Biomedical subjects

N Carbuccia

Publications and source records attributed to N Carbuccia.

8 recordsLinked to original sources

PubMed2006

Gene expression profiling identifies molecular subgroups among nodal peripheral T-cell lymphomas.

The classification of peripheral T-cell lymphomas (PTCL) is still a matter of debate. To establish a molecular classification of PTCL, we analysed 59 primary nodal T-cell lymphomas using cDNA microarrays, including 56 PTCL and three T-lymphoblastic lymphoma (T-LBL). The expression profiles could discriminate angioimmunoblastic lymphoma, anaplastic large-cell lymphoma and T-LBL. In contrast, cases belonging to the broad category of 'PTCL, unspecified' (PTCL-U) did not share a single molecular profile. Using a multiclass predictor, we could separate PTCL-U into three molecular subgroups called U1, U2 and U3. The U1 gene expression signature included genes known to be associated with poor outcome in other tumors, such as CCND2. The U2 subgroup was associated with overexpression of genes involved in T-cell activation and apoptosis, including NFKB1 and BCL-2. The U3 subgroup was mainly defined by overexpression of genes involved in the IFN/JAK/STAT pathway. It comprised a majority of histiocyte-rich PTCL samples. Gene Ontology annotations revealed different functional profile for each subgroup. These results suggest the existence of distinct subtypes of PTCL-U with specific molecular profiles, and thus provide a basis to improve their classification and to develop new therapeutic targets.

Gene Expression Profiling↗

PubMed1999

Simple variant t(8;21) acute myeloid leukemias harbor insertions of the AML1 or ETO genes.

We report on the molecular characterization of two acute myeloid leukemias (AML), one AML-M1 (patient 1) and one AML-M2 (patient 2) with t(8;21)(p21;q22) and t(8;20)(q22;p13), respectively, at diagnosis. The locations of the breakpoints, 21q22 in patient 1 and 8q22 in patient 2, prompted us to search for a cryptic t(8;21)(q22;q22) and involvement of the AML1 and ETO genes. Dual-color fluorescence in situ hybridization (FISH) using whole chromosome painting probes for chromosomes 8, 20, and 21 confirmed the conventional cytogenetic karyotypes. However, dual-color FISH using appropriate ETO and AML1 probes disclosed an insertion of AML1 into 8q22 on the derivative chromosome 8 in patient 1 and of ETO into 21q22 on one chromosome 21 in patient 2, leading to AML1-ETO fusion signals. Both cases expressed an AML1-ETO transcript, shown by reverse transcriptase polymerase chain reaction and cDNA sequencing. Creation of functional AML1-ETO fusion genes in these two simple variant t(8;21) probably occurred through complex mechanisms, combining translocation and insertion of chromosomal segments.

Adolescent↗

PubMed1995

Unbalanced translocation t(5;17) in an typical acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL; M3 in the FAB classification) is specifically associated with the t(15;17)(q23;q12) and the consequent formation of a PML/RARA fusion gene. A few cases of APL with a t(11;17)(q23;q12) and a PLZF/RARA fusion gene have recently been reported. In addition, a new variant, t(5;17)(q32;q12), with a RARA rearrangement was described in a child with atypical APL. We report an unbalanced der(5)t(5;17) in an atypical APL case showing unusual dysgranulopoiesis and some M2 features. The breakpoints were difficult to localize precisely on chromosome 5, because the translocation may have occurred on a previous del(5q). The karyotype also showed del(8q) and multiple double-minutes (dmin). Molecular studies evidenced RARA rearrangement but showed neither PML rearrangement nor PML/RARA fusion. Fluorescence in situ hybridization revealed that the dmin were of chromosome 8 origin and that they accounted for the MYC amplification observed in Southern blots. The patient did very poorly despite chemotherapy and all-trans retinoic acid (ATRA) treatment. Thus, the t(5;17) could represent a second type of variant translocation in APL that, like the disease associated with t(11;17), does not seem to respond to ATRA therapy. Whereas RARA rearrangement appears sufficient for an APL-like phenotype, it seems that the presence of a classical PML/RARA is required for typical APL with response to ATRA.

Aged↗

PubMed1995

Search for rearrangements and/or allelic loss of the fas/APO-1 gene in 101 human lymphomas.

The authors analyzed the possible occurrence of rearrangements and/or allelic loss of the fas/APO-1 gene in a representative series of human lymphomas, including 101 cases of Hodgkin's disease (HD) and non-Hodgkin's lymphomas (NHL). The rationale for this study was double. Chromosome 10 alterations, frequently observed in lymphoma subtypes, encompass the chromosomal localization of fas/APO-1. In addition, Ipr mouse mutants, which present with a generalized lymphoproliferative disease, were shown to exhibit alterations of fas/APO-1 structure and expression. In this retrospective study, the authors performed gene dosage of fas/APO-1 by Southern blots. No fas/APO-1 alterations were observed in the 31 HD cases. Among 70 T-cell and B-cell NHL, allelic loss of fas/APO-1 was observed in three cases. Two cases with different clinical, phenotypic, and histologic presentations showed a rearrangement of fas/APO-1. A third case showed amplification. Thus fas/APO-1 alterations do occur in human lymphomas, although at a relatively low frequency.

Alleles↗

PubMed1995

Frequent expression of FAS/APO-1 in Hodgkin's disease and anaplastic large cell lymphomas.

FAS/APO-1 (CD95) is a membrane glycoprotein belonging to the tumour necrosis factor/nerve growth factor receptor family, and which can trigger apoptosis in some lymphoid cell lines. Immunohistochemistry combined with Northern blotting allowed determination of the pattern of FAS/APO-1 expression in a series of Ki-1 [CD30] positive lymphoid malignancies, including 27 Hodgkin's disease and eight anaplastic large cell lymphomas. CD30 negative tumours used as controls included 27 B-cell non-Hodgkin's lymphomas. 14 T-cell non-Hodgkin's lymphomas, four reactive lymphadenitis, and non-lymphoid tissues. Immunohistochemistry, performed on frozen sections, revealed a strong FAS/APO-1 expression in 25 out of 27 (92%) Hodgkin's disease cases, predominantly in Reed Sternberg cells; 50 to 100% of the neoplastic cells in eight out of (100%) anaplastic large cell lymphoma cases were positive. In contrast, positive FAS/APO-1 immunostaining was observed only in 22 out of 41 (53%) CD30 negative non-Hodgkin's lymphomas. Northern blot analysis detected variable amounts of the FAS/APO-1 transcript in the immunohistochemistry-positive samples. These results suggest possible hyper-expression of FAS/APO-1 (CD95) in Hodgkin's disease and anaplastic large cell lymphomas.

Gene Expression Regulation, Neoplastic↗

PubMed1994

The expression of FMS, KIT and FLT3 in hematopoietic malignancies.

Three receptor molecules, belonging to the class III of receptor tyrosine kinases, namely the receptors for colony-stimulating factor 1, CSF1R (product of the FMS proto-oncogene) and Steel factor, SLFR (product of the KIT proto-oncogene), as well as the recently identified FLT3/FLK2 gene product, appear to play distinct roles in normal hematopoietic differentiation. Their potential role in leukemic hematopoiesis has been approached by expression studies in hematopoietic malignancies, especially in acute leukemias of the myeloid and lymphoid lineages. We present here a review of available data, and discuss the possible significance and potential applications of these results.

Acute Disease↗

PubMed1992

Monensin action on the Golgi complex in perfused rat liver: evidence against bile salt vesicular transport.

Several studies suggest that bile salts are transported from the basolateral to the canalicular membrane of hepatocytes by a vesicular pathway, possibly in part via the Golgi complex. To test this hypothesis, the present study examined, in the perfused rat liver, the influence of the Na+ ionophore monensin on the biliary secretion of taurocholate and biliary lipids. The effects of the drug have been checked by the study of the ultrastructural modifications of the Golgi complex, secretion of horseradish peroxidase, and bile salt uptake. An infusion of monensin (1, 3, or 5 mumol/L) into the liver induced considerable swelling of the Golgi complex within 5 minutes. After a bolus injection of horseradish peroxidase during monensin infusion, the biliary secretion of the protein was delayed (1 mumol/L monensin) and markedly reduced (5 mumol/L monensin). Bile salt uptake was virtually unchanged except with 5 mumol/L monensin. This suggests that monensin has the same effects on the subcellular traffic in the perfused liver as in cultured cells. After a bolus injection of taurocholate (0.25, 5.0, or 8.5 mumol/100 g body wt) during monensin infusion, the pattern of biliary secretion of the bile salt was identical to that of controls. During continuous infusion of taurocholate, a 10-minute monensin infusion (1 or 3 mumol/L) had no effect on the biliary secretion of taurocholate and on the secretion of lecithin and cholesterol induced by taurocholate. High concentrations (5 mumol/L) or prolonged infusions (20 minutes) of monensin decreased the biliary secretion of bile salts but corresponded to a marked decrease of taurocholate uptake. In summary, the Na+ ionophore monensin altered the Golgi complex and the vesicular transport of horseradish peroxidase, whereas taurocholate biliary secretion was not influenced unless taurocholate biliary secretion was not influenced unless taurocholate uptake by the liver was markedly decreased. It may be concluded that taurocholate and biliary lipid secretion, under these conditions, does not depend essentially on pathways involving acidic transporting vesicles and particularly the trans-Golgi complex.

Animals↗

PubMedDate not supplied

A defective retroviral vector encoding human interferon-alpha2 can transduce human leukemic cell lines.

Using the LXSN backbone, a defective retroviral vector (LISN) was constructed that encodes the human interferon (IFN)-alpha2 (hIFN-alpha2) gene and the neomycin resistance gene; the hIFN-alpha2 gene was cloned from human placental genomic DNA. High titers of the LISN retrovirus were produced by the amphotropic packaging cell line GP+envAM12. LISN is able to infect three human hematopoietic and leukemic cell lines: K562, LAMA-84, and TF-1. G418-resistant cells were detected in a similar proportion after infection with either the LISN retroviral vector or the LnLSN retroviral vector (encoding the nlsLacZ gene instead of hIFN-alpha2), suggesting that hIFN-alpha2 does not inhibit (or only partially inhibits) the production of retroviral particles by the packaging cell line and the infection of human cells. LISN-infected cells express and secrete hIFN-alpha2 as demonstrated by Northern blot analysis of poly(A)+ RNA, detection of the intracellular protein by fluorescence-activated cell sorter analysis, and detection of secreted hIFN-alpha in cell supernatants using an enzyme-linked immunosorbent assay. Retrovirally produced hIFN-alpha2 is biologically active, as demonstrated by the partial inhibition of the growth of K562 and TF-1, the modulation of the expression of cell surface antigens, the induction of the (2'-5') oligoadenylate synthetase, and, for LAMA-84, the down-modulation of the BCR-ABL protein. We conclude that the infection of human leukemic cell lines with a retroviral vector encoding hIFN-alpha2 is feasible and induces the expected biological effects. This experimental model will be useful in investigating the possibility of transducing normal and leukemic cells and hematopoietic progenitors and in determining the consequences of the autocrine production of hIFN-alpha2 on the behavior of these cells.

Animals↗