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G Gaidano

Publications and source records attributed to G Gaidano.

At least 109 records · Page 6Linked to original sources
PubMed1996

Distribution of TP53 mutations among acute leukemias with MLL rearrangements.

Acute leukemias carrying MLL rearrangements are characterized by a high degree of clinical and immunologic heterogeneity, as demonstrated by variability in their immunophenotype, consistent with lymphoid or myeloid/monoblastic derivation, as well as their occurrence in distinct age groups from infancy to adulthood. Recently, it was shown that inactivation of the TP53 tumor suppressor gene occurs frequently in cases of acute lymphoblastic leukemia carrying MLL rearrangements. In order to assess the extent of TP53 inactivation throughout the immunophenotypic and clinical spectrum of MLL+ acute leukemias, we tested for TP53 mutations 29 cases of MLL+ acute leukemias displaying lymphoid (13 cases) or myeloid/monoblastic (16 cases) features and belonging to different age groups. Mutations were detected in 6/16 myeloid/monoblastic cases and in 3/13 lymphoid cases. Among myeloid/monoblastic leukemias, the TP53 mutations occurred in 3/4 infants, but only in 3/16 cases in other age groups. Overall, our data suggest that (1) TP53 inactivation is a relatively common event in leukemias with MLL rearrangements irrespective of the leukemic phenotype and of the patients' age; (2) at least two genetic lesions (i.e., MLL rearrangement and TP53 mutation) have accumulated in the short time (few weeks after the birth or conception of the child) corresponding to the development of acute leukemias of infancy.

Acute Disease↗
PubMed1996

Molecular heterogeneity of B-lineage diffuse large cell lymphoma.

B-lineage diffuse large cell lymphoma (B-DLCL) arising de novo is characterized by a marked degree of clinical heterogeneity. To determine whether or not the clinical heterogeneity of de novo B-DLCL is reflected by heterogeneity in the molecular features of these tumors, we investigated the pattern of distribution of several genetic lesions in 70 cases of de novo B-DLCL at diagnosis. The panel of genetic lesions tested comprised the molecular alterations most frequently detected in B-DLCL, including rearrangements of BCL2, BCL6, and MYC as well as deletions of 6q and mutations of TP53. One or more genetic lesions were detected in 39/70 cases of B-DLCL. Isolated structural alterations of BCL2, BCL6, 6q or TPS3 were detected in 8/70, 10/70, 11/70, and 3/70 cases, respectively. No isolated MYC lesions were detected. Six cases carried different combinations of two genetic lesions, including lesions of BCL2 + BCL6 (1 case), BCL2 + MYC (1 case), BCL2 + 6q (2 cases), or BCL6 + 6q (2 cases). One case had accumulated three genetic lesions, namely a rearrangement of BCL2 and BCL6 and a mutation of TPS3. Overall, these data show that multiple distinct patterns of genetic lesions may associate with de novo B-DLCL, indicating that the molecular pathogenesis of this group of lymphomas is characterized by a high degree of molecular heterogeneity.

Chromosome Deletion↗
PubMed1996

Analysis of microsatellite instability in chronic lymphoproliferative disorders.

Microsatellite instability (MSI) represents one specific pattern of genomic instability and is one of the genetic lesions most frequently detected in human neoplasia. Although MSI has been found to be associated with a wide variety of solid cancers, its involvement in lymphoid malignancies is virtually unexplored. In this study, we have investigated the presence of MSI in chronic lymphoproliferative disorders by comparing the pattern of nine microsatellite repeats (two tetranucleotides, two trinucleotides, and five dinucleotides) on autologous germline and tumor DNA of 23 patients, including 17 with B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL), four with hairy cell leukemia, one with lymphoplasmacytoid lymphoma, and one with T-cell chronic lymphocytic leukemia. All samples at diagnosis displayed a germline pattern of the microsatellites examined, thus suggesting that MSI is not involved in the pathogenesis of these lymphoproliferations. Also, no microsatellite alterations were observed in consecutive samples of B-CLL/SLL obtained from the same patient at various stages of the disease both before and after chemotherapy. Conversely, alterations in 3/9 microsatellite repeats were detected in one case of Richter's syndrome which had evolved from a pre-existent B-CLL/SLL phase. Overall, the low frequency of MSI among chronic lymphoproliferative disorders adds further weight to the common view that the mechanisms and patterns of genomic instability in lymphoid neoplasia differ markedly from those commonly observed in solid cancers.

Base Sequence↗
PubMed1996

Persistence of E2A/PBX1 transcripts in t(1;19) childhood acute lymphoblastic leukemia: correlation with chemotherapy intensity and clinical outcome.

The occurrence of t(1;19) translocation was investigated by reverse transcriptase-polymerase chain reaction (RT-PCR) for the E2A/PBX1 hybrid message in a panel of 37 consecutive childhood acute lymphoblastic leukemias (ALLs). Three patients with B-precursor ALL were found to be positive at diagnosis and were re-tested during follow-up to assess the presence of minimal residual disease (MRD). Two of them became PCR-negative during treatment, whereas one remains positive 3 years after diagnosis. Since all three patients are presently in clinical and hematological complete remission, PCR detection of persistent E2A/ PBX1 transcript does not seem to affect significantly the DFS at 3 years. However, the predictivity for an eventual late relapse still remains to be assessed.

Adolescent↗
PubMed1996

Kaposi's sarcoma-associated herpesvirus DNA sequences in AIDS-related and AIDS-unrelated lymphomatous effusions.

Primary effusions presenting as the sole lymphoma localization are also known as body-cavity-based-lymphoma (BCBL), and have been shown to carry Kaposi's sarcoma herpesvirus (KSHV) DNA sequences. The aim of this study was a comparative analysis of the clinical, pathologic and molecular features of BCBL and lymphomatous effusions secondary to tissue-based lymphomas occurring both in the general population and in HIV-1-infected individuals. All the lymphomatous effusion samples (seven AIDS-related and nine AIDS-unrelated) were subjected to an identical multiparameter investigation, including collection of clinical data, analysis of morphology and immunophenotype, as well as the study of viral sequences and genetic lesions. In six cases defined as BCBL (four AIDS-related and two AIDS-unrelated), the patients exhibited exclusive or predominant involvement of the body cavities. BCBL tended to display indeterminate phenotypes (4/6), whereas all AIDS-related and AIDS-unrelated lymphomatous effusions secondary to tissue-based lymphomas consistently expressed B-cell phenotype. Detection of KSHV DNA sequences was restricted to cases of BCBL (3/4 AIDS-related and 1/2 AIDS-unrelated), whereas EBV association (3/4) and expression of EBV-encoded antigens (LMP-1, 2/3; EBNA-2, 1/3) were confined to the AIDS-related BCBL. Overall, our results confirm that both AIDS-related and AIDS-unrelated BCBL preferentially associate with peculiar clinical, immunophenotypic and molecular features among lymphomatous effusions and therefore should be singled out as a specific clinico-pathologic entity.

Adult↗
PubMed1996

Distribution of human herpesvirus-8 sequences throughout the spectrum of AIDS-related neoplasia.

OBJECTIVE: AIDS frequently associates with certain malignancies, including Kaposi's sarcoma, non-Hodgkin's lymphoma (NHL), and anogenital neoplasia. In this study we aimed to define the frequency of infection by human herpesvirus (HHV)-8 throughout the spectrum of AIDS-related neoplasia in Europe. DESIGN: A tumour panel representative of the distinct types of AIDS-related neoplasms was tested for the presence of HHV-8 DNA sequences. Autologous uninvolved tissues were also tested in selected cases. METHODS: The presence of HHV-8 DNA sequences was assayed by a combination of polymerase chain reaction followed by oligohybridization and Southern blot hybridization of genomic DNA with an HHV-8-specific probe. RESULTS: HHV-8 sequences were detected in 100% of AIDS-related Kaposi's sarcoma (all 35 cases). Among AIDS-related NHL, HHV-8 sequences selectively clustered with body-cavity-based lymphomas (BCBL; all three cases), although they were consistently negative in small non-cleaved cell lymphomas (none in 18 cases), diffuse large cell lymphomas (none in seven), or anaplastic large cell lymphomas (none in three). No HHV-8 sequences were found in cases of anogenital neoplasia (out of 14) or Hodgkin's disease (out of three). HHV-8 DNA sequences were also positive in the uninvolved skin of all six AIDS-related Kaposi's sarcoma patients, but not in the circulating lymphocytes of a BCBL patient. Positivity for HHV-8 sequences occurred in patients belonging to all major AIDS risk categories. CONCLUSIONS: These data confirm that HHV-8 sequences associate at high frequency with selected types of AIDS-related neoplasia, namely Kaposi's sarcoma and BCBL, although they are consistently absent in other types of AIDS-NHL and AIDS-related anogenital neoplasia.

AIDS-Related Opportunistic Infections↗
PubMed1996

AIDS-related non-Hodgkin's lymphomas: molecular genetics, viral infection and cytokine deregulation.

AIDS-related non-Hodgkin's lymphomas (AIDS-NHLs) are almost invariably derived from B cells and are grouped into three distinct histologic categories, including small-non-cleaved-cell lymphoma (SNCCL), diffuse large-cell lymphoma (DLCL), and anaplastic large-cell lymphoma (ALCL). In addition, AIDS-NHLs presenting solely as a body cavity effusion are thought to be a peculiar clinicopathologic entity and are defined as body-cavity-based lymphoma (BCBL). At the biologic level, AIDS-related lymphomagenesis is characterized by activation of proto-oncogenes, inactivation of tumor suppressor genes, viral infection of the tumor clone, and deregulated cytokine production. Distinct AIDS-NHL types associate with specific molecular pathways. The first pathogenetic pathway clusters with AIDS-SNCCL, and is characterized by a relatively mild degree of host immunodeficiency. AIDS-SNCCL consistently associates with c-myc rearrangements and p53 inactivation in 100 and 60% of cases, respectively, whereas infection by Epstein-Barr virus (EBV) is restricted to 30% of the cases. Production of high levels of interleukin-10 is an additional peculiar feature of EBV-positive AIDS-SNCCL. The second pathogenetic pathway associates with AIDS-DLCL, which is usually accompanied by marked host immunodeficiency. AIDS-DLCL is characterized by EBV infection in the large majority of cases and by the mutually exclusive presence of bcl-6 rearrangements and c-myc translocations in 40% of the cases. A third pathway characterizes AIDS-BCBL, which associates in virtually all cases with infection by EBV and with the presence of DNA sequences of the recently identified Kaposi sarcoma herpesvirus in the apparent absence of other known genetic lesions. Finally, the pathogenetic features of AIDS-ALCL are still under investigation.

Cytokines↗
PubMed1996

Morphologic patterns and molecular pathways of AIDS-related head and neck and other systemic lymphomas.

Head and neck manifestations of human immunodeficiency virus (HIV) infection include lymph nodal and extranodal localization of non-Hodgkin's lymphoma (NHL). A histopathologic characteristic common to head and neck NHLs and to all the other systemic lymphomas in HIV patients is the frequent occurrence of cases displaying pleomorphic features and some overlap between established histologic subtypes. This article highlights the difficulties in defining HIV-related NHLs correctly, and proposes a specific pathologic categorization of these disorders accounting for their pathogenic aspects as gathered from molecular data.

Acquired Immunodeficiency Syndrome↗
PubMed1996

AIDS-related Burkitt's-type lymphomas are a target for lymphokine-activated killers induced by interleukin-2 and prolactin.

The development of non-Hodgkin's lymphomas (NHL) is one of the major complications of AIDS. Although several biologic aspects of AIDS-related NHL have been clarified, their sensitivity to immune system cytotoxic effectors has not been tested. In this study, we have investigated the susceptibility of one major AIDS-related NHL type, Burkitt's-type lymphoma (BL), to the cytotoxic activity of lymphokine-activated killers (LAK) and prolactin-activated killers (PAK), which were generated from peripheral blood mononuclear cells upon stimulation with interleukin-2 (in the case of LAK cells) and prolactin (in the case of PAK cells). The sensitivity of AIDS-related BL to in vitro raised cytotoxic effectors was compared with that of BL variants of the general population, including sporadic BL and endemic BL. The data show that AIDS-related BL is susceptible to cytolysis by LAK cells, whereas both LAK and PAK cells can efficiently kill endemic BL. In contrast, sporadic BL showed resistance to all cytotoxic effectors tested. Intriguingly, in the case of AIDS-related and endemic BL suboptimal doses of interleukin-2 in combination with prolactin displayed a cytotoxic effect similar to that of LAK cells, suggesting a synergistic activity of the two agents. Overall, these data corroborate the notion that the distinct BL variants differ in their biologic features despite their morphologic and genetic similarity.

Burkitt Lymphoma↗
PubMed1996

Association of 6q deletions with AIDS-related diffuse large cell lymphoma.

Deletions of chromosome 6 at band q27 represent the site of a putative novel tumor suppressor gene in non-Hodgkin's lymphomas (NHL) of the immunocompetent host. Although several genetic lesions have been identified in AIDS-related NHL (AIDS-NHL), the involvement of 6q27 loss has not been investigated in this NHL category. In this report, we tested the presence of a 6q deletion at the molecular level in a panel of AIDS-NHL representative of the major histologic types, including AIDS-related small non-cleaved cell lymphoma (AIDS-SNCCL; n = 10), AIDS-related diffuse large cell lymphoma (AIDS-DLCL; n = 13) and AIDS-related anaplastic large cell lymphoma (AIDS-ALCL; n = 3). We report that 6q deletions occur in 5/26 AIDS-NHL tested (19.2%). Notably, 6q deletions do not randomly distribute throughout the spectrum of AIDS-NHL histologic types, but rather selectively cluster with AIDS-DLCL (5/13; 38.4%). Overall, these data add to the notion that the molecular pathogenesis of AIDS-NHL is heterogeneous and that distinct genetic pathways associate with specific histologic categories of AIDS-NHL.

Blotting, Southern↗
PubMed1996

Establishment of AIDS-related lymphoma cell lines from lymphomatous effusions.

AIDS-related non-Hodgkin lymphomas (AIDS-NHL) are most frequently derived from B cells and include small non-cleaved cell lymphoma (SNCCL) and diffuse large cell lymphoma (DLCL) and less frequently anaplastic large cell lymphoma (ALCL) or body cavity-based lymphoma (BCBL). AIDS-NHL cell lines have proved useful to study AIDS-NHL pathogenesis. In this report, we describe the establishment and molecular characterization of two novel AIDS-NHL cell lines (HBL-4 and HBL-6) derived from lymphomatous effusions. HBL-4 was derived from a patient with SNCCL, whereas HBL-6 was derived from a patient with BCBL. The identity of the cell lines with the original tumor clone was established by immunoglobulin gene rearrangement analysis. Both HBL-4 and HBL-6 carry a monoclonal EBV infection and do not contain HIV. In addition, HBL-6 harbors DNA sequences of the recently identified Kaposi's sarcoma-associated herpesvirus (KSHV), now formally called human herpesvirus 8 (HHV8). Finally, HBL-4, but not HBL-6, harbors a rearranged c-MYC allele, while the BCL-6 gene displayed a germline configurations in both cell lines. These AIDS-NHL cell lines may prove useful in understanding the biologic events contributing to AIDS-NHL development.

Ascitic Fluid↗
PubMed1995

Cellular origin, antigen reactivity, and VH segment structure of IgM mAbs from AIDS lymphomas.

In the present studies we analyzed the Ag specificity, VH gene structure, and cellular origin of three IgM mAb-producing cell lines established in vitro from bioptic specimens of three AIDS patients with BL. We found that (i) both HBL-2 and HBL-3 IgM mAbs were cold agglutinins highly specific for the i blood group determinant, a self Ag the expression of which is dominant in the early stages of life, and both mAbs used somatically point-mutated VH 4-21 segments; (ii) HBL-1 IgM mAb, the Ag-specificity of which has not been determined, used a putatively mutated member of the VHIII family; and (iii) both HBL-1 and HBL-2, but not HBL-3, cells expressed CD5 mRNA, suggesting a B-1 cell origin. The utilization of VH4-21 by the HBL-2 and HBL-3 cold agglutinins is consistent with the usage of this gene segment by all the reported pathogenic except the naturally occurring cold agglutinins. This restricted VH gene usage may reflect an inherent affinity of the germline VH4-21 gene product for the i/I carbohydrate structure, and, perhaps, an overrepresentation of VH4-21 in the human early and late B-cell repertoire. Consistent with both an early and late developmental expression of the VH4-21 gene is the B-1 and B-2 cellular origin of the two VH4-21+ cold agglutinins reported here. Thus, the two cold agglutinin autoantibodies possibly emerged at different stages of the natural history of the B-cell repertoires of these patients and might display a different temporal relationship, as discussed below, to the time of emergence of the respective tumoral cells. The somatically mutated status of the HBL-2 and HBL-3 mAb VH segments was suggested by the monomorphism of the human VH4-21 gene, the extension of the nucleotide differences to the, in general, highly conserved JH segment; and it was formally proved in HBL-3 mAb. Positive selection by Ag of the R mutations in the HBL-2 and HBL-3 mAb VH segments was suggested by the differential R:S mutation ratios in the CDRs and FRs (HBL-2 mAb, 5.0 and 1.1, respectively; HBL-3 mAb, 2.2 and 0.3, respectively) but not substantiated by appropriate statistical analysis according to the binomial distribution model.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1995

High frequency of EBV association with non-random abnormalities of the chromosome region 1q21-25 in AIDS-related Burkitt's lymphoma-derived cell lines.

Chromosome 1q abnormalities represent the second most frequent cytogenetic lesion of Burkitt lymphoma (BL) and acute lymphoblastic leukemia (ALL)-L3. The most frequent change is partial duplication of the long arm of chromosome 1, involving variable bands but consistently including 1q23. Among AIDS-related BL similar chromosome 1q abnormalities have also been found. We have now characterized in detail the chromosome 1q abnormalities of 4 AIDS-BL cell lines and compared them to other molecular features of the tumor clone, namely infection by Epstein Barr virus (EBV). Immunophenotypic characteristics were also assessed by conventional in situ immunocytochemical and flow cytometric procedures. The B-cell origin of all cell lines was demonstrated by the expression of B-cell-restricted markers (e.g., CD19). Analysis of Ig light chains confirmed their monoclonal nature. The t(8;14) was present in 3 of the 4 lines, whereas variant translocation t(8;22) was detected in the remaining cell line. Additional chromosomal changes were found in all cases, with chromosome 1 being involved in all. Structural changes encompassed in each case the 1q21-25 bands, in either duplication or partial trisomy. EBER ISH studies identified EBV association in 3 of the 4 AIDS-BL cell lines in contrast to previous studies of BL of immunocompetent individuals. Our findings of a high frequency of chromosome 1q abnormalities in EBV-infected AIDS-related BL cell lines demonstrate that such chromosomal abnormality and EBV positivity are not mutually exclusive and are possibly independent factors, whereas their close association in AIDS may be related to the immunodeficiency.

Burkitt Lymphoma↗