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L Degos

Publications and source records attributed to L Degos.

At least 19 recordsLinked to original sources
PubMed1992

Interferon-alpha downregulates the abnormal intracytoplasmic free calcium concentration of tumor cells in hairy cell leukemia.

Hairy cell leukemia (HCL) is a B-cell tumor affecting the preplasma stage of B-cell differentiation. One important feature of the disease is its exquisite sensitivity to interferon-alpha (IFN-alpha) therapy. Because we showed earlier that the CD20 molecule is consistently hyperphosphorylated in hairy cells and because previous studies showed that CD20 is involved in regulating intracytoplasmic free calcium concentrations ([Ca2+]i) in normal B lymphocytes, we measured [Ca2+]i in tumor cell samples from patients with HCL and studied the effect of IFN-alpha on this parameter. Using the Ca(2+)-sensitive fluorophore fura-2, we observed that hairy cells display a slightly but consistently higher [Ca2+]i than normal 48-hour-activated B cells or other leukemic cells. Furthermore, both in vitro preincubation of cell samples with IFN-alpha and in vivo administration of this cytokine reduced the [Ca2+]i in hairy cells. This effect was observed together with a decrease in transmembrane Ca2+ influx. However, preincubation with IFN-gamma had no effect. The in vivo correlation between the diminution of CD20 phosphorylation and [Ca2+]i in tumor cell samples from patients at the beginning of IFN-alpha therapy suggests that these two parameters are connected.

Antigens, CD↗
PubMed1992

Induction of retinoic acid-binding protein in normal and malignant human myeloid cells by retinoic acid in acute promyelocytic leukemia patients.

Retinoic acid has striking effects on development and cell differentiation. Its biological effect is a highly regulated process that is controlled by specific proteins. In the nucleus, different retinoic acid receptors have been identified and their genes cloned. In the cytosol, retinoid binding proteins, cellular retinoic acid-binding protein and cellular retinol-binding protein, have been correlated with normal and malignant tissue differentiation. Recently, differentiation therapy of acute promyelocytic leukemias (AML3 subtype) with all-trans-retinoic acid has been shown to be an efficient alternative to chemotherapy. The retinoic acid receptor alpha gene has been shown to be specifically rearranged in AML3 through the t(15;17) translocation. The molecular basis of the effect to reverse the leukemic phenotype of all-trans-retinoic acid is not yet elucidated. To further study retinoic acid efficacy in AML3 leukemia, retinoic acid-binding proteins were studied in the cytosol extracts of hematopoietic cells. No retinoic acid binding activity was detected in normal or malignant hematopoietic cells whether sensitive or not to retinoic acid. However, detectable binding to a cytosolic protein corresponding to cellular retinoic acid-binding protein (M(r) 15,000, Kd 3 nM) was observed in the bone marrow cells of AML3 patients undergoing all-trans-retinoic acid therapy. We suggest that both the induction and subsequent presence of cellular retinoic acid-binding protein may influence the therapeutic efficacy of retinoic acid and must be taken into account when studying its effect in acute promyelocytic patients.

Animals↗
PubMed1992

A PML/retinoic acid receptor alpha fusion transcript is constantly detected by RNA-based polymerase chain reaction in acute promyelocytic leukemia.

The t(15;17) translocation is specifically observed in patients with promyelocytic leukemia (AML3). The chromosomal rearrangement juxtaposes the retinoic acid receptor alpha (RAR alpha) and PML genes, resulting in PML/RAR alpha fusion transcripts. Our previous studies have shown that a polymerase chain reaction (PCR) amplification product could be obtained from the cDNA of the NB4 promyelocytic cell line from which the chimaeric PML/RAR alpha was cloned. We report here that in all 14 AML3 patients tested, reverse transcriptase-PCR (RT-PCR) allows the detection of three specific fusion products. In eight patients, one amplification product was detected corresponding to the previously described abnormal fusion. Five patients displayed a different amplified fragment corresponding to a different fusion point. One other patient always showed a third different-sized product. The different types of fusion transcripts amplified were correlated to the size of the abnormal RAR alpha transcripts detected in these patients by Northern analysis, but did not prove determinant for either the phenotypic features or the retinoic acid responsiveness in AML3 cells in this group of patients. The consistent identification by RT-PCR of the fusion of the PML and RAR alpha genes in AML3 patients suggest that this method will provide a useful tool for the diagnosis and detection of minimal residual disease in these patients.

Base Sequence↗
PubMed1992

Altered binding of regulatory factors to HLA class I enhancer sequence in human tumor cell lines lacking class I antigen expression.

Class I antigens encoded in the major histocompatibility complex (MHC) (HLA in man, H-2 in the mouse) play a key role in the recognition of target cells by cytolytic T lymphocytes. Tumor cells frequently do not express class I MHC molecules, which strongly suggests that down-regulation of the latter facilitates escape of tumor cells from immune surveillance. The expression of class I MHC genes is tightly regulated. An enhancer element, conserved in the promoters of mouse and human MHC genes, has been shown to be important for mouse class I MHC gene expression. At least two related regulatory factors (KBF1 and NF-kappa B) bind to this regulatory element. We have analyzed the binding of these factors in cellular extracts of 23 human tumor cell lines displaying various levels of class I mRNA and surface expression. In this panel, combined deficiency of KBF1- and NF-kappa B-like DNA-binding activities was frequent among the class I-negative cell lines and correlated with the absence of class I mRNA. A few cell lines that lack KBF1 binding activity still display NF-kappa B-like activity and express normal levels of MHC class I mRNA. These results suggest (i) that, in the absence of KBF1, NF-kappa B or a related factor promotes MHC class I gene transcription; and (ii) that a combined defect in KBF1/NF-kappa B DNA-binding activity can cause a pleiotropic defect in class I gene expression, which may facilitate tumor progression.

Antibodies, Monoclonal↗
PubMed1992

Acute lysis pneumopathy after chemotherapy for acute myelomonocytic leukemia with abnormal marrow eosinophils.

Acute respiratory failure developed in two patients with hyperleukocytic acute myelomonocytic leukemia with abnormal marrow eosinophils within 1 to 3 days after the beginning of high-dose induction chemotherapy. The presence of moderate pulmonary leukostasis before chemotherapy initiation, the simultaneous occurrence of an acute tumor lysis syndrome, the lack of evidence of any other cause of respiratory distress, and the clinical evolution lead the authors to attribute pulmonary injury to lysis of resident leukemic cells. The responsibility of eosinophilic cellular constituents for the diffuse alveolar damage is discussed.

Acute Disease↗
PubMed1992

All-trans-retinoic acid treatment and retinoic acid receptor alpha gene rearrangement in acute promyelocytic leukemia: a model for differentiation therapy.

All-trans-retinoic acid (ATRA), a vitamin A derivative, is a safe and effective drug in the obtention of complete remission in acute promyelocytic leukemia (APL). ATRA is able to activate the maturation of malignant cells from patients with APL either in vitro or in vivo. Complete remission was obtained without any feature of aplastic phase and the severe bleeding diathesis rapidly disappeared. The major adverse effect is the occurrence of hyperleukocytosis which is prevented by the addition of chemotherapy. A progressive acquired resistance appears during ATRA treatment and prolonged event free survival time is obtained after consolidation with cytotoxic drugs. In APL the retinoic acid receptor alpha gene is rearranged and fused with a novel gene called PML. The hybrid PML-RAR product could have a role in the leukemogenesis blocking the effect of the normal RAR on target genes. Retinoic acid exerts a differentiating effect either by the induction of a normal activity of the aberrant product in the presence of pharmacological concentration, or by an over-expression of the normal allele. The results obtained by cellular and molecular biology gave opportunities to confirm the diagnosis, to follow the assessment of the minimal residual disease and to understand the acquired resistance.

Carrier Proteins↗
PubMed1992

Localization of the conformational alteration of MHC molecules induced by the association of mouse class I heavy chain with a xenogeneic beta 2-microglobulin.

Changes in the antigenicity of major histocompatibility complex (MHC) class I molecules resulting from the association of bovine beta 2-microglobulin (beta 2-m) with mouse class I heavy chains were investigated. Mice (H-2b) were immunized with syngeneic Concanavalin A (Con A) blasts induced in the presence of fetal calf serum (FCS) in conditions allowing exchange between mouse and bovine beta 2-microglobulin (beta 2-m). Spleen cells from hyperimmunized mice were fused with myeloma cells and two monoclonal antibodies which required for their reactivity the presence of FCS have been further studied. One of them (CAB 297) recognized a determinant of bovine beta 2-m which is present on free molecules in solution as well as when they are associated with either mouse or bovine class I heavy chains. In contrast, the second monoclonal antibody (CBB 70) did not react with free bovine beta 2-m molecules, nor with beta 2-m associated with bovine class I heavy chains. It did react with cells of some H-2 haplotypes (b, f, p and r) but only when their class I heavy chains are associated with bovine or with human beta 2-m. Therefore, expression of the CBB 70 defined antigenic determinant requires both xenogeneic beta 2-m and class I heavy chain of a given H-2 molecule. In order to precisely localize the antigenic determinant defined by this monoclonal antibody and therefore the region altered by the association of class I heavy chain with xenogeneic beta 2-m, we made use of exon shuffled class I molecules. The results indicate that changes induced by the association of bovine beta 2-m with H-2 class I heavy chain affect the conformation of the alpha 2 domain. These studies illustrate that MHC class I molecules exhibit a considerable conformational flexibility which could influence their ability to bind and present various peptides to the T-cell receptor.

Animals↗
PubMed1992

All-trans retinoic acid (ATRA) therapeutical effect in acute promyelocytic leukemia.

All-trans retinoic acid (ATRA) is able to specifically differentiate acute promyelocytic leukemic cells (APL) in short-term culture. Patients with APL achieved complete remission within 1-3 months by a progressive maturation of leukemic cells. The advantages of this differentiation therapy are the rapid disappearance of the bleeding disorders and the absence of aplastic phase avoiding the early deaths occurring in 15-30% of patients with conventional chemotherapy. However, relapses occurred when ATRA alone was maintained. For this reason, a chemotherapy is added after complete remission obtained by ATRA. A pilot study on 27 patients was proposed with the sequential combination of ATRA and chemotherapy. A European trial randomizes conventional therapy to the sequential ATRA-chemotherapy protocol. Retinoic acid receptor (RAR alpha) is rearranged by the specific translocation t(15;17) of APL; a PCR technique was developed in order to ensure the diagnosis and to follow the minimal residual disease. Transfection experiment of the chimaeric gene inhibits the transactivation of the natural RAR. ATRA is able to revert the arrest of maturation perhaps through an increase of the expression of the normal allele of RAR, which could overpass the impairment induced by the chimaeric protein on target responsive elements. One of the steps of the repair is the modulation of programmed cell death (PCD). Bcl-2, a gene involved in the PCD, is modulated in in vitro studies, arguing for the engagement of the cell in the natural death. The beneficial effect of differentiation therapy is probably due to the induction of the natural death of the malignant cell.

Antineoplastic Agents↗
PubMed1992

Retinoic acid in acute promyelocytic leukemia: a model for differentiation therapy.

Acute promyelocytic leukemia is a clonal expansion of malignant cells blocked at a specific stage of myeloid differentiation. The disease is associated with a specific translocation between chromosome 17 and chromosome 15 [t(15;17)] and with a bleeding diathesis previously attributed to disseminated intravascular coagulation, which has recently also been related to primary fibrinolysis. The high percentage of early deaths, about 20%, experienced by acute promyelocytic leukemia patients, is generally due to the hemorrhagic syndrome. A new finding is the high effectiveness of treatment with all-trans retinoic acid, a vitamin A derivative, for inducing complete remission. The induction of cellular maturation by this agent represents the first model of differentiation therapy. Furthermore, recent molecular studies revealed that the breakpoints of the t(15;17) translocation are clustered in the gene of retinoic acid receptor-alpha, generating a hybrid gene product. Gene transfection experiments disclosed the impairment of gene transactivation due to the hybrid gene products, opening new concepts for understanding leukemogenesis. Understanding the mechanisms of action of retinoic acid could extend differentiation therapy to other malignancies with aberrant gene transcription.

Carrier Proteins↗
PubMed1992

TCR gamma delta bearing T lymphocytes infiltrating human primary cutaneous melanomas.

In situ immunophenotypic studies show that tumor infiltrating T lymphocytes from six of 11 fresh cutaneous primary melanomas tested contain T-cell receptor gamma delta expressing cells whereas those from 8 metastatic melanomas did not. In three cases these cells represent an unexpectedly high proportion of the lymphocytic infiltrate, ranging from 15 to 25%. This elevated percentage is maintained when tumor infiltrating lymphocytes are propagated in vitro for 2 or 3 weeks in the presence of recombinant interleukin 2 and autologous tumor cells. Functional studies reveal that gamma delta lines or clones developed from lymphocytes infiltrating primary melanoma display, in addition to their natural killer-like activity, a potent autologous tumor cell cytotoxic activity that does not seem to be restricted by major histocompatibility complex gene products.

Humans↗
PubMed1992

The HLA-DRB1*0405 haplotype is most strongly associated with IDDM in Algerians.

Insulin-dependent diabetes mellitus (IDDM) in Caucasians is strongly associated with HLA-DR3-DQ2 and DR4-DQ8. In order to investigate the HLA class II associations with IDDM in Algerians, we have used polymerase chain reaction (PCR) and sequence specific oligonucleotide analysis (SSO) to identify DQA1, DQB1, and DRB1 alleles, haplotypes and genotypes in 50 unrelated IDDM patients and 46 controls from a homogeneous population in Western Algeria. Both DRB1*0301-DQA1*0501-DQB1*0201 (DR3-DQ2) and DRB1*04-DQA1*0301-DQB1*0302 (DR4-DQ8) haplotypes were found at increased frequencies among the patients compared to controls (45% vs. 13%, RR = 5.5, Pc < 10(-5) and 37% vs. 4%, RR = 12.9, Pc < 10(-4), respectively). Among the latter, in contrast to other Caucasian populations, only DRB1*0405-DQA1*0301-DQB1*0302 was significantly increased in the Algerian patients (25% vs. 1% in controls, RR = 30.3, Pc < 10(-3). Accordingly, the highest risk of disease was observed in DRB1*0301-DQA1*0501-DQB1*0201/DRB1*0405-DQA1+ ++*0301-DQB1*0302 heterozygotes (34% in patients vs. 0% in controls; RR = 49; Pc < 10(-3). This observation and its comparison with DR-DQ haplotypes in other ethnic groups suggest that the DRB1*0405 allele which encodes an Asp57-negative beta chain may contribute to IDDM susceptibility in a similar way as Asp57-negative DQ beta chains.

Algeria↗
PubMed1992

Dose effect of cis- and trans-encoded HLA-DQ alpha beta heterodimers in IDDM susceptibility.

Insulin-dependent diabetes mellitus (IDDM) in whites is strongly associated with particular HLA-DQ alpha beta heterodimers composed of a DQ alpha chain with an arginine at residue 52 (Arg52+) combined to a DQ beta chain lacking an aspartic acid at residue 57 (Asp57-). With the aim of confirming this association, clarifying which heterodimers account for the highest risk of IDDM and explaining the excess risk of DR3-DQw2/DR4-DQw8, 115 unrelated white IDDM patients and 108 unrelated healthy nondiabetic control subjects were studied. With polymerase chain reaction and sequence-specific oligonucleotide probes, both patients and control subjects were typed for their HLA-DQA1 and DQB1 alleles and their DQA1-DQB1 haplotype and genotype frequencies were compared. Four major findings emerged from our analysis. 1) Arg52+ DQ alpha/Asp57- DQ beta heterodimers, formed in cis and/or in trans, are strongly associated with susceptibility to IDDM; 97% of patients and 46% of control subjects had at least one such susceptibility heterodimer (relative risk [RR] 32, confidence interval [Cl] 14.25-71.86, P less than 10(-7). 2) The degree of disease susceptibility depends on the number of such DQ heterodimers that a subject can express according to his or her DQA1-DQB1 genotype. The highest RR was observed in patients with four susceptibility DQ heterodimers (RR 41, Cl 17.05-95.9). 3) Only part of the susceptibility DQ heterodimers were significantly increased in patients, conferring IDDM susceptibility of different strength. The strongest association was with the DQA1*0501-DQB1*0302 combination formed in trans position (RR 35.2, CI 12.88-96.78, P less than 10(-7).(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1992

[Mechanism of action of retinoids in a new therapeutic approach to acute promyelocytic leukemia].

Vitamin A (retinol) and retinoic acid, its natural derivative, play an important role in the growth, differentiation and development of known normal tissues. Retinoids have recently become of interest to research in areas as diverse as dermatology, embryonal development and cancer research. Retinol is the major retinoid transported in the blood and tissues by its specific carrier retinol binding protein (RBP). The normal level of retinol in plasma is regulated very precisely by retinol homeostasis. RBP-retinol circulation supplies target cells, which then activate retinol into retinoic acid (RA) if they possess the NAD-dependent enzymatic oxidation system. RA, which is one of the most active metabolites of retinol, is also present in low concentration in the blood and the RA rate formation varies from tissues depending on specific need of the cell. The cellular transport and biological activity of retinoids may be mediated by their specific cytoplasmic binding proteins cellular retinol binding protein (CRBP) and the cellular retinoic acid binding protein (CRABP) which may function as shuttles targetting RA to nucleosol fraction and/or as regulator of cellular concentration of RA. The nuclear proteins RARs (retinoic acid receptors), which are members of the nuclear receptor superfamily are likely to be the final transducers of the RA signal at the gene expression. All-trans retinoic acid (ATRA) is able to specifically differentiate the malignant cells from leukemic patients with APL in short-term culture. For this reason, APL patients were successfully treated with ATRA (Chinese and French results). Acute promyelocytic leukemia M3 (French-American-British FAB classification) is a rare disease (10% of AML), characterized by a reciprocal chromosome 15-17 translocation. It has been shown that the chromosome 17 breakpoint of the translocation is localized within the RAR alpha gene. Due to the t(15;17) RAR alpha gene translocated to a gene PML on chromosome 15 resulting in synthesis of PML/RAR alpha fusion messenger RNA. Detection of PML/RAR alpha transcript is now a molecular marker of the disease. The abnormal PML/RAR alpha protein exhibits altered transcription activation properties when compared with RAR alpha. Clinical trials have demonstrated that ATRA is extremely efficient in inducing complete remission in APL patients. The morphologic finding of maturing elements in the bone marrow and peripheral blood during retinoic acid treatment indicates that the remission is obtained without hypoplasia and suggests that a differentiating mechanism is involved.(ABSTRACT TRUNCATED AT 400 WORDS)

Carrier Proteins↗
PubMed1992

Combined therapy with all-trans-retinoic acid and high-dose chemotherapy in patients with hyperleukocytic acute promyelocytic leukemia and severe visceral hemorrhage.

Acute promyelocytic leukemia (APL) is associated with a high incidence of disseminated intravascular coagulation (DIC) and early hemorrhagic death. The risk of early fatal hemorrhage is increased when high peripheral-blood blast count and severe DIC accompanied by visceral hemorrhage are present at diagnosis. Progressive cytolysis induced by daily increased doses of chemotherapy, or differentiation all-trans-retinoic acid (ATRA) therapy have been proposed for initial control of DIC, but both are dangerous in hyperleukocytic APL patients. We report our results obtained in three high-risk APL patients treated with a combination of conventional chemotherapy and ATRA. All patients had documented hyperleukocytic APL [M3 or M3-variant subtype, (15, 17) translocation] with DIC, and all had critical clinical course before treatment. Patient 1 presented with cerebral hemorrhage, patients 2 and 3 had acute respiratory failure probably due to pulmonary leukemic infiltration and pulmonary hemorrhage. In order to minimize the severity of DIC during chemotherapy-induced acute cytolysis, ATRA (45 mg/m2 per day) was started on the first or second day of chemotherapy and withdrawn when complete remission (CR) was achieved. Despite adverse clinical features, CR was obtained in these three high-risk patients. Patient 1 showed no increase of cerebral bleeding during therapy. Patients 2 and 3 required transient intensive care, with mechanical ventilation from day 4 to day 11 for one of them. Differentiating granular cells were present in peripheral blood of all patients from the day 5, 12 and 8 of cytotoxic therapy. For the three patients, the number of days with white blood cell count < 1 x 10(9)/l was only 2, 7 and 11 days respectively. These results suggest that differentiation therapy with ATRA may be useful even in hyperleukocytic APL patients, when ATRA is used in combination with chemotherapy. The mechanisms of this putative beneficial effect are discussed.

Adult↗
PubMed1992

[HLA and cancer].

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Genes, MHC Class I↗