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I Radford-Weiss

Publications and source records attributed to I Radford-Weiss.

At least 19 recordsLinked to original sources
PubMed2006

NUP98 rearrangements in hematopoietic malignancies: a study of the Groupe Francophone de Cytogénétique Hématologique.

The NUP98 gene is fused with 19 different partner genes in various human hematopoietic malignancies. In order to gain additional clinico-hematological data and to identify new partners of NUP98, the Groupe Francophone de Cytogénétique Hématologique (GFCH) collected cases of hematological malignancies where a 11p15 rearrangement was detected. Fluorescence in situ hybridization (FISH) analysis showed that 35% of these patients (23/66) carried a rearrangement of the NUP98 locus. Genes of the HOXA cluster and the nuclear-receptor set domain (NSD) genes were frequently fused to NUP98, mainly in de novo myeloid malignancies whereas the DDX10 and TOP1 genes were equally rearranged in de novo and in therapy-related myeloid proliferations. Involvement of ADD3 and C6ORF80 genes were detected, respectively, in myeloid disorders and in T-cell acute lymphoblastic leukemia (T-ALL), whereas the RAP1GDS1 gene was fused to NUP98 in T-ALL. Three new chromosomal breakpoints: 3q22.1, 7p15 (in a localization distinct from the HOXA locus) and Xq28 were detected in rearrangements with the NUP98 gene locus. The present study as well as a review of the 73 cases previously reported in the literature allowed us to delineate some chromosomal, clinical and molecular features of patients carrying a NUP98 gene rearrangements.

Adolescent↗
PubMed2005

Transient familial haemophagocytic lymphohistiocytosis reactivation post-CD34 haematopoietic stem cell transplantation.

Familial haemophagocytic lymphohistiocytosis (FHLH) is a genetic disorder caused by defective lymphocyte cytotoxicity, resulting in impaired lymphocyte homeostasis and macrophage infiltration of solid tissues and bone marrow, with extensive haemophagocytosis. It is invariably fatal unless treated by allogeneic haematopoietic stem cell transplantation (HSCT). In a retrospective analysis of 11 cases of FHLH, transplanted in one centre between January 1999 and December 2003, it was found that host T cell expansion occurred early after HSCT in a setting of a viral infection (cytomegalovirus and Epstein-Barr virus respectively) in two cases who received T cell-depleted HSCT. Transient recurrence of clinical and biological manifestations of FHLH was observed, despite evidence for donor cell engraftment. Secondary development of donor T cells led to stable mixed chimaerism and sustained remission of FHLH. Detection of host-derived T cells soon after HSCT in a patient with FHLH should thus not mistakenly be taken as a manifestation of graft rejection.

Antigens, CD34↗
PubMed2004

Prognostic impact of p27KIP1 expression in cyclin D1 positive lymphoproliferative disorders.

Nodal mantle cell lymphoma (MCL) is a well-defined entity, but non-nodal leukemic cyclin D1 positive lymphoproliferative disorders have been reported and their relationship with MCL remains controversial and their prognosis heterogeneous. We prospectively studied the expression of cyclin D1 in CD5 positive leukemic B lymphoproliferative disorders at diagnosis and identified 65 cases overexpressing cyclin D1. We did not distinguish any clinical or biological criteria allowing one to identify a non-MCL group. Multivariate analysis identified age, anemia and p27kip1 expression as independent prognostic factors of survival. By univariate analysis, p27kip1 high expression proved to be the strongest predictor of prolonged survival. The median survival of p27 low expressors was 30 months, while it was not reached for p27 high expressors. A high level of p27 expression was often found associated with the absence of nodal involvement and the presence of somatic mutations, but neither of them was restricted to the p27 high expression group. In conclusion, we hypothesize that MCL and these cyclin D1 positive leukemic lymphoproliferative disorders represent a continuous spectrum of diseases. Determination of p27 expression level appears as a routine applicable test allowing identification of a subset of patients who could be considered for different therapeutic approaches.

Adult↗
PubMed2003

LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1.

We have previously shown correction of X-linked severe combined immunodeficiency [SCID-X1, also known as gamma chain (gamma(c)) deficiency] in 9 out of 10 patients by retrovirus-mediated gamma(c) gene transfer into autologous CD34 bone marrow cells. However, almost 3 years after gene therapy, uncontrolled exponential clonal proliferation of mature T cells (with gammadelta+ or alphabeta+ T cell receptors) has occurred in the two youngest patients. Both patients' clones showed retrovirus vector integration in proximity to the LMO2 proto-oncogene promoter, leading to aberrant transcription and expression of LMO2. Thus, retrovirus vector insertion can trigger deregulated premalignant cell proliferation with unexpected frequency, most likely driven by retrovirus enhancer activity on the LMO2 gene promoter.

Adaptor Proteins, Signal Transducing↗
PubMed2003

T-cell prolymphocytic leukemia with autoimmune manifestations in Nijmegen breakage syndrome.

Nijmegen breakage syndrome (NBS) is characterized by growth retardation, microcephaly, mental retardation, immunodeficiency, and predisposition to malignancies, especially B-cell lymphomas. In contrast, leukemia is rare. A 23-year-old NBS patient presented with anemia, thrombocytopenia, and hyperlymphocytosis. The diagnosis of T-cell prolymphocytic leukemia (T-PLL) was confirmed by cytological and immunological assays (TdT(-), CD2(+), CD5(+), CD3m, and CD7(+)). Biological assays also showed a hemolytic anemia and a clotting factor V decrease. The patient was first treated by methylprednisone for 3 weeks. During this period the lymphocyte count decreased. The simultaneous normalization of the hemolysis and of factor V suggested that both could be related to T-PLL. Since T-PLL is refractory to conventional therapies with a poor prognosis, an intensive chemotherapy such as 2'-deoxycoformycin with anti-CDw52 monoclonal antibodies is usually favored. In the present case, however, because of the specific context (i.e., NBS-induced immunodepression, severe hemolytic anemia, and acquired factor V deficiency), he received pentostatin weekly during 1 month and in maintenance during 6 months. At last follow-up (7 months) he showed a persistent control of the lymphocytosis with no side effect.

Adolescent↗
PubMed2002

Typical essential thrombocythaemia does not express bcr-abelson fusion transcript.

Essential thrombocythaemia (ET) is a chronic myeloproliferative disorder (MPD) characterized by an elevated platelet count and no identifiable underlying primary cause. According to the diagnostic criteria of the Polycythemia Vera Study Group (PVSG), ET lacks features diagnostic for other MPDs, including the Philadelphia chromosome (Ph) or bcr-abl rearrangement. Recently, some authors have reported bcr-abl transcript positivity in ET patients, but these findings remain controversial. The aim of this study was to investigate whether the bcr-abl transcript could be found in ET patients and to verify the hypothesis of a new ET variant. ET patients (n = 121) with a median age at diagnosis of 55 years were enrolled. The bcr-abl transcript status was examined by multiplex reverse transcription-polymerase chain reaction. Only two cases were positive for bcr-abl, one of which had the Ph at diagnosis. The positive bcr-abl transcript was associated, in both cases, with mild basophilia at diagnosis. After a median follow-up of 43 months (0-309 months), two patients in the bcr-abl-negative group developed Ph and bcr-abl-negative acute myeloid leukaemia (AML). In contrast, one of the two patients in the bcr-abl-positive group died from AML 13 years after diagnosis. In conclusion, our data on a large group of patients shows the rarity of the bcr-abl transcript in well-established ET. However, a subset of patients with apparent ET and basophilia may express the transcript and may constitute a novel entity intermediate between chronic myeloid leukaemia (CML) and typical ET. A prospective study is warranted in order to define better the clinical and biological characteristics of bcr-abl-expressing ET.

Adolescent↗
PubMed2001

Reassessment of childhood B-lineage lymphoblastic leukemia karyotypes using spectral analysis.

We studied a stratified cohort of 51 childhood B-lineage acute lymphoblastic leukemias (B-ALLs) to evaluate the efficiency of spectral karyotyping (SKY) in the detection of chromosome aberrations previously diagnosed using chromosome banding and/or reverse transcriptase polymerase chain reaction. Despite the small number of cases analyzed, several important features emerge from the study: (a) The result of banding analysis was revised in two-thirds of the cases. Eighty-three chromosome anomalies previously undetected or not characterized using chromosome banding were identified by spectral karyotyping, even in patients with apparently normal karyotypes. (b) All hyperdiploidy cases showed one or more extra copies of chromosomes X, 14, and 21. (c) Two hidden rearrangements, a t(7;12)(?p12;p13), and a new translocation, a t(9;12)(q31;p13), both involving the TEL gene, were characterized. (d) Some cryptic rearrangements, such as the der(21) t(12;21) translocation, remained undetected. (e) No new recurrent chromosome anomalies were discovered with this technique. In conclusion, the present study confirms the efficiency of the SKY technique in resolving and characterizing many complex chromosome anomalies seen in childhood B-ALLs, but it raises questions about the ability of this technique to detect cryptic rearrangements, such as the t(12;21) translocation.

Burkitt Lymphoma↗
PubMed2000

Characterization of acute promyelocytic leukemia cases lacking the classic t(15;17): results of the European Working Party. Groupe Français de Cytogénétique Hématologique, Groupe de Français d'Hematologie Cellulaire, UK Cancer Cytogenetics Group and BIOMED 1 European Community-Concerted Action "Molecular Cytogenetic Diagnosis in Haematological Malignancies".

Acute promyelocytic leukemia (APL) is typified by the t(15;17), generating the PML-RAR alpha fusion and predicting a beneficial response to retinoids. However, a sizeable minority of APL cases lack the classic t(15;17), prompting the establishment of the European Working Party to further characterize this group. Such cases were referred to a workshop held in Monza, Italy and subjected to morphologic, cytogenetic, and molecular review, yielding 60 evaluable patients. In the majority (42 of 60), molecular analyses revealed underlying PML/RAR alpha rearrangements due to insertions (28 of 42) or more complex mechanisms, including 3-way and simple variant translocations (14 of 42). Metaphase fluorescence in situ hybridization (FISH) demonstrated that insertions most commonly led to formation of the PML-RAR alpha fusion gene on 15q. In 11 of 60 workshop patients, PLZF/RAR alpha rearrangements were identified, including 2 patients lacking the t(11;17)(q23;q21). In one case with a normal karyotype, FISH analysis revealed insertion of RAR alpha into 11q23, and PLZF-RAR alpha was the sole fusion gene formed. Two patients were found to have t(5;17), one with a diffuse nuclear NPM staining pattern and with NPM-RAR alpha and RAR alpha-NPM transcripts detected. In the other with an unbalanced der(5)t(5;17)(q13;q21) and a nucleolar NPM localization pattern, an NPM/RAR alpha rearrangement was excluded, and FISH revealed deletion of one RAR alpha allele. In the remaining 5 workshop patients, no evidence was found for a rearrangement of RAR alpha, indicating that in rare instances, alternative mechanisms could mediate the differentiation block that typifies this disease. This study highlights the importance of combining morphologic, cytogenetic, and molecular analyses for optimal management of APL patients and better understanding of the pathogenesis of the disease. (Blood. 2000;96:1297-1308)

Adult↗
PubMed2000

Langerhans cell deficiency in reticular dysgenesis.

Reticular dysgenesis is a rare inherited immunodeficiency characterized by the lack of blood monocytes and neutrophils and low lymphocyte counts, contrasting with normal red blood cell counts and normal or decreased platelet counts. Whether dendritic cells or macrophages, both of which derive primarily from blood monocytes, are affected in this condition remains unknown. We studied 7 patients with reticular dysgenesis. Macrophages were present in normal numbers in the dermis and in the atrophic lymphoid tissues of these patients, proving that at least some subsets of macrophages can differentiate despite very low monocyte counts. By contrast, Langerhans cells, which are CD1a-positive epidermal dendritic cells, were absent in all (n = 5) patients before bone marrow transplantation. After bone marrow transplantation, Langerhans cells were present (n = 2), suggesting that the defect is not related to keratinocyte dysfunction. A split chimeric reconstitution, characterized by the presence of autologous blood monocytes able to differentiate in vitro into CD1a-positive dendritic cells, was observed in a patient who underwent successful engraftment. These results suggest that an intrinsic cell defect is unlikely and that a bone marrow-derived factor may be defective in reticular dysgenesis; it may be responsible for the Langerhans cell defect but not involved in macrophage differentiation.

Antigens, CD↗
PubMed1999

Fluorescence in situ hybridization analysis of masked (8;21)(q22;q22) translocations.

The translocation (8;21)(q22;q22) is associated with acute myeloblastic leukemia (AML M2). The accurate detection of this chromosomal rearrangement is vital due to its association with a favorable prognosis. Variant translocations exist; these may be hidden within an unusual or complex karyotype. In such cases, it is often difficult to confirm the presence of t(8;21)(q22;q22) by conventional cytogenetic analysis alone. The molecular detection of the AML1/ETO fusion gene is possible by reverse transcriptase polymerase chain reaction (RT-PCR) or dual-color fluorescence in situ hybridization (FISH) using probes specific for AML1 and ETO. Four cases of AML M2, with unusual or complex structural chromosomal abnormalities, without cytogenetic evidence of the classical t(8;21)(q22;q22), were studied by FISH. Two were AML1/ETO positive by RT-PCR, one showed a rearrangement by AML1 by Southern analysis, and the fourth had morphological features characteristic of t(8;21). The FISH results showed a co-localization of one AML1 and one ETO signal in interphase and metaphase nuclei in all four cases, demonstrating the presence of variant t(8;21)(q22;q22) rearrangements. Therefore, FISH analysis with the AML1 and ETO probes is extremely valuable, in cases of AML M2, because of its ability to reveal masked t(8;21)(q22;q22) translocations and thus quickly confirm the diagnosis, allowing patients to be assigned to the correct risk group in terms of treatment.

Adult↗
PubMed1999

NG2 expression in MLL rearranged acute myeloid leukaemia is restricted to monoblastic cases.

Expression of NG2 has been reported in the majority of paediatric acute leukaemia (AL) cases with MLL rearrangement. We demonstrated 7. 1 positivity in 2/3 paediatric and 4/11 adult MLL rearranged acute myeloid leukaemia (AML) but in 0/28 adult AML without MLL rearrangement, thus extending the 100% specificity to adult cases. Positivity correlated with stage of maturation arrest since it was found in 0/6 immature AML but in 6/8 monoblastic cases. These data demonstrate that, if NG2 expression in AL is the (in)direct result of MLL rearrangement, such activation is restricted to a monoblastic population in AML. They also have practical implications for NG2 diagnostic screening strategies.

Acute Disease↗
PubMed1998

Quantitative RNA slot-blot analysis of CCND1/cyclin D1 expression in suspected mantle cell lymphoma.

Abnormal CCND1 expression is found in the majority of mantle cell lymphomas (MCL) and in a minority of other mature B cell malignancies. Its evaluation can therefore aid diagnostic classification, in conjunction with clinical, morphological, immunophenotypic and cytogenetic analysis. We describe a rapid slot-blot hybridization technique allowing quantitative assessment of CCND1 expression relative to beta-actin, with a sensitivity cut-off of approximately 10%. This allowed clear separation (P < 0.01) of CCND1 MCL (0.89 +/- 0.4; range 0.23-1.81; n = 25) from control samples (0.02 +/- 0.04; range 0-0.09; n = 22) on limited quantities of RNA (1-3.5 microg). Of nine samples in which a potential diagnosis of MCL lymphoma was based on morphological analysis of paraffin-embedded material, without adequate immunophenotype analysis, all were CCND1 negative and subsequent immunophenotype demonstrated features compatible with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) (CD5+, CD23+, FMC7-) in all cases tested. This study demonstrates the feasibility of slot-blot CCND1 quantification and the importance of the availability of cryopreserved material.

Adult↗
PubMed1998

Genetic analysis of splenic lymphoma with villous lymphocytes: a Groupe Français d'Hématologie Cellulaire (GFHC) study.

In order to characterize the genetic diversity in splenic lymphoma with villous lymphocytes (SLVL), we have undertaken cytogenetic and molecular analyses of CCND1 expression and BCL1-IgH PCR rearrangement in 76 cases diagnosed predominantly on morphological criteria. Cytogenetic abnormalities were detected in 19/44 (43%) of cases, including in 16/25 (64%) of cases with an absolute lymphocytosis. Abnormalities included those involving chromosome 14q32 (9/19, 47%), predominantly t(11;14)(q13;q32) (5/19, 26%), chromosome 3 (26%), predominantly 3q, chromosome 17p (26%) and trisomy 12 (3/19, 16%) and were thus suggestive of pathogenetic diversity. CCND1 was expressed in 8/30 (27%) cases, including in all t(11;14) cases, 5/10 (50%) CD5-positive cases and also in 3/20 (15%) CD5-negative cases. Three CCND1-positive SLVL demonstrated immunophenotypic features similar to mantle cell lymphoma (MCL) but the majority differed in their CD5 negativity or CD23 positivity. BCL1-IgH rearrangement was only seen in 1/62 (2%) of cases overall and in none of the t(11;14) cases, which demonstrated FISH breakpoints both centromeric and telomeric to the BCL1/MTC, suggesting that, if genomic clustering exists in t(11;14) SLVL, it differs from MCL. Although CCND1 expressing SLVL more commonly had marked lymphocytosis, they did not demonstrate a more aggressive clinical course than their negative counterparts, demonstrating that the detection of CCND1 expression or of a t(11;14) should not suffice to alter diagnostic classification in the absence of other criteria.

Aged↗
PubMed1998

FISH detection of chromosome 14q32/IgH translocations: evaluation in follicular lymphoma.

A FISH strategy capable of detecting chromosome 14q32 rearrangements involving the IgH locus, including in interphase nuclei, was developed using Ig variable and constant region cosmids from the extremities of the locus in a dual hybridization approach, using signal splitting as evidence of rearrangement. The large size of the locus (1.3 Mb) and the propensity for internal deletion due to physiological VDJ recombination and isotype switching complicate analysis of this locus. We used the Ig10 cosmid, which hybridizes to C epsilon and C alpha2 at the 3' end of the constant region, in order to minimize deletion and/or splitting of the constant region probe. Cos Ig10 and the IgV18 VH probes were compared with a specific IgH-BCL2 FISH dual hybridization approach in follicular lymphoma (FL). Both were capable of detecting the t(14;18) in interphase nuclei, including in cases with no apparent abnormality by classic karyotype analysis, although the sensitivity of the IgH approach was slightly lower. We have also successfully applied these probes to whole cell cytospin preparations, rendering analysis of cryopreserved material possible, although interpretation should be limited to frequent events, particularly following cell manipulation. Analysis of flow cytometric sorted bone marrow fractions from three FL patients by FISH and FICTION showed that the t(14;18) was present in a much lower proportion of CD34 positive than negative cells but that the higher level of background hybridization limits use of these techniques for the reliable quantification of rare events.

Cell Separation↗
PubMed1998

Simultaneous detection of MYC, BVR1, and PVT1 translocations in lymphoid malignancies by fluorescence in situ hybridization.

The rapid detection of chromosome band 8q24 rearrangements, including classical translocations involving MYC and variant 3' translocations, is important for the accurate diagnosis and appropriate treatment of lymphoid malignancies. We have identified and characterized a CEPH YAC, 934e1, which extends from at least 190 kbp upstream to over 280 kbp downstream to MYC, allowing detection of classical t(8; 14)(q24;q32) and variant t(8;22)(q24;q11) and t(8;14)(q24;q11), extending distal to PVT1 and therefore, by extrapolation, to BVR1. This YAC also allowed clarification of complex chromosome 8 abnormalities and the identification of translocations in interphase nuclei. A second CEPH YAC, 904c3, previously shown to contain the PVT1 locus but not MYC, allowed distinction between translocations occurring centromeric and telomeric to MYC. Use of the 934e1 YAC will aid classification of a variety of lymphoid proliferations and further characterization of rearranged cases with the 904c3 YAC will simplify mapping of their diverse breakpoints.

Chromosomes, Artificial, Yeast↗
PubMed1997

A chromosome 14q11/TCR alpha/delta specific yeast artificial chromosome improves the detection rate and characterization of chromosome abnormalities in T-lymphoproliferative disorders.

The rate of detection of chromosome abnormalities in T-cell proliferations is lower than that observed in B-cell malignancies. The former frequently involve the TCR alpha/delta locus at chromosome band 14q11. We have identified a YAC encompassing 70% of the TCR alpha/delta locus, which has been used as a fluorescence in situ hybridization probe to detect chromosome rearrangements involving 14q11, both at metaphase and within interphase nuclei, in patients with a variety of T-lymphoproliferative disorders. Its use allowed detection of previously unsuspected TCR alpha/delta rearrangements in 4/13 (30%) immature T-lineage acute leukemias, including two t(10;14) and 2 minor inversion 14s. It also clarified interpretation of complex chromosome 14 abnormalities in mature T-cell proliferations (T-prolymphocytic leukemia and ataxia telangiectasia). Use of this probe will aid the detection and characterization of abnormalities involving the TCR alpha/delta locus, particularly in cases with normal or complex karyotypes and in those proliferations for which mitoses are difficult to obtain.

Chromosome Aberrations↗