) could not be shown to be the primary lesion in any case in T-PLL and the role of trisomy for 8q, as well of the associated monosomy 8p, is entirely unknown.
Adult↗
Proliferative response of B chronic lymphocytic leukemia lymphocytes stimulated with IL2 and soluble CD23.
The in vitro proliferative response of purified B-chronic lymphocytic leukemia (B-CLL) lymphocytes cultured in the presence of soluble CD23 (sCD23) with or without IL2 was compared to the responses induced by phorbol 12-myristate 13-acetate (PMA), Staphylococcus aureus strain Cowan I (SAC), IL1, IL2, IL4, IL6 and the combination of IL2 and interferon (IFN) alpha or IFN gamma. As expected, B-CLL lymphocytes proliferated with PMA, SAC and IL2 with a clear enhancement of the IL2-induced response by IFN alpha or IFN gamma. They failed to proliferate in response to sCD23, IL1, IL4 or IL6 alone nor to the combinations of sCD23 and any of the 3 latter cytokines. However, sCD23 significantly increased the proliferation of B-CLL cells induced by IL2, suggesting a protective effect of sCD23 on apoptosis. Serum levels of sCD23 and CD23 membrane expression were high in every patient which is compatible with the hypothesis of an autocrine or paracrine activation loop. Detectable CD23 expression was lost in all cultures except for that stimulated by PMA. Only supernatants of PMA-stimulated cultures contained high sCD23 levels.
Adult↗