Tretinoin with chemotherapy in newly diagnosed acute promyelocytic leukaemia. European APL Group.
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
L Degos
Publications and source records attributed to L Degos.
PLZF-RAR alpha fusion proteins generated from the variant t(11;17)(q23;q21) translocation in acute promyelocytic leukemia inhibit ligand-dependent transactivation of wild-type retinoic acid receptors.
Recently, we described a recurrent variant translocation, t(11;17)(q23;q21), in acute promyelocytic leukemia (APL) which juxtaposes PLZF, a gene encoding a zinc finger protein, to RARA, encoding retinoic acid receptor alpha (RAR alpha). We have now cloned cDNAs encoding PLZF-RAR alpha chimeric proteins and studied their transactivating activities. In transient-expression assays, both the PLZF(A)-RAR alpha and PLZF(B)-RAR alpha fusion proteins like the PML-RAR alpha protein resulting from the well-known t(15;17) translocation in APL, antagonized endogenous and transfected wild-type RAR alpha in the presence of retinoic acid. Cotransfection assays showed that a significant repression of RAR alpha transactivation activity was obtained even with a very low PLZF-RAR alpha-expressing plasmid concentration. A "dominant negative" effect was observed when PLZF-RAR alpha fusion proteins were cotransfected with vectors expressing RAR alpha and retinoid X receptor alpha (RXR alpha). These abnormal transactivation properties observed in retinoic acid-sensitive myeloid cells strongly implicate the PLZF-RAR alpha fusion proteins in the molecular pathogenesis of APL.
Amino Acid Sequence↗
Multiple nuclear factors bind to novel positive and negative regulatory elements upstream of the human MHC class I gene HLA-A11.
Quantitative expression of class I genes varies widely in different tissues, during development and in some neoplastic cells. Regulatory DNA sequences controlling levels of transcription of class I genes have been characterized in the murine and swine promoters. Although some regulatory features appear to be retained in humans, most of them are not evolutionary conserved. In this study, we identify novel DNA sequences and factors which contribute to the regulation of the human HLA-A11 gene. Two activator elements (-155 to -91 and -335 to -206) and one negative element (-172 to -156), distinct from those previously described are mapped within 335 bp upstream of exon 1 of the human HLA-A11 gene. Various nuclear factors bind to these regulatory elements, some of which are cell restricted or interact with evolutionary divergent regulatory sequences of the human class I gene promoter. Two of the five DNA-binding sites characterized in this work bind at least two proteins which compete for the occupancy of their site. The identification of these new regulatory elements provides a more comprehensive basis for the understanding of physiological or pathological modulation of MHC class I transcription in humans.
Base Sequence↗
Simultaneous occurrence of two rare cutaneous markers of poor prognosis in myelodysplastic syndrome: erythema elevatum diutinum and specific lesions.
We report the concomitant occurrence of erythema elevatum diutinum and specific skin lesions in a patient with a myelodysplastic syndrome (MDS). This patient's course, and review of other reported cases, support the opinion that neutrophilic dermatoses are associated with a poor prognosis of MDS. The simultaneous appearance of these manifestations could be the consequence of a particular chemotactism of myeloid cells, expressed after acute transformation.
Aged↗
HLA-DRB1, DQA1 and DQB1 DNA polymorphisms in healthy Algerian and genetic relationships with other populations.
This study presents the results of HLA-DRB1, -DQA1, and -DQB1 sequence-specific oligonucleotide probe (SSOP) typings for a population sample of 47 individuals originating from Western Algeria. Allele and haplotype frequencies, as well as linkage disequilibria are computed by the standard methods used for the XIth International Histocompatibility Workshop data. A total of 24 alleles are detected at the DRB1 locus, where a very high heterozygosity level (0.914) is found. The highest DRB1 frequencies are 0.160, DRB1*1101, and 0.138, for DRB1*0301 and DRB1*0701. The DQA1 and DQB1 loci are less polymorphic. Among the 8 DQA1 alleles detected, DQA1*0501 is highly predominant with a frequency of 0.383. Thirteen DQB1 alleles are observed among which DQB1*0301 and DQB1*0201 are the most frequent (0.351 and 0.245, respectively). Three haplotypes predominate clearly: DRB1*1101-DQA1*0501-DQB1*0301 (0.138), DRB1*0701-DQA1*0201-DQB1*0201 (0.128) and DRB1*0301-DQA1*0501-DQB1*0201 (0.117). The two latter are among the most frequent haplotypes found in European and North American Caucasoid populations, but the DQA1*0501-DQB1*0201 association is not significant in Algerians. The genetic distances computed for each locus among a set of populations from different continents are significantly correlated to geography. They indicate that the Algerians are very close to South European populations, particularly to Sardinians, Italians, Romanians and French, with some intermediate characteristics between Europeans and sub-Saharan Africans. These results may serve as reference for future studies of HLA and disease in the Algerian population.
Adult↗
Differentiation therapy of leukemia.
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Cell Differentiation↗
Modulation of IL-8, IL-1 beta, and G-CSF secretion by all-trans retinoic acid in acute promyelocytic leukemia.
Acute promyelocytic leukemia (APL) is a homogeneous subgroup of acute myeloid leukemias (AML) characterized by the presence of the t(15;17) translocation and the resulting PML/RAR alpha fusion proteins. To date APL is the only AML which is sufficiently sensitive to all-trans retinoic acid (ATRA) differentiating effect. We have recently reported that APL express and secrete hematopoietic growth factors (HGF) such as IL-1 beta, TNF alpha, and IL-6. In vivo ATRA alone allows achievement of complete remission in APL patients. One of ATRA therapy's drawbacks is the increase of peripheral blast cells often associated with the ATRA leukocyte activation syndrome. To determine if this specific side-effect was linked to an increase of HGF release by APL cells, we studied the modulation of cytokine production by APL cells, we studied the modulation of cytokine production by APL samples (n = 12) before and after incubation with ATRA. ATRA failed to modulate TNF alpha, IL-6 or GM-CSF secretion levels; however, IL-8 levels decreased in 11 cases, and in four cases up-regulation of IL-1 beta and G-CSF protein expression was observed. These modulations were found to be linked to ATRA sensitivity as ATRA failed to modulate cytokine production in non-APL cells (n = 8). Interestingly, the increase of IL-1 beta and G-CSF production in the presence of ATRA was highly correlated to an increase in APL cell count in vitro and in vivo hyperleukocytosis, resulting in fatal outcome. IL-1 beta, TNF alpha, IL-6, and IL-8 are known to be implicated in leukocyte activation. The results of this study suggest that ATRA-induced hyperleukocytosis and ATRA leukocyte activation syndrome in APL may be inherent to the secretion of specific hematopoietic growth factors by the APL cells.
Blotting, Northern↗
Induction treatment of acute promyelocytic leukemia using all-trans retinoic acid. Controversies about dosage, advantages and side-effect management.
All-trans retinoic acid (ATRA) in acute promyelocytic leukemia (APL) represents the leading example of targetted drugs for inducing an in vivo differentiation of malignancy (1,2). A fixed dose of 45 mg/m2/day was proposed for the treatment of patients (3), according to the results obtained by retinoic acid derivatives in skin diseases. We report that 25 mg (4), and even 15 mg/m2/day are still effective dosages. Absence of drug resistance, rapid correction of fibrinogenopenia and the absence of hypoplasia are the apparent major advantages and consequently high frequency of early mortality generally reported during chemotherapy is expected to be reduced. In fact the same risk of early death (10%) is recorded in all available data (5), due to coagulation disorders and to a leukocyte activation syndrome. Management of these side-effects is based on the prevention and treatment of the irreversible state as soon as first symptoms appear. Actually the major advantage of ATRA treatment in addition to chemotherapy is the decrease of relapse rate (6), the increase of event-free survival, and thus the increase of survival.
Adolescent↗
Synopsis of the discussions of the workshop: hematology.
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Antineoplastic Agents↗
In vitro all-trans retinoic acid (ATRA) sensitivity and cellular retinoic acid binding protein (CRABP) levels in relapse leukemic cells after remission induction by ATRA in acute promyelocytic leukemia.
The current treatment of acute promyelocytic leukemia (APL, also called AML3 subtype) is focused on differentiating agents such as the vitamin A derivative all-trans retinoic acid (ATRA). This agent is a novel and very promising therapy for this disease characterized cytogenetically by a translocation t(15;17)(q21;q22) involving the alpha retinoic acid receptor on chromosome 17 and the PML gene on chromosome 15. Clinical trials have demonstrated that ATRA followed by or combined with conventional chemotherapy may be more beneficial than chemotherapy for inducing complete remission. Unfortunately, ATRA as a single agent, does not appear able to maintain patients in remission (median 5 months), and when relapse occurs resistance to a second induction of ATRA therapy is observed in almost all cases. Recently our laboratory investigated whether specific features of the AML3 cells at relapse could explain the in vivo resistance observed. We have demonstrated that AML3 patients' cells (from four patients) at relapse show high levels of CRABP, a cytosolic retinoic acid binding protein and this protein was not detected prior to ATRA therapy. Relapse-AML3 cells (n = 12) showed reduced differentiation induction when compared with 'virgin'-AML3 cells. Results from this study suggest that CRABP could modulate ATRA cellular concentrations reaching the nucleus. This induced ATRA hypercatabolytic state should be monitored during consolidation therapy and at relapse by evaluating CRABP and RA metabolite levels, in order to detect ATRA resistance in patients with AML3.
Clinical Trials as Topic↗
Treatment of newly diagnosed acute promyelocytic leukemia (APL) by a combination of all-trans retinoic acid (ATRA) and chemotherapy. French APL Group.
All-trans retinoic acid (ATRA) is very effective in newly diagnosed acute promyelocytic leukemia (APL), yielding remission (CR) rates of 80 to 90%. However, it is associated with a rapid rise in WBC in some patients, with potentially fatal ATRA syndrome. Furthermore, most patients relapse with maintenance therapy using ATRA alone or low-dose chemotherapy. The French APL group thus designed a treatment approach with ATRA followed by intensive chemotherapy. The latter was administered after CR achievement with ATRA, or was rapidly added to ATRA in the case of rapid rise in leukocyte counts. This combined approach, in a pilot study and in a randomized trial, proved superior to intensive chemotherapy alone, by slightly increasing the CR rate but more importantly by reducing the relapse rate. The French group (and other European groups) are now testing in a new randomized trial the better timing of ATRA and chemotherapy administration (ATRA followed by chemotherapy or ATRA plus chemotherapy), and the role (after an intensive consolidation) of maintenance treatment with intermittent ATRA, continuous low-dose chemotherapy, or both.
Aged↗
Is acute promyelocytic leukemia a curable disease? Treatment strategy for a long-term survival.
The major cause of early death in acute promyelocytic leukemia (APL), the high risk of a bleeding diathesis is now successfully counteracted within a few days by differentiation therapy using ATRA. Moreover, no resistance to this drug has been recorded during induction when the usual presence of PML/RAR alpha was confirmed by molecular study (some M3 cases do lack rearrangement of PML/RAR alpha). Paradoxically, a hypercoagulable clotting tendency may occur in these patients during the first month of ATRA treatment. Leucocyte activation (retinoic acid syndrome), often secondary to hyperleukocytosis, is prevented by early addition of chemotherapy when WBCs exceed defined limits, and is successfully treated by high dose corticosteroids. Routine acquired progressive in vivo resistance to all trans retinoic acid (ATRA) requires consolidation of ATRA-induced complete remission (CR) with intensive chemotherapy. Prevention of relapses using maintenance therapy is questionable and has not been tested in randomized trials. Actually the event-free survival of APL patients treated by the combination of ATRA and chemotherapy is 80% at 1 year, and the cure of 50% of patients is within our reach.
Antineoplastic Combined Chemotherapy Protocols↗
Retinoic acid receptors: involvement in acute promyelocytic leukemia.
Acute promyelocytic leukemia (APL), is a homogeneous subgroup of acute myelogenous leukemias characterized by phenotypic and genetic markers. APL is associated with a reciprocal chromosomal translocation t(15,17) which has been shown to disrupt the retinoic acid receptor alpha (RAR alpha) gene. As a result, a portion of the RAR alpha gene becomes fused with a chromosome 15 locus termed PML (promyelocytic myeloid leukemia) from which chimeric PML/RAR alpha fusion mRNAs are expressed. The presence of these fusion transcripts in APL patients strongly support the hypothesis that both the t(15;17), and thus PML/RAR alpha, play a crucial role in the leukemogenesis of this disease. APL cells are specifically responsive to all-trans retinoic acid (ATRA) and this characteristic has allowed the first differentiation therapy with retinoic acid. However, failure or partial responses are observed and, though this has most frequently been reported in patients at second or third relapse. The molecular basis of the absence of ATRA response in these patients has not been determined.
Cell Differentiation↗
Induction of high-affinity GM-CSF receptors during all-trans retinoic acid treatment of acute promyelocytic leukemia.
Differentiation of normal myeloid cells is accompanied by the increase of high-affinity GM-CSF receptors necessary for progenitor proliferation/differentiation and mature neutrophil function. All-trans retinoic acid (ATRA) induces terminal differentiation of acute promyelocytic leukemia cells (AML3 subtype). We report in this study that AML3 cells, like other AML subtypes, harbor high-affinity GM-CSF R (n = 138.3 +/- 69.3 sites/cell, Kd = 76.9 +/- 68.8 pM). In all cases, incubation with ATRA induces either an increase in the number of affinity of GM-CSF R (n = 212.7 +/- 116.2 sites/cell, Kd = 43.2 +/- 22.5 pM). The data presented show that modulation of GM-CSF receptors cells is correlated to the degree of ATRA-induced granulocytic differentiation but not to increased cell growth.
Cell Differentiation↗
Is acute promyelocytic leukemia a curable disease? Treatment strategy for a long-term survival.
The major cause of early death in acute promyelocytic leukemia (APL), the high risk of a bleeding diathesis is now successfully counteracted within a few days by differentiation therapy using ATRA. Moreover, no resistance to this drug has been recorded during induction when the usual presence of PML/RAR alpha was confirmed by molecular study (some M3 cases do lack rearrangement of PML/RAR alpha). Paradoxically, a hypercoagulable clotting tendency may occur in these patients during the first month of ATRA treatment. Leucocyte activation (retinoic acid syndrome), often secondary to hyperleukocytosis, is prevented by early addition of chemotherapy when WBCs exceed defined limits, and is successfully treated by high dose corticosteroids. Routine acquired progressive in vivo resistance to all trans retinoic acid (ATRA) requires consolidation of ATRA-induced complete remission (CR) with intensive chemotherapy. Prevention of relapses using maintenance therapy is questionable and has not been tested in randomized trials. Actually the event-free survival of APL patients treated by the combination of ATRA and chemotherapy is 80% at 1 year, and the cure of 50% of patients is within our reach.
Hemorrhage↗
In vitro all-trans retinoic acid (ATRA) sensitivity and cellular retinoic acid binding protein (CRABP) levels in relapse leukemic cells after remission induction by ATRA in acute promyelocytic leukemia.
The current treatment of acute promyelocytic leukemia (APL, also called AML3 subtype) is focused on differentiating agents such as the vitamin A derivative all-trans retinoic acid (ATRA). This agent is a novel and very promising therapy for this disease characterized cytogenetically by a translocation t(15;17)(q21;q22) involving the alpha retinoic acid receptor on chromosome 17 and the PML gene on chromosome 15. Clinical trials have demonstrated that ATRA followed by or combined with conventional chemotherapy may be more beneficial than chemotherapy for inducing complete remission. Unfortunately, ATRA as a single agent, does not appear able to maintain patients in remission (median 5 months), and when relapse occurs resistance to a second induction of ATRA therapy is observed in almost all cases. Recently our laboratory investigated whether specific features of the AML3 cells at relapse could explain the in vivo resistance observed. We have demonstrated that AML3 patients' cells (from four patients) at relapse show high levels of CRABP, a cytosolic retinoic acid binding protein and this protein was not detected prior to ATRA therapy. Relapse-AML3 cells (n = 12) showed reduced differentiation induction when compared with 'virgin'-AML3 cells. Results from this study suggest that CRABP could modulate ATRA cellular concentrations reaching the nucleus. This induced ATRA hypercatabolytic state should be monitored during consolidation therapy and at relapse by evaluating CRABP and RA metabolite levels, in order to detect ATRA resistance in patients with AML3.
Drug Screening Assays, Antitumor↗
The PML-RAR alpha gene product of the t(15;17) translocation inhibits retinoic acid-induced granulocytic differentiation and mediated transactivation in human myeloid cells.
Acute promyelocytic leukemia (APL) is characterized by an arrest of granulocytic differentiation and a reciprocal t(15;17) translocation fusing the PML gene to the retinoic acid receptor alpha (RAR alpha) gene. PML was recently identified as a potential transcription factor. In non hematopoietic cells, the transfected PML-RAR alpha product binds all trans retinoic acid and exhibits altered transactivating properties when compared with RAR alpha. A major question raised by these observations is whether PML-RAR alpha contributes to the inhibition of myeloid differentiation. We find that in myeloid cell lines responsive to retinoic acid, PML-RAR alpha blocks retinoic acid mediated transactivation and totally abrogates the retinoic acid mediated granulocytic differentiation. These findings strongly suggest that PML-RAR alpha may, by blocking normal retinoic acid dependent myeloid differentiation, participate in the leukemogenesis of APL. The fact that high doses of all-trans retinoic acid relieve the inhibitory effect of PML-RAR alpha corroborates the therapeutic effect of all-trans retinoic acid in APL patients.
Base Sequence↗
Poor response to all-trans retinoic acid therapy in a t(11;17) PLZF/RAR alpha patient.
All-trans retinoic acid (ATRA) is a potent inducer of differentiation and cell death in malignant cells. Its effect is known to be mediated through binding to specific nuclear (RARs and RXRs) or cytoplasmic (CRABP) proteins. ATRA is strikingly effective in acute promyelocytic leukemia (the AML3 subtype) inducing a high incidence of complete remissions. Paradoxically, most AML3 cells harbor an abnormal retinoic acid receptor (PML/RAR alpha) resulting from the t(15;17) translocation. Though few AML3 patients do not respond to ATRA therapy, individualization of these cases is of practical importance. Recently the RAR alpha gene has been demonstrated to be involved in a novel fusion transcript (PLZF/RAR alpha) through a t(11;17) translocation. We describe here the second case of such a patient with a t(11;17)-PLZF/RAR alpha leukemic clone. Southern analysis revealed that the breakpoint in the RAR alpha gene was within the second intron (as for PML/RAR alpha) and the intron separating the second and third zinc finger of the PLZF gene. In vitro, the leukemic cells did not show increased NBT reduction or loss of self-renewal after incubation with ATRA. After therapy with ATRA, only partial remission was obtained. These results suggest that the t(11;17) (PLZF/RAR alpha) case of this study was less responsive to ATRA therapy than t(15;17) (PML/RAR alpha) cases and raises the question of the definition of this novel AML subtype.
Aged↗