Showing papers by "Fausto Grignani published in 1992"
TL;DR: The results suggest that the SHC gene products couple activated growth factor receptors to a signaling pathway that regulates the proliferation of mammalian cells.
1,355 citations
TL;DR: Findings indicate that two potential oncogenic proteins are generated by the acute promyelocytic leukaemia (APL) 15;17 translocation and suggest that the PML activation pathway is altered in APLs.
Abstract: The acute promyelocytic leukaemia (APL) 15;17 translocation generates a PML/RAR alpha chimeric gene which is transcribed as a fusion PML/RAR alpha mRNA. Molecular studies on a large series of APLs revealed great heterogeneity of the PML/RAR alpha transcripts due to: (i) variable breaking of chromosome 15 within three PML breakpoint cluster regions (bcr1, bcr2 and bcr3), (ii) alternative splicings of the PML portion and (iii) alternative usage of two RAR alpha polyadenylation sites. Nucleotide sequence analysis predicted two types of proteins: multiple PML/RAR alpha and aberrant PML. The PML/RAR alpha proteins varied among bcr1, 2 and 3 APL cases and within single cases. The fusion proteins contained variable portions of the PML N terminus joined to the B-F RAR alpha domains; the only PML region retained was the putative DNA binding domain. The aberrant PML proteins lacked the C terminus, which had been replaced by from two to ten amino acid residues from the RAR alpha sequence. Multiple PML/RAR alpha isoforms and aberrant PML proteins were found to coexist in all APLs. These findings indicate that two potential oncogenic proteins are generated by the t(15;17) and suggest that the PML activation pathway is altered in APLs.
262 citations
TL;DR: Tests for a unique fusion transcript, PML/RAR alpha, in 35 APL patients who were in apparent remission after various treatments found 11 of 13 patients who tested positive 4 months after achieving remission were in relapse 1-4 months later.
237 citations
TL;DR: Data indicate that peritoneal mesothelial cells produce many cytokines and suggest that IL-1 is a regulatory molecule for peritoneals mesothelium, as well as suggesting that it was able to upregulate the expression of the genes that code for G-CSF, GM- CSF,IL-1 alpha, and IL- 1 beta in these cells.
183 citations
Journal Article•
TL;DR: RNAase protection experiments revealed that the different PML isoforms are equally expressed in established cell lines of different histological origin, and the structure of the PML genomic locus was characterized and its expression pattern preliminarily characterized.
Abstract: The acute promyelocytic leukaemia (APL)-specific chromosome 15;17 translocation leads to the fusion of a newly identified putative transcription factor, PML, and the retinoic acid receptor alpha. We have characterized the structure of the PML genomic locus and preliminarily characterized its expression pattern. The PML locus spans a minimum of 35 kb and is subdivided into nine exons. The putative PML DNA binding site is encoded by exons 2 and 3. We isolated a large number of alternatively spliced PML transcripts that encode numerous PML isoforms. Two groups of isoforms were identified that differed either in their C-terminal region or in the length of their central region, but retained the putative DNA-binding and dimerization domains. RNAase protection experiments revealed that the different PML isoforms are equally expressed in established cell lines of different histological origin.
165 citations
TL;DR: Two chimeric genes, PML-RAR alpha and RAR alpha-PML, are formed as a consequence of the acute promyelocytic leukemia (APL)-specific reciprocal translocation of chromosomes 15 and 17 and the organization and expression pattern is investigated.
Abstract: Two chimeric genes, PML-RAR alpha and RAR alpha-PML, are formed as a consequence of the acute promyelocytic leukemia (APL)-specific reciprocal translocation of chromosomes 15 and 17 [t(15;17)]. PML-RAR alpha is expressed as a fusion protein. We investigated the organization and expression pattern of the RAR alpha-PML gene in a series of APL patients representative of the molecular heterogeneity of the t(15;17) and found (i) two types of RAR alpha-PML mRNA junctions (RAR alpha exon 2/PML exon 4 or RAR alpha exon 2/PML exon 7) that maintain the RAR alpha and PML longest open reading frames aligned and are the result of chromosome 15 breaking at two different sites; and (ii) 10 different RAR alpha-PML fusion transcripts that differ for the assembly of their PML coding exons. A RAR alpha-PML transcript was present in most, but not all, APL patients.
140 citations
TL;DR: It seems likely that the bcr rearrangement plays an important role in the pathogenesis of CML, and is likely to be a protein with increased tyrosine-kinase activity.
Abstract: INTRODUCTION Philadelphia positive chronic myelogenous leukemia (Ph1+ CML) is a myeloproliferative disorder of clonal origin, due to neoplastic transformation of a pluripotent stem cell, and characterized by excessive proliferation of hemopoietic precursors and expansion of the myeloid cellular mass1. In 90-95% of cases, the disease is associated with a chromosomal abnormality, the Ph1 chromosome, derived from a reciprocal translocation t(9;22) (q34;q11) between chromosomes 9 and 222. The translocation of the proto-oncogene c-abl from its normal location on chromosome 9 to the break-point cluster region (bcr) of chromosome 22 involves the formation of a chimeric gene (abl-bcr), the product of which is a protein with increased tyrosine-kinase activity3,4. It seems likely that the bcr rearrangement plays an important role in the pathogenesis of CML. Characteristically, the disease presents two phases: a “benign” or chronic phase lasting about 3 years, well controlled by chemotherapy, and a terminal blastic ...
24 citations
TL;DR: A prospective study of intravenous immunoglobulin substitutive therapy involving two patients with recurrent pneumonia and very low serum IgG2 values demonstrated a reduction in the number of respiratory infectious episodes as well as an increase in both serum and, to a lesser extent, bronchoalveolar lavage fluid IgG 1 and IgG 2 levels as discussed by the authors.
Abstract: Abnormalities in IgG subclass distribution were sought in serum samples and bronchoalveolar lavage fluid from 15 patients with alcoholic liver disease to explain their increased susceptibility to bacterial respiratory infections. Serum IgG4 deficiency alone or in association with low IgG2 levels was revealed in approximately 30% of patients with alcoholic liver disease. This fact prompted us to further investigate the immunoglobulin concentrations in bronchoalveolar lavage fluid, paying special attention to the distribution of IgA and IgG subclasses. IgA levels were found to be normal or slightly elevated. However, there were substantial defects in total IgG and IgG1 concentrations, often associated with reduced IgG2 and IgG4 levels, in approximately 70% of patients with alcoholic liver disease, which proved to be closely correlated with the number and type (pneumonia) of bacterial respiratory infections. A prospective study of intravenous immunoglobulin substitutive therapy involving two patients with recurrent pneumonia and very low serum IgG2 values demonstrated a reduction in the number of respiratory infectious episodes as well as an increase in both serum and, to a lesser extent, bronchoalveolar lavage fluid IgG1 and IgG2 levels. We identified immune defects that may represent an important pathogenetic mechanism that, when considered together with the alcohol-related suppression of alveolar macrophage and ciliary functions and the inhibition of leukocyte migration into the lungs, should help clarify the complex relationships between alcohol and immune defense. (Arch Intern Med.1992;152:99-104)
24 citations
Journal Article•
12 citations
TL;DR: It would, therefore, seem that a predominance of T cells capable of delivering IgG1-specific, as opposed to IgG2- specific, help is an essential factor for the preferential induction of IgG 1 antibodies during B cell proliferation and differentiation.
8 citations