Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 The aberrant PML proteins lacked the C terminus, which had been replaced by from two to ten amino acid residues from the RAR alpha sequence.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.
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PMID:Genomic variability and alternative splicing generate multiple PML/RAR alpha transcripts that encode aberrant PML proteins and PML/RAR alpha isoforms in acute promyelocytic leukaemia. 131 66

We have previously shown that all-trans retinoic acid therapy is an alternative therapy for acute promyelocytic leukemia (AML3) via differentiation of the leukemic cells. The t(15;17) translocation is specifically found in this leukemia. We and others have shown that through this translocation the RAR alpha gene is rearranged and its expression altered in AML3 cells. The gene is truncated and fused to a novel gene (PLM). This results in a fusion protein whose transactivating properties may be implicated in the leukemogenesis of this disease. Retinoic acid cytoplasmic binding proteins (CRABP and CRBP) are not detected by PAGE chromatography in normal or malignant hematopoietic cells. During all-trans RA therapy, a) all-trans RA plasma concentrations are within in vitro differentiating concentration (med. 0.4 microgram/ml); b) increased expression of the normal remaining RAR alpha allele is rapidly observed and may explain the paradoxical induction of RA differentiation in these cells; c) CRABPII is induced in the bone marrow cells of AML3 patients and remains detectable 1 month after withdrawal of RA. AML3 in relapse after RA therapy is always less sensitive to RA in vitro and in vivo. Our data suggest that modification of the metabolisation pathways of RA may be one of parameters linked to this resistance. It appears that the efficacy of all-trans RA is the resultant of multiple parameters (RA concentration, ratio of PML/RAR alpha transcripts to normal RAR alpha, CRABP) which need to be defined to efficiently monitor all-trans RA therapy in APL.
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PMID:[Biological parameters of the efficiency of retinoic acid in acute leukemia]. 182 94

Expression of P-glycoprotein (Pgp), the product of the multidrug resistance (MDR1) gene, detected by flow cytometric analysis of the binding of antibody 4E3.16, was found on significantly fewer leukemic cells in 35 adult patients with de novo acute promyelocytic leukemia (APL) (mean 14.8%, median 7%) than in 184 patients with non-APL acute myeloid leukemia (AML) at diagnosis (mean 28.3%, median 18%) (p = 0.0038). APL was diagnosed based on morphology, the detection of t(15;17) and of the chimeric fusion transcript PML/RAR alpha by PCR. To further substantiate low MDR1 expression in APL, we studied cells from 11 APL patients at the molecular and functional level in comparison to 48 non-APL cases. The diagnosis of APL was associated with the absence of Pgp function by the rhodamine efflux assay (p = 0.0001). Furthermore, MDR1-specific transcript levels, determined by quantitative PCR with two distinct sets of primers, were significantly lower in mononuclear cells from the APL than the other AML cases (p = 0.013). The frequency of leukemic cells positive for CD34, an antigen presumably associated with Pgp expression in AML, was significantly lower in APL than other AMLs (p = 0.0001). In contrast to non-APL leukemias, those few cases of CD34 strongly positive APL neither expressed Pgp nor contained significant MDR1 transcript levels. Low expression of Pgp by APL cells may provide the biologic basis for the high sensitivity of this leukemia subtype to chemotherapeutic agents in vivo.
Leukemia 1994 Jun
PMID:Significantly lower P-glycoprotein expression in acute promyelocytic leukemia than in other types of acute myeloid leukemia: immunological, molecular and functional analyses. 751 29

We have analyzed the differentiation program of a U937 promonocytic leukemia clone transduced with the acute promyelocytic leukemia specific PML/RAR alpha fusion gene, the expression of which is under the control of the inducible metallothionine (MT) I promoter (MTPR9 clone). MTPR9 cells treated with Zn2+ hence exhibit levels of PML-RAR alpha protein as high as fresh acute promyelocytic leukemia blasts. In the absence of Zn2+, i.e., upon low level PML/RAR alpha expression, 1,25-dihydroxyvitamin D3 (D3) and particularly D3 plus transforming growth factor beta 1 (TGF-beta 1) induced terminal differentiation of MTPR9 cells (as observed in "wild-type" U937 cells), on the basis of morphology, membrane antigen pattern, and functional criteria. Conversely, in the presence of Zn2+, D3 and D3 plus TGF-beta 1 failed to induce terminal differentiation, as evaluated by the above parameters. Interestingly, retinoic acid (RA) treatment suppresses the differentiation blockade induced by high level PML-RAR alpha protein; indeed, Zn(2+)-treated MTPR9 cells incubated with RA plus D3 exhibited significant terminal monocytic maturation, comparable to that of cells treated with D3 alone or combined with RA in absence of Zn2+. Similar observations were made in NB4, a PML-RAR+ human acute leukemic line. As expected RA treatment of NB4 cells causes granulocytic differentiation. Interestingly, the cell line is only scarcely induced to mature monocytic cells by D3 or D3 plus TGF-beta 1 treatment, whereas it is effectively induced to monocytic maturation by combined treatment with D3 and RA. Accordingly, the rate of NB4 cell proliferation is only slightly affected by D3 or D3 plus TGF-beta 1 treatment, mildly inhibited by RA, and markedly decreased by D3 plus RA. These results indicate that in both U937 and NB4 cells high level PML/RAR alpha expression inhibits the monocytic terminal differentiation program triggered by D3 or D3 plus TGF-beta 1, whereas RA treatment effectively antagonizes this inhibitory PML-RAR alpha action and restores the D3 differentiative effect.
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PMID:PML/RAR alpha+ U937 mutant and NB4 cell lines: retinoic acid restores the monocytic differentiation response to vitamin D3. 751 22

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.
Leukemia 1994 Oct
PMID:Modulation of IL-8, IL-1 beta, and G-CSF secretion by all-trans retinoic acid in acute promyelocytic leukemia. 752

Acute promyelocytic leukemia (APL) is a subtype of acute myelogenous leukemia (AML) that is characterized by the presence of a PML/RAR alpha fusion gene resulting from t(15;17). Peripheral stem cell transplantation (PSCT) has been used to treat patients with AML. To assess the presence of minimal residual disease (MRD) and the contamination of leukemic cells in peripheral stem cells (PSCs), we examined six patients with APL who were undergoing PSCT, using reverse transcriptase polymerase chain reaction analysis to detect the mRNA of the PML/RAR alpha fusion gene. The fusion gene was expressed in the bone marrow cells during the early phase of a complete remission and in some of the PSCs. Detection of the fusion gene can be useful in monitoring for leukemic cell contamination of PSCs and for predicting a relapse of APL.
Leukemia 1995 May
PMID:Detection of minimal residual disease by reverse transcriptase polymerase chain reaction for the PML/RAR alpha fusion mRNA: a study in patients with acute promyelocytic leukemia following peripheral stem cell transplantation. 753 17

PML/RAR alpha is the putative transforming sequence of acute promyelocytic leukemias. We investigated the effects of PML/RAR alpha on cell survival by expressing the fusion protein in the growth factor-dependent TF-1 cell line and analyzing the kinetics of cell death after GM-CSF deprivation. Results showed that PML/RAR alpha expression markedly delayed apoptotic cell death (3 weeks vs 1 week) without inducing growth factor independence. Growth factor deprivation caused rapid and massive apoptosis of control TF-1 cells (>95% apoptotic cells after 4-5 days). Factor-deprived control cells were synchronously and irreversibly committed to apoptosis as shown by their inability to re-enter the cell cycle after GM-CSF re-addition. The percentage of apoptotic cells in the PML/RAR alpha expressing cells was low (approximately 30-35%) and constant over the 4 weeks of factor deprivation. GM-CSF re-addition produced rapid increase in cell number at all time points during the 4 weeks of factor deprivation, suggesting that commitment to apoptosis was asynchronous and delayed in PML/RAR alpha-expressing TF-1 cells. We conclude that PML/RAR alpha interferes with the genetic pathways which regulate survival by reducing the frequency of commitment to apoptosis. This biological effect of PML/RAR alpha may contribute to its leukemogenetic potential.
Leukemia 1995 Sep
PMID:The acute promyelocytic leukemia-specific PML/RAR alpha fusion protein reduces the frequency of commitment to apoptosis upon growth factor deprivation of GM-CSF-dependent myeloid cells. 765 13

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.
Leukemia 1994
PMID:Is acute promyelocytic leukemia a curable disease? Treatment strategy for a long-term survival. 781 40

Scanty information is available on acute promyelocytic leukemia (APL) in children, and whether differences are present with respect to the adult form. The experience of the Italian Pediatric Hematology and Oncology Group (AIEOP) will be presented with respect to the following aspects: 1. Incidence of APL. The incidence of APL is generally considered to account for 3-9% of acute myelogenous leukemia (AML) in children and approximately 10-15% in adults. Recently a single Italian pediatric institution reported that APL constituted one third of observed acute nonlymphocytic leukemia (AnLL) cases. Data from the AIEOP cooperative study group have confirmed that APL in Italy is more frequently observed in children as compared to other countries. Environmental and/or genetic factors should be considered to explain such differences. 2. Diagnosis of M3v. The clinical and biological features of the largest series of childhood M3v will be presented and the problems encountered in the proper separation of 'classic' M3 and M3v in children will be discussed. 3. Clinical Aspects. The clinical features of the APL patients enrolled in the AIEOP study groups since 1989, will be presented with emphasis on the recent experience with the use of all-trans retinoic acid. 4. Analysis of PML/RAR alpha Fusion Transcripts. An RT-PCR analysis of 32 pediatric APL cases from cryopreserved bone marrow samples has been performed. It is concluded that APL in children did not differ significantly from the adult form, with the exception of a higher incidence of PML bcr3 breakpoint.
Leukemia 1994
PMID:Acute promyelocytic leukemia in children: experience of the Italian Pediatric Hematology and Oncology Group (AIEOP). 781 42

Chemotherapy may decrease relapses of acute promyelocytic leukemia (APL) following induction with all-trans retinoic acid (ATRA), however the optimal timing of these two modalities remains to be determined. We treated eight patients with morphologic evidence of APL with intensive induction chemotherapy followed by ATRA (45 mg/m2/d for 10 weeks). All eight patients achieved a complete remission following chemotherapy. After a median follow-up of 29.0 months, seven patients remain in complete remission; one patient relapsed at 26.9 months. RT-PCR analysis for the PML/RAR alpha rearrangement was performed to monitor patients for evidence of minimal residual disease. Both of the patients with persistence of this rearrangement after induction chemotherapy converted to negative following ATRA. Toxicity of ATRA given in the post-remission setting was mild and consisted of headache, dry skin, and elevations of triglycerides and transaminases. No patient developed evidence of the retinoic acid syndrome. The administration of ATRA after intensive induction chemotherapy is associated with durable remissions and minimal toxicity in patients with APL. Disappearance of the PML/RAR alpha rearrangement after ATRA suggests that ATRA is effective against minimal residual disease.
Leukemia 1995 Jan
PMID:Pilot study of all-trans retinoic acid as post-remission therapy in patients with acute promyelocytic leukemia. 784 10


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