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See detailPeripheral T-cell lymphoma with t(6;14)(p25;q11.2) translocation presenting with massive splenomegaly.
SOMJA, Joan ULg; Bisig, B.; de Leval, L. et al

in Virchows Archiv : An International Journal of Pathology (2014)

Recurrent chromosomal translocations associated to peripheral T-cell lymphomas (PTCL) are rare. Here, we report a case of PTCL, not otherwise specified (NOS) with the karyotype 46,Y,add(X)(p22),t(6;14 ... [more ▼]

Recurrent chromosomal translocations associated to peripheral T-cell lymphomas (PTCL) are rare. Here, we report a case of PTCL, not otherwise specified (NOS) with the karyotype 46,Y,add(X)(p22),t(6;14)(p25;q11) and FISH-proved breakpoints in the IRF4 and TCRAD loci, leading to juxtaposition of both genes. A 64-year-old male patient presented with mild cytopenias and massive splenomegaly. Splenectomy showed diffuse red pulp involvement by a pleomorphic medium- to large-cell T-cell lymphoma with a CD2+ CD3+ CD5− CD7− CD4+ CD8+/− CD30− TCRbeta-F1+ immunophenotype, an activated cytotoxic profile, and strong MUM1 expression. The clinical course was marked by disease progression in the bone marrow under treatment and death at 4 months. In contrast with two t(6;14)(p25;q11.2)-positive lymphomas previously reported to be cytotoxic PTCL, NOS with bone marrow and skin involvement, this case was manifested by massive splenomegaly, expanding the clinical spectrum of PTCLs harboring t(6;14)(p25;q11.2) and supporting consideration of this translocation as a marker of biological aggressiveness. [less ▲]

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See detailPatterns of genomic aberrations suggest that Burkitt lymphomas with complex karyotype are distinct from other aggressive B-cell lymphomas with MYC rearrangement.
Havelange, Violaine; Ameye, Genevieve; Theate, Ivan et al

in Genes, Chromosomes & Cancer (2013), 52(1), 81-92

We previously showed that complex karyotypes (CK) and chromosome 13q abnormalities have an adverse prognostic impact in childhood Burkitt lymphomas/leukemias (BL) and diffuse large B-cell lymphomas (DLBCL ... [more ▼]

We previously showed that complex karyotypes (CK) and chromosome 13q abnormalities have an adverse prognostic impact in childhood Burkitt lymphomas/leukemias (BL) and diffuse large B-cell lymphomas (DLBCL). The aim of our study was to identify recurrent alterations associated with MYC rearrangements in aggressive B-cell lymphomas with CK. Multicolor fluorescence in situ hybridization (M-FISH) was performed in 84 patient samples (59 adults and 25 children), including 37 BL (13 lymphomas and 24 acute leukemias), 12 DLBCL, 28 B-cell lymphomas with intermediate features (DLBCL/BL), 4 B-cell precursor acute lymphoblastic leukemias (BCP-ALL), and 3 unclassifiable B-cell lymphomas. New (cytogenetically undetected) abnormalities were identified in 80% of patients. We also refined one-third of the chromosomal aberrations detected by karyotyping. M-FISH proved to be more useful in identifying chromosomal partners involved in unbalanced translocations and in revealing greater complexity of 13q rearrangements. Most of the newly identified or refined recurrent alterations involved 1q, 13q and 3q (gains/losses), 7q and 18q (gains), or 6q (losses), suggesting that these secondary aberrations may play a role in lymphomagenesis. Several patterns of genomic aberrations were identified: 1q gains in BL, trisomies 7 in DLBCL, and 18q-translocations in adult non-BL. BCP-ALL usually displayed an 18q21 rearrangement. BL karyotypes were less complex and aneuploid than those of other MYC-rearranged lymphomas. BCP-ALL and DLBCL/BL were associated with a higher rate of early death than BL and DLBCL. These findings support the categorization of DLBCL/BL as a distinct entity and suggest that BL with CK are indeed different from other aggressive MYC-rearranged lymphomas, which usually show greater genetic complexity. (c) 2012 Wiley Periodicals, Inc. [less ▲]

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See detailPRDM16 (1p36) translocations define a distinct entity of myeloid malignancies with poor prognosis but may also occur in lymphoid malignancies.
Duhoux, Francois P; Ameye, Genevieve; Montano-Almendras, Carmen P et al

in British Journal of Haematology (2012), 156(1), 76-88

The PRDM16 (1p36) gene is rearranged in acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) with t(1;3)(p36;q21), sharing characteristics with AML and MDS with MECOM (3q26.2) translocations ... [more ▼]

The PRDM16 (1p36) gene is rearranged in acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) with t(1;3)(p36;q21), sharing characteristics with AML and MDS with MECOM (3q26.2) translocations. We used fluorescence in situ hybridization to study 39 haematological malignancies with translocations involving PRDM16 to assess the precise breakpoint on 1p36 and the identity of the partner locus. Reverse-transcription polymerase chain reaction (PCR) was performed in selected cases in order to confirm the partner locus. PRDM16 expression studies were performed on bone marrow samples of patients, normal controls and CD34(+) cells using TaqMan real-time quantitative PCR. PRDM16 was rearranged with the RPN1 (3q21) locus in 30 cases and with other loci in nine cases. The diagnosis was AML or MDS in most cases, except for two cases of lymphoid proliferation. We identified novel translocation partners of PRDM16, including the transcription factors ETV6 and IKZF1. Translocations involving PRDM16 lead to its overexpression irrespective of the consequence of the rearrangement (fusion gene or promoter swap). Survival data suggest that patients with AML/MDS and PRDM16 translocations have a poor prognosis despite a simple karyotype and a median age of 65 years. There seems to be an over-representation of late-onset therapy-related myeloid malignancies. [less ▲]

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See detailPrimary central nervous system lymphoma in a patient treated with Natalizumab.
Phan-Ba, Rémy ULg; Bisig, Bettina ULg; Deprez, Manuel ULg et al

in Annals of Neurology (2011), 69(6), 1060-1

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See detailRefinement of 1p36 alterations not involving PRDM16 in myeloid and lymphoid malignancies.
Duhoux, Francois P; Ameye, Genevieve; Lambot, Virginie et al

in PLoS ONE (2011), 6(10), 26311

Fluorescence in situ hybridization was performed to characterize 81 cases of myeloid and lymphoid malignancies with cytogenetic 1p36 alterations not affecting the PRDM16 locus. In total, three subgroups ... [more ▼]

Fluorescence in situ hybridization was performed to characterize 81 cases of myeloid and lymphoid malignancies with cytogenetic 1p36 alterations not affecting the PRDM16 locus. In total, three subgroups were identified: balanced translocations (N = 27) and telomeric rearrangements (N = 15), both mainly observed in myeloid disorders; and unbalanced non-telomeric rearrangements (N = 39), mainly observed in lymphoid proliferations and frequently associated with a highly complex karyotype. The 1p36 rearrangement was isolated in 12 cases, mainly myeloid disorders. The breakpoints on 1p36 were more widely distributed than previously reported, but with identifiable rare breakpoint cluster regions, such as the TP73 locus. We also found novel partner loci on 1p36 for the known multi-partner genes HMGA2 and RUNX1. We precised the common terminal 1p36 deletion, which has been suggested to have an adverse prognosis, in B-cell lymphomas [follicular lymphomas and diffuse large B-cell lymphomas with t(14;18)(q32;q21) as well as follicular lymphomas without t(14;18)]. Intrachromosomal telomeric repetitive sequences were detected in at least half the cases of telomeric rearrangements. It is unclear how the latter rearrangements occurred and whether they represent oncogenic events or result from chromosomal instability during oncogenesis. [less ▲]

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See detailCHIC cells: a novel ALK+ cell line derived from a relapsed anaplastic large cell lymphoma
Thielen, Caroline ULg; Bisig, Bettina ULg; Gofflot, Stéphanie ULg et al

in British Journal of Haematology (2011), 152

Since the initial description of anaplastic large cell lymphoma (ALCL) as a proliferation of large CD30+ lymphoid cells, the morphological spectrum of ALCL positive for anaplastic lymphoma kinase (ALCL ... [more ▼]

Since the initial description of anaplastic large cell lymphoma (ALCL) as a proliferation of large CD30+ lymphoid cells, the morphological spectrum of ALCL positive for anaplastic lymphoma kinase (ALCL, ALK+) has expanded, and beyond the common pattern most frequently encountered, several variants have been identified, including the lymphohistiocytic and the small cell patterns (Swerdlow et al, 2008). Only ten ALK+ ALCL cell lines are currently available, and most were derived from tumours demonstrating the common type morphology (Drexler & MacLeod, 2004). We have established a novel cell line (CHIC) from the cerebrospinal fluid of a 32-year-old man with relapsing/refractory ALK+ ALCL with a t(2;5)(p23;q35) translocation whose initial tumour exhibited lymphohistiocytic features. This cell line is now made available to the scientific community. In addition to multiple in vitro applications, the tumourigenic capacity of these cells represents a useful property for in vivo drug testing. [less ▲]

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See detailSystematic chromosomal aberrations found in murine bone marrow-derived mesenchymal stem cells.
Josse, Claire ULg; Schoemans, R.; Niessen, Neville-Andrew ULg et al

in Stem Cells & Development (2010), 19(8), 1167-1173

Mesenchymal stem cells (MSCs) are studied as a cellular source for the treatment of various diseases. In this work, we isolated and cultivated murine bone marrow-derived MSCs. After a first observation of ... [more ▼]

Mesenchymal stem cells (MSCs) are studied as a cellular source for the treatment of various diseases. In this work, we isolated and cultivated murine bone marrow-derived MSCs. After a first observation of a solid tumour in a mouse injected with these cells, we systematically explored their chromosomal stability. We observed in all the cytogenetically analysed cases gross chromosomal alterations every time the MSCs went through the senescence crisis while the lymphocytes from the same animals showed a normal chromosome count. This observation was confirmed in different mouse strains, with different culture protocols, and even in short-term cultures after an hematopoietic cell negative immunodepletion performed in order to accelerate the isolation procedure. Therefore, we conclude that murine MSCs display high chromosomal instability, can generate tumours, and that care must be taken before using them for the evaluation of MSC therapeutic potential. [less ▲]

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See detailFish and chips
DELVENNE, Philippe ULg; Deprez, Manuel ULg; BISIG, Bettina ULg et al

in Revue Médicale de Liège (2010), 65 Spec no.

Academic hospital laboratories should offer patients the possibility to have the most accurate diagnosis by the development of new analyses, such as molecular biology tests including FISH (Fluorescent In ... [more ▼]

Academic hospital laboratories should offer patients the possibility to have the most accurate diagnosis by the development of new analyses, such as molecular biology tests including FISH (Fluorescent In Situ Hybridization) and chips (microarrays,...). The purpose of this article is to describe the principles and the potential applications of these techniques. [less ▲]

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See detailImproved detection of chromosomal abnormalities in chronic lymphocytic leukemia by conventional cytogenetics using CpG oligonucleotide and interleukin-2 stimulation: A Belgian multicentric study.
Put, Natalie; Konings, Peter; Rack, Katrina et al

in Genes, Chromosomes & Cancer (2009), 48(10), 843-53

We performed a multicentric study to assess the impact of two different culture procedures on the detection of chromosomal abnormalities in 217 consecutive unselected cases with chronic lymphocytic ... [more ▼]

We performed a multicentric study to assess the impact of two different culture procedures on the detection of chromosomal abnormalities in 217 consecutive unselected cases with chronic lymphocytic leukemia (CLL) referred for routine analysis either at the time of diagnosis (n = 172) or during disease evolution (n = 45). Parallel cultures of peripheral blood or bone marrow were set up with the addition of either the conventional B-cell mitogen 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or a combination of CpG oligonucleotide (CpG) and interleukin-2 (IL-2). Cytogenetic analyses were performed on both cultures. Clonal abnormalities were identified in 116 cases (53%). In 78 cases (36%), the aberrant clone was detected in both cultures. Among these, the percentages of aberrant metaphases were similar in both conditions in 17 cases, higher in the CpG/IL-2 culture in 43 cases, and higher in the TPA culture in 18 cases. Clonal aberrations were detected in only one culture, either in CpG/IL-2 or TPA in 33 (15%) and 5 (2%) cases, respectively. Taken together, abnormal karyotypes were observed in 51% with CpG/IL-2 and 38% with TPA (P < 0.0001). Application of FISH (n = 201) allowed the detection of abnormalities not visible by conventional cytogenetic analysis in 80 cases: del(13q) (n = 71), del(11q) (n = 5), +12 (n = 2), del(14q) (n = 1), and del(17p) (n = 1). In conclusion, our results confirm that CpG/IL-2 stimulation increases the detection rate of chromosomal abnormalities in CLL compared with TPA and that further improvement can be obtained by FISH. However, neither conventional cytogenetics nor FISH detected all aberrations, demonstrating the complementary nature of these techniques. [less ▲]

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See detailNon-myeloablative transplantation with CD8-depleted or unmanipulated peripheral blood stem cells: a phase II randomized trial.
Willems, Evelyne ULg; Baron, Frédéric ULg; Baudoux, Etienne ULg et al

in Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K (2009), 23(3), 608-10

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See detailCyclin D1-negative mantle cell lymphoma with cryptic t(12;14)(p13;q32) and cyclin D2 overexpression.
Herens, Christian ULg; Lambert, Frédéric ULg; Quintanilla-Martinez, Leticia et al

in Blood (2008), 111(3), 1745-6

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See detailEvidence for neo-generation of T cells by the thymus after non-myeloablative conditioning.
Castermans, Emilie ULg; Baron, Frédéric ULg; Willems, Evelyne ULg et al

in Haematologica (2008), 93(2), 240-7

BACKGROUND: Background and objective. We investigated immune recovery in 50 patients given either unmanipulated or CD8-depleted allogeneic peripheral blood stem cells after non-myeloablative conditioning ... [more ▼]

BACKGROUND: Background and objective. We investigated immune recovery in 50 patients given either unmanipulated or CD8-depleted allogeneic peripheral blood stem cells after non-myeloablative conditioning. DESIGN AND METHODS: Fifty patients were randomized to receive either CD8-depleted (n=22) or non-manipulated (n=28) peripheral blood stem cells. The median patients age was 57 (range 36-69) years. The conditioning regimen consisted of 2 Gy total body irradiation with or without added fludarabine. Twenty patients received grafts from related donors, 14 from 10/10 HLA-allele matched unrelated donors, and 16 from HLA-mismatched unrelated donors. Graft-versus-host disease pro-phylaxis consisted of mycophenolate mofetil and cyclosporine. Immune recovery during the first year after hematopoietic cell transplantation was assessed by flow cytometry phenotyping, analyses of the diversity of the TCRBV repertoire, and quantification of signal-joint T-cell receptor excision circles (sjTREC). RESULTS: CD8-depletion of the graft reduced the recovery of CD8(+) T-cell counts in the first 6 months following transplantation (p<0.0001) but had no significant impact on the restoration of other T-cell subsets. Both sjTREC concentration and CD3(+) T-cell counts increased significantly between day 100 and 365 (p=0.010 and p=0.0488, respectively) demonstrating neo-production of T cells by the thymus. Factors associated with high sjTREC concentration 1 year after transplantation included an HLA-matched unrelated donor (p=0.029), a high content of T cells in the graft (p=0.002), and the absence of chronic graft-versus-host disease (p<0.0001). CONCLUSIONS: Our data suggest that while immune recovery is mainly driven by peripheral expansion of the graft-contained mature T cells during the first months after non-myeloablative transplantation, T-cell neo-generation by the thymus plays an important role in long term immune reconstitution in transplanted patients. [less ▲]

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See detailAcute myeloid leukaemia with 8p11 (MYST3) rearrangement : an integrated cytologic, cytogenetic and molecular study by the groupe francophone de cytogénétique hématologique
Gervais, C.; Murati, A.; Helias, C. et al

in Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K (2008), 22(8), 1567-1575

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See detailHyperdiploid karyotypes in acute myeloid leukemia define a novel entity : a study of 38 patients from the Groupe Francophone de Cytogenetique Hematologique (GFCH)
Luquet, I.; Laï, J. L.; Barin, C. et al

in Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K (2008), 22(1), 132-137

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See detailHigh frequency of JAZF1-JJAZ1 gene fusion in endometrial stromal tumors with smooth muscle differentiation by interphase FISH detection
Oliva, E.; de Leval, Laurence ULg; Soslow, R. A. et al

in American Journal of Surgical Pathology (2007), 31(8), 1277-1284

The most common cytogenetic alteration observed in low-grade endometrial stromal tumors (EST) is the t(7;17)(p15.-q21) translocation, resulting in the fusion of the JAZF1 and JJAZ1 genes. By reverse ... [more ▼]

The most common cytogenetic alteration observed in low-grade endometrial stromal tumors (EST) is the t(7;17)(p15.-q21) translocation, resulting in the fusion of the JAZF1 and JJAZ1 genes. By reverse-transcription polymerase chain reaction, the translocation has been detected overall in one-third of ESTs. but only rarely in its variants. The purpose of this study was to develop a fluorescence in situ hybridization assay for detection of this translocation using archival paraffin-embedded samples of ESTs with smooth muscle differentiation and to assess the nature of the smooth Muscle component of these tumors. Representative paraffin blocks of 9 endometrial stromal nodules and I low-grade endometrial stromal sarcoma were collected for the study. In I case, the block selected also contained areas of sex cordlike differentiation. A fluorescence in situ hybridization probe set was designed to detect the t(7;17)(p15;q12) on tissue sections. Six Out of 10 collected ESTs were assessable. Fusion signals were detected in 3 out of 6 cases (50%) in both the conventional endometrial stromal and the smooth muscle components of the tumors. The tumor sample with sex cordlike differentiation harbored the fusion signal in all the 3 components. Out-results Support the contention that the endometrial stromal and smooth muscle components of these tumors have the same ori.-in, either from a common precursor cell with pluripotential differentiation or from endometrial stromal cells that have undergone smooth muscle metaplasia. Our results indicate that the detection of this chromosomal abnormality can be used to diagnose ESTs with smooth muscle differentiation when the smooth muscle component is predominant. [less ▲]

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See detailConsultations in molecular diagnostics - A case of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia with a rare FIP1L1 breakpoint
Lambert, Frédéric ULg; Heimann, Pierre; Herens, Christian ULg et al

in Journal of Molecular Diagnostics (2007), 9(3), 414-419

The idiopathic hypereosinophilic syndrome (HES) has remained for a long time a diagnosis of exclusion. Differential diagnosis between the HES and the related chronic eosinophilic leukemia (CEL) relied on ... [more ▼]

The idiopathic hypereosinophilic syndrome (HES) has remained for a long time a diagnosis of exclusion. Differential diagnosis between the HES and the related chronic eosinophilic leukemia (CEL) relied on the identification of signs of clonality that allowed, when present, the reclassification of patients as CEL. Recently, a new acquired mutation was described in approximately 50% of the HES/CEL patients: a cryptic deletion on chromosome band 4q12 generating a FIP1IL1-PDGFRA fusion gene. According to the World Health Organization classification, this clonal abnormality has been proposed as a new surrogate marker for chronic eosinophilic leukemia diagnosis. Fluorescence in situ hybridization and reverse transcriptase-polymerase chain reaction protocols were developed for an accurate del(4)(q12q12) and FIP1L1-PDGFRA fusion gene detection. Here, we report a patient with a rare FIP1L1 intron 16 breakpoint located outside of the reported FIP1L1 breakpoint region (ie, from FIP1L1 introns 9 to 13). This case illustrates the risk of false-negative results with diagnostic procedures that do not take into account the occurrence of rare FIP1L1 breakpoints. As targeted therapy with tyrosine kinase inhibitors has dramatically changed the prognosis of FIP1L1-PDGFRA (+) CEL, false-negative results could hamper accurate diagnosis and treatment. [less ▲]

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See detailEstablishment and characterisation of two novel human KSHV- and EBV-negative Burkitt cell lines, GAL-01 and GAL-02, from a primary lymphomatous effusion
Thielen, Caroline ULg; Herens, Christian ULg; Fassotte, Marie-France ULg et al

in European Journal of Haematology (2006), 77(4), 318-326

Objectives: Burkitt's lymphoma (BL) is a highly aggressive mature B-cell neoplasm comprising endemic, sporadic and immunodeficiency-associated variants. Human cell lines constitute a very useful tool to ... [more ▼]

Objectives: Burkitt's lymphoma (BL) is a highly aggressive mature B-cell neoplasm comprising endemic, sporadic and immunodeficiency-associated variants. Human cell lines constitute a very useful tool to investigate the biology of lymphoid neoplasia. In this study, we succeeded in establishing two human cell lines, GAL-01 and GAL-02, from a HIV-negative patient with Epstein-Barr virus (EBV) -negative sporadic BL presenting as an effusion. GAL-01 and GAL-02 were established at diagnosis and after one course of polychemotherapy, respectively. The in vivo effusion occurred in a very peculiar clinical setting; the patient having a previous history of intestinal diffuse large B-cell lymphoma. Methods: The morphologic, immunophenotypic and molecular genetic features of GAL cell lines are reported and compared with those of the parental tumour. The findings clearly demonstrated that the Burkitt effusion did not represent disease progression of the intestinal tumour, but represented a second primary haematological malignancy. The in vivo tumorigenic properties of the cells were tested by subcutaneous injection to NOD/SCID mice. Results: Both cell lines were composed of medium-sized lymphoid cells with clumped chromatin, multiple medium-sized nucleoli and moderate amounts of vacuolated cytoplasm. GAL cells display the phenotype and genotype of a B-cell lineage (positive for CD20, CD79a and clonal rearrangement of Ig heavy chain), carry the c-MYC rearrangement by t(8;22)(q24;q11) translocation and are characterised by the expression of the germinal centre-associated antigens CD10, BCL6, CD38 and absent to low BCL2 expression. EBV and HHV8 were not identified within parental tumour or in cultured cells. Subcutaneous injection of both cell lines to NOD/SCID mice induced tumour formation. Conclusions: GAL-01 and GAL-02, two novel EBV-negative human BL cell lines represent a potentially useful experimental model to study the biology of BL possibly including the resistance to chemotherapy. [less ▲]

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