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1.
Eur J Haematol ; 81(3): 218-25, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18510704

ABSTRACT

B-cell lymphomas/leukemias with simultaneous t(14;18)(q32;q21) and MYC rearrangements have recently been shown to constitute a separate diagnostic entity, presenting with a rapid clinical course and a very poor prognosis. We describe the establishment of an Epstein-Barr virus negative cell line, designated U-2973, from a male patient with a de novo aggressive B-cell lymphoma/leukemia and very high peripheral blast cell count. Flow cytometry of bone marrow cells and U-2973 displayed a mature B-cell phenotype, and immunostaining showed expression of MYC and BCL2. IG gene rearrangement data were consistent with a lymphoid neoplasm of germinal centre derivation. Cytogenetic studies using conventional G-banding, fluorescent in situ hybridization, spectral karyotyping and single nucleotide polymorphism array demonstrated a complex karyotype with both a t(14;18) and double translocations between MYC and a non-IG gene partner located at chromosome 12p12.1.


Subject(s)
Cell Line , Chromosomes, Human, Pair 14/genetics , Chromosomes, Human, Pair 18/genetics , Leukemia, B-Cell/genetics , Lymphoma, B-Cell/genetics , Proto-Oncogene Proteins c-myc/genetics , Translocation, Genetic , Adult , Base Sequence , Bone Marrow Cells/pathology , Chromosome Aberrations , Chromosomes, Human, Pair 12/genetics , Cytogenetic Analysis , Flow Cytometry/methods , Genes, Immunoglobulin/genetics , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Leukemia, B-Cell/diagnosis , Leukocyte Count , Lymphoma, B-Cell/diagnosis , Male , Molecular Sequence Data , Oligonucleotide Array Sequence Analysis/methods , Phenotype , Polymorphism, Single Nucleotide/genetics , Proto-Oncogene Proteins c-bcl-2/genetics
2.
Eur J Haematol ; 78(4): 283-9, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17286609

ABSTRACT

Telomere length was recently reported to correlate with cellular origin of B-cell malignancies in relation to the germinal center (GC). In this report, we measured telomere length by quantitative-PCR in 223 B-cell lymphomas/leukemias and correlated results with immunoglobulin (Ig) mutation status and immunostainings for GC/non-GC subtypes of diffuse large B-cell lymphoma (DLBCL). Shortest telomeres were found in Ig-unmutated chronic lymphocytic leukemia (CLL) [median telomere to single copy gene value (T/S) 0.33], differing significantly to Ig-mutated CLL (0.63). Contrary to this, mantle cell lymphomas (MCLs) exhibited similar telomere lengths regardless of Ig mutation status (0.47). Telomere length differed significantly between GC-like (0.73) and non-GC-like DLBCLs (0.43), and follicular lymphomas (FLs) had shorter telomeres (0.53) than GC-DLBCL. Hairy cell leukemias, which display Ig gene intraclonal heterogeneity, had longer telomeres (0.62) than FLs and non-GC-DLBCL, but shorter than GC-DLBCL. We conclude that although DLBCL and CLL subsets can be clearly distinguished, telomere length reflects many parameters and may not simply correlate with GC-related origin.


Subject(s)
Germinal Center/pathology , Immunoglobulins/genetics , Leukemia, B-Cell/genetics , Lymphoma, B-Cell/genetics , Mutation , Telomere/genetics , DNA Mutational Analysis , Humans , Leukemia, B-Cell/diagnosis , Lymphoma, B-Cell/diagnosis , Reverse Transcriptase Polymerase Chain Reaction/methods , Sensitivity and Specificity
3.
Blood ; 109(7): 2989-98, 2007 Apr 01.
Article in English | MEDLINE | ID: mdl-17148579

ABSTRACT

IGHV3-21-using chronic lymphocytic leukemia (CLL) is a distinct entity with restricted immunoglobulin gene features and poor prognosis and is more frequently encountered in Northern than Southern Europe. To further investigate this subset and its geographic distribution in the context of a country (Italy) with both continental and Mediterranean areas, 37 IGHV3-21 CLLs were collected out of 1076 cases enrolled by different institutions from Northern or Central Southern Italy. Of the 37 cases, 18 were identified as homologous (hom)HCDR3-IGHV3-21 CLLs and were found almost exclusively (16 of 18) in Northern Italy; in contrast, 19 nonhomHCDR3-IGHV3-21 cases were evenly distributed throughout Italy. Clinically, poor survivals were documented for IGHV3-21 CLLs as well as for subgroups of mutated and homHCDR3-IGHV3-21 CLLs. Negative prognosticators CD38, ZAP-70, CD49d, and CD79b were expressed at higher levels in homHCDR3 than nonhomHCDR3-IGHV3-21 cases. Differential gene expression profiling (GEP) of 13 IGHV3-21 versus 52 non-IGHV3-21 CLLs identified, among 122 best-correlated genes, TGFB2 and VIPR1 as down- and up-regulated in IGHV3-21 CLL cases, respectively. Moreover, GEP of 7 homHCDR3 versus 6 nonhomHCDR3-IGHV3-21 CLLs yielded 20 differentially expressed genes, with WNT-16 being that expressed at the highest levels in homHCDR3-IGHV3-21 CLLs. Altogether, IGHV3-21 CLLs, including those with homHCDR3, had a peculiar global phenotype in part explaining their worse clinical outcome.


Subject(s)
Immunoglobulin Heavy Chains/genetics , Immunoglobulin Variable Region/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Amino Acid Sequence , Base Sequence , Case-Control Studies , DNA Primers/genetics , Female , Gene Expression Profiling , Gene Frequency , Gene Rearrangement, B-Lymphocyte, Heavy Chain , Genes, Immunoglobulin Heavy Chain , Humans , Italy/epidemiology , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Male , Middle Aged , Molecular Sequence Data , Mutation , Prognosis , Sequence Homology, Amino Acid , Survival Rate
4.
Blood ; 107(7): 2889-94, 2006 Apr 01.
Article in English | MEDLINE | ID: mdl-16317103

ABSTRACT

We recently reported that Swedish VH3-21-using chronic lymphocytic leukemia (CLL) patients showed restricted immunoglobulin gene features and poor prognosis despite VH mutation status. To investigate this further, we analyzed the VH and VL gene rearrangements in 90 VH3-21+ patients from Sweden, Germany, Italy, United States, Finland, and Australia and correlated these data with survival and other prognostic markers. Sixty-three percent exhibited mutated VH genes and 37% unmutated VH genes. Fifty (56%) patients displayed a short and homologous heavy-chain CDR3, many of these with the amino acid motif DANGMDV. Also, a highly biased Vlambda2-14 use was evident in 72% of patients with a restricted light-chain CDR3, QVWDS(S/G)SDHPWV. Combined restricted heavy- and light-chain CDR3s were found in patients from all included countries. Although VH3-21+ CLLs have a remarkably predominant lambda expression, analyses of kappa deleting element indicated a conserved light-chain rearrangement order. The overall survival was poor in the VH3-21+ cohort (median survival, 88 months), with no significant difference in relation to mutation status or CDR3 homology. High ZAP-70 and CD38 expression was found in both mutated and unmutated VH3-21+ cases as well as a slight increase of 11q-aberrations. In summary, highly restricted B-cell receptors and worse outcome characterize VH3-21+ CLLs independent of geographic origin and mutation status.


Subject(s)
Immunoglobulin Heavy Chains/genetics , Immunoglobulin Light Chains/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Amino Acid Sequence , Australia , Chromosome Aberrations , Europe , Geography , Humans , Immunoglobulin Fragments/chemistry , Immunoglobulin Fragments/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Molecular Sequence Data , Mutation , Survival Analysis , Treatment Outcome , United States
5.
Leuk Res ; 29(2): 153-8, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15607363

ABSTRACT

Hairy cell leukemia (HCL) is thought to arise from a post-germinal center (GC) B-cell, however the exact normal counterpart remains unclear. We performed VH gene analysis of 32 HCL cases, revealing somatically mutated VH genes (<98% homology) in 27 cases and unmutated VH genes in five cases, four of which displayed germline VH genes. Intraclonal heterogeneity was evident in the majority of eight mutated HCLs investigated, although at a lower level compared to GC-derived lymphomas. A novel finding of preferential VH3-30 gene usage was detected (19% of HCLs). Our data confounds the postulated post-GC origin in HCL considering (1) the finding of unmutated HCLs, generally correlating with a pre-GC origin, and (2) the presence of intraclonal variation in mutated HCLs. The latter suggests that the transformed B-cell was frozen when it still had an active mutation process, implying a closer relation to the GC than previously assumed. Furthermore, restricted VH3-30 usage indicates that antigen selection could be a promoting factor in HCL development.


Subject(s)
Gene Rearrangement, B-Lymphocyte, Heavy Chain , Immunoglobulin Heavy Chains/genetics , Leukemia, Hairy Cell/genetics , Somatic Hypermutation, Immunoglobulin/genetics , Adult , Aged , Aged, 80 and over , Base Sequence , Female , Humans , Immunoglobulin Heavy Chains/analysis , Leukemia, B-Cell/genetics , Leukemia, B-Cell/immunology , Leukemia, B-Cell/pathology , Leukemia, Hairy Cell/immunology , Leukemia, Hairy Cell/pathology , Male , Middle Aged , Molecular Sequence Data
6.
Mod Pathol ; 18(3): 331-9, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15257315

ABSTRACT

A preferential use of one particular immunoglobulin variable heavy chain gene, V(H)3-21, has recently been reported in mantle cell lymphoma, where almost all of these V(H)3-21+ mantle cell lymphomas showed usage of the same light chain Vlambda gene (Vlambda3-19) and also had a tendency towards improved prognosis. These findings suggested that V(H)3-21+ mantle cell lymphomas constitute a distinct subgroup, possibly with antigen stimulation involved in disease pathogenesis. In this study, we applied the comparative genomic hybridization (CGH) method on 37 mantle cell lymphoma tumors in order to investigate if the V(H)3-21+ tumors are different at the genomic level. Interestingly, V(H)3-21+ mantle cell lymphomas (n=14) showed significantly fewer genomic aberrations (mean 2.4) compared to non-V(H)3-21 mantle cell lymphomas (n=23) (mean 4.9). The chromosomal aberrations identified in our study were generally in accordance with previous CGH studies of mantle cell lymphoma; the most frequent aberration was complete or partial loss of chromosome 13, followed by recurrent losses within 6q, 9p, 9q and 11q and frequent gains in 3q, 7p, 8q and 15q. Deletions within 8p and 9p as well as gains in 7p and 15q were found exclusively in the non-V(H)3-21-utilizing tumors. In summary, V(H)3-21+ mantle cell lymphomas demonstrated both a lower number and a different spectrum of genomic aberrations than mantle cell lymphoma in general, thus supporting the hypothesis that V(H)3-21+ mantle cell lymphomas constitute a new subgroup. The findings presented in this report may explain the tendency for a better clinical outcome for patients whose tumors utilize V(H)3-21.


Subject(s)
Gene Rearrangement , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Variable Region/genetics , Loss of Heterozygosity , Lymphoma, Mantle-Cell/genetics , Aged , Aged, 80 and over , Chromosome Aberrations , Female , Humans , Lymphoma, Mantle-Cell/pathology , Male , Middle Aged , Nucleic Acid Hybridization/methods , Survival Analysis
7.
Blood ; 101(10): 4047-54, 2003 May 15.
Article in English | MEDLINE | ID: mdl-12637326

ABSTRACT

Mantle cell lymphoma (MCL) is believed to originate from a naive B cell. However, we recently demonstrated that a subset of MCL displayed mutated V(H) genes. We also reported restricted use of certain V(H) genes. To assess the prognostic impact of these new findings, we performed V(H) gene analysis of 110 patients, revealing that 18 (16%) patients had mutated and 92 (84%) patients had unmutated V(H) genes. Because the mutation rate was low in the mutated group (2.2%-6.7%), further investigation of the germline V(H) gene in T cells from 5 patients with mutated V(H) genes was carried out; results showed that the unrearranged V(H) gene was identical to the published sequence. These data confirm that the base pair substitutions within the rearranged V(H) genes represent hypermutations, and indicate germinal center exposure. However, V(H) gene mutation status did not correlate with prognosis because there was no difference in clinical outcome between the unmutated and mutated groups. The most frequently used V(H) genes were V(H)3-21 (21 patients) and V(H)4-34 (19 patients). A novel finding was that V(H)3-21(+) MCL almost exclusively expressed lambda light chains and displayed highly restricted use of the V(lambda)3-19 gene. V(H)3-21(+) patients had longer median survival than the remaining patients (53 vs 34 months; P =.03), but they tended to be younger at diagnosis. The combined use of V(H)3-21/V(lambda)3-19 suggests a possible role for antigen(s) in the pathogenesis of these tumors and indicates that V(H)3-21(+) patients constitute a new MCL entity.


Subject(s)
Genes, Immunoglobulin , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Variable Region/genetics , Lymphoma, Mantle-Cell/genetics , Lymphoma, Mantle-Cell/immunology , Mutation , Adult , Aged , Aged, 80 and over , DNA Primers , Female , Humans , Immunoglobulin Light Chains/genetics , Lymphoma, Mantle-Cell/classification , Lymphoma, Mantle-Cell/mortality , Male , Middle Aged , Neoplasm Staging , Polymerase Chain Reaction , Retrospective Studies , Survival Analysis , Time Factors
8.
Eur J Haematol ; 68(4): 217-24, 2002 Apr.
Article in English | MEDLINE | ID: mdl-12071937

ABSTRACT

Mantle cell lymphoma (MCL) is considered to derive from naïve, pregerminal center (GC) CD5+ B-cells. However, the cell of origin has been questioned in recent studies that showed somatic hypermutations in the immunoglobulin (Ig) variable heavy chain (V(H)) genes in subsets of MCL. To clarify this issue, we analyzed the IgV(H) genes for the presence of somatic hypermutations in 51 MCL cases. Twenty percent of the MCL cases displayed somatically mutated V(H) genes (defined as >2% mutated), whereas 80% showed unmutated V(H) genes. This finding suggests that MCL is a genetically heterogeneous disease, with the majority of cases originating from unmutated pre-GC B-cells and a subset deriving from more mature B-cells which have been exposed to the GC environment and have undergone somatic hypermutation. A biased V(H) gene usage has been demonstrated in several B-cell malignancies; however, this has not yet been investigated in MCL, although V(H)4-34 overusage has been indicated by small studies. Interestingly, we found a restricted usage of three individual V(H) genes in our MCL material; V(H)4-34 (22%), V(H)3-21 (16%) and V(H)5-51 (12%). This novel finding of preferential V(H) gene usage in half of the MCL cases may suggest an antigen driven process occurring in B-cells expressing specific VH genes, thus implicating that Ig specificity could be involved in mantle cell lymphoma development.


Subject(s)
Genes, Immunoglobulin , Immunoglobulin Variable Region/genetics , Lymphoma, Mantle-Cell/genetics , Somatic Hypermutation, Immunoglobulin , Adult , Aged , Aged, 80 and over , Base Sequence , Female , Humans , Male , Middle Aged , Molecular Sequence Data , Polymerase Chain Reaction
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