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)

Acute promyelocytic leukemia is characterized by a specific t(15;17) chromosomal translocation and a particular sensitivity to retinoic acid. The translocation fuses the PML gene to the retinoic acid receptor alpha (RAR alpha) gene resulting in the production of a PML-RAR alpha fusion protein. The hybrid molecule retains most of the functional domains of both native products, PML and RAR alpha, but it has novel features. Its cellular distribution is completely reorganized when compared to that of PML: the hybrid is found in multiple small nuclear substructures and upon retinoic acid treatment, it goes back to the normal PML localization, that is in typical well organized nuclear bodies. PML-RAR alpha also acquires novel transcriptional properties if compared to RAR alpha, it does so either by direct binding to target gene regulatory sequences or by protein interaction with cofactors. Expression of PML-RAR alpha in HL60 or U937 cell has been shown to block their maturation while it can force their differentiation at high doses of retinoic acid. Different mechanisms are proposed to explain how PML-RAR alpha blocks differentiation and how this may be reversed by retinoic acid. A likely hypothesis might be the delocalization of critical cofactors into the aberrant PML-RAR alpha substructures while the therapeutic effect of retinoic acid would be correlated to its capacity to restore a normal nuclear organization.
Leukemia 1994 Oct
PMID:The t(15;17) translocation in acute promyelocytic leukemia. 793 55

NB4 cells were derived from a patient with acute promyelocytic leukemia (APL) and, unlike HL-60 cells, display the characteristic translocation t(15:17) involving the RAR alpha receptor. NB4 cells differentiate into granulocytes in response to all-trans retinoic acid, but little is known about the ability of these cells to form monocytes and macrophages. We show here that NB4 cells treated individually with a variety of agents, including recombinant human macrophage colony-stimulating factor (M-CSF), 1,25 dihydroxy vitamin D3 (1,25 D3) or 12-O-tetradecanoyl-phorbol-13-acetate (TPA), resulted in only partial or incomplete differentiation along the monocyte/macrophage pathway. However, when M-CSF was combined with TPA, or 1,25 D3 with TPA, a synergistic response was observed such that differentiation to fully functioning monocytes or macrophages occurred. In contrast, 1,25 D3 with M-CSF resulted in only a modest increase in the number of non-specific esterase positive cells and no increase in the phagocytic activity (ingestion of latex beads) when compared to either agent alone. We suggest that TPA and 1,25 D3 are monocyte/macrophage-specific differentiation inducing agents in NB4 cells but that both are required to achieve optimal macrophage function. We suggest a model for the synergistic action of TPA and 1,25 D3 and propose that inducing monocytic differentiation could also be considered in designing clinical protocols for the treatment of acute leukemia.
Leukemia 1994 Oct
PMID:M-CSF and 1,25 dihydroxy vitamin D3 synergize with 12-O-tetradecanoylphorbol-13-acetate to induce macrophage differentiation in acute promyelocytic leukemia NB4 cells. 793 71

The retinoid receptors belong to a large superfamily of ligand-inducible transcription factors that include the steroid, vitamin D and thyroid hormone receptors, the peroxisome proliferator-activated receptor, the insect edysteroid receptor, and a number of orphan receptors whose ligands are unknown. All nuclear receptors have several well-characterized structural domains, including a conserved DNA-binding domain, and a ligand binding domain at the carboxyl terminus of the receptor. The RAR and RXR classes of nuclear retinoic acid receptors are each composed of alpha, beta and gamma subtypes with more than one isoform for each receptor subtype. Data from many investigators suggest there are RAR- and RXR-dependent gene pathways, and that the individual receptor subtypes may control distinct gene expression patterns. In addition, RXR has been found to heterodimerize with other nuclear receptors to form active transcriptional complexes, which influence the activity of a variety of gene pathways important in growth and differentiation. As a result, retinoids have been useful clinical agents in Dermatology and Oncology. However, upon prolonged exposure to retinoic acid, resistance to retinoids has often been encountered both in the clinical setting and in long-term cell culture (HL60R and RAC65 cells). In the latter case, retinoid resistance has been associated with a mutation in the RAR gene which transcribes a RAR receptor truncated at the C-terminal end. These mutated RAR receptors exhibit a reduced affinity for retinoic acid while retaining the ability to bind to a retinoic acid response element on DNA. As a result, these mutant receptors exhibit dominant-negative activity by binding to the DNA without activating transcription and by competing with other receptors for sites on the response element. In fact, dominant-negative activity may be very important in the development of many neoplastic diseases, including acute promyelocytic leukemia (APL), where a t(15;17) chromosomal translocation fuses the PML gene to the RAR gene, to produce a PML-RAR fusion protein in large excess in the cell. However, retinoid resistance in the patient is most probably the result of pharmacokinetic problems, whereby, with continuous retinoid treatment, the plasma levels of retinoic acid gradually decrease to below that required to maintain differentiation of leukemic cells in vivo. A major challenge for drug discovery is to design a drug which circumvents these pharmacokinetic problems either by designing novel drug delivery systems or by employing retinoids which do not bind to CRABP, such as 9-c-RA.(ABSTRACT TRUNCATED AT 400 WORDS)
Leukemia 1994 Nov
PMID:The retinoid receptors. 796 25

Acute promyelocytic leukemia (APML) almost always involves a chromosomal translocation t(15:17) that results in the fusion of the retinoic acid receptor alpha (RAR alpha) gene with a transcription factor gene called PML. Several cases of APML with t(11;17) have recently been described, involving fusion of the RAR alpha gene with a new zinc finger gene named PLZF. We report here a second non-classical translocation, t(5;17), with a rearranged RAR alpha gene in a child with APML. Based on restriction endonuclease analysis, the rearrangement of RAR alpha occurred within the second intron, the common breakpoint site for t(15;17). The leukemic cells in the bone marrow aspirate were a mixture of hypergranular and hypogranular bilobed promyelocytes. Although less than 1% abnormal promyelocytes were identified after induction therapy, cytogenetics revealed persistent t(5;17). Therefore, the child was treated with all-trans-retinoic acid (ATRA). There was no disease progression, and one marrow was interpreted as remission, with confirmation by cytogenetics which failed to reveal the translocation. However, disease reoccurred shortly after completion of ATRA. This poor response to ATRA may be an additional characteristic associated with non-classical translocations in APML. The identification of a second variant translocation involving the RAR alpha gene in APML suggests yet another RAR alpha rearrangement related to neoplastic myelopoiesis.
Leukemia 1994 Aug
PMID:A non-classical translocation involving 17q12 (retinoic acid receptor alpha) in acute promyelocytic leukemia (APML) with atypical features. 805 72

Acute promyelocytic leukaemia (APL) is a rare acute myeloid leukaemia characterized by a distinctive coagulopathy, the differentiation of promyelocytes in response to all-trans retinoic acid and a reciprocal chromosomal translocation, t(15;17)(q22;q12-q21). Molecular analysis of the APL breakpoint has revealed the involvement of the retinoic acid receptor alpha (RARA) gene on chromosome 17 and the promyelocytic leukaemia (PML) gene on chromosome 15. Both reciprocal fusion products which arise as a result of the translocation, PML/RAR alpha and RAR alpha/PML, are expressed in many patients. PML/RAR alpha, is implicated in leukaemogenesis, and may block myeloid differentiation directly and/or interfere with the normal function(s) of PML and/or RAR alpha.
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PMID:Acute promyelocytic leukaemia and the t(15;17) translocation. 814 21

The characteristic balanced 15;17 translocation, t(15;17), of acute promyelocytic leukemia (APL) fuses the retinoic acid receptor alpha (RAR alpha) gene on chromosome 17 to PML, a recently described gene of unknown function, on chromosome 15. It is this fusion gene and consequent fusion protein that is thought to be responsible for both the block in normal myelocyte differentiation as well as the dramatic in vitro and in vivo response to the differentiating effects of all-trans retinoic acid (RA). The t(15;17) also provides a genetic marker for the presence of leukemic cells. PML/RAR alpha fusion mRNA's can be detected by a reverse transcription polymerase chain reaction (RT-PCR) assay. Using this assay, at least three distinct patterns, differing in the 3' region of the PML breakpoint, can be identified. The detection of abnormal mRNA's by the RT-PCR assay has proven to be an important aid in the diagnosis of APL as well as the best predictor of an initial clinical response to RA. The results of an ongoing, longitudinal evaluation of patients with APL show that the RT-PCR assay may also be a useful indicator of minimal residual disease (MRD). Negative RT-PCR assays following completion of all therapy are associated with prolonged disease free survival, whereas persistence or return of a positive test is highly correlated with subsequent relapse. Further studies will determine whether patients who test positive may benefit from the introduction of additional antileukemic therapy.
Leukemia 1994 Apr
PMID:Molecular diagnosis and monitoring of acute promyelocytic leukemia treated with retinoic acid. 815 76

We performed clonality studies of hemopoietic reconstitution in 24 female patients (pts) with leukemias characterized by specific tumor markers. Thirteen pts had Acute Promyelocytic Leukemia (APL) with rearrangements of the RAR-a and PML genes, 8 BCR rearranged (BCR+)/Ph+ Chronic Myeloid Leukemia (CML) and 3 BCR+/Ph+ Acute Lymphoid Leukemia (ALL). Bone marrow (BM) DNA samples were obtained at diagnosis and at remission after Southern blot documented suppression of specific markers. The clonal or non-clonal nature of hemopoietic reconstitution was assessed by hybridizing the same DNAs with the M27 beta probe, in order to detect methylation differences at the X-linked DXS255 locus. Twenty four pts showed a polyclonal methylation pattern at remission, whereas in 3 cases an apparently clonal pattern was observed despite no evidence of specific gene rearrangement. In 2 of these 3 cases, however, DNAs derived from non-affected tissues (T lymphocytes, skin and BM fibroblasts) revealed the presence of the same DXS255 unmethylated allele detected at diagnosis, while in the third case we found the same apparently clonal pattern in blood mononuclear cells obtained from her healthy female BM donor. These data indicate that polyclonal hematopoiesis occur in APL and CML pts after therapy induced suppression of specific tumor markers, and that unbalanced or aberrant X chromosome methylation patterns are observed in some cases, most likely reflecting constitutional features.
Leukemia 1994 Apr
PMID:Polyclonal hemopoiesis in leukemia patients following molecularly documented remission. 815 81

Acute promyelocytic leukaemia is characterized by an expansion of haematopoietic precursors arrested at the promyelocytic stage (1). The differentiation block can be reversed by retinoic acid, which induces blast differentiation both in vitro (2) and in vivo (3-4). Acute promyelocytic leukaemia is also characterized by a 15;17 chromosome translocation (5) with breakpoints within the retinoic acid alpha receptor (RAR alpha) gene on 17 and within the PML gene, that encodes a putative transcription factor of unknown function (6-7), on 15 (8-10). As a consequence of the translocation a PML/RAR alpha gene is formed. It is transcriptionally active and encodes a PML/RAR alpha fusion protein detectable in all APL cases (11-14). We expressed the PML/RAR alpha protein in U937 myeloid precursor cell line and show that they: 1) lose the capacity to differentiate under the action of different stimuli (vitamin D3, transforming growth factor beta 1); ii) acquire enhanced sensitivity to retinoic acid; iii) exhibit a higher growth rate that is due to a reduction in apoptotic cell death. These results provide the first evidence of biological activity of PML/RAR alpha and recapitulate critical features of the promyelocytic leukemia phenotype.
Leukemia 1994 Apr
PMID:Effect of the acute promyelocytic leukemia PML/RAR alpha protein on differentiation and survival of myeloid precursors. 815 8

The molecular mechanisms underlying the t(15;17) cytogenetic translocation of acute promyelocytic leukaemia (APL) have been recently elucidated. Together with new insights into the understanding of APL pathogenesis, such investigations also provided the availability of a novel leukemia-specific marker to be used for both diagnostic and monitoring studies. The chromosome breakpoints of the t(15;17) have been shown to involve the retinoic acid receptor alpha (RAR-a) gene and the newly described PML gene on chromosomes 17 and 15, respectively. Rearrangements of these loci are found in virtually 100% of APLs, including the microgranular variant subtype and cases displaying apparently normal karyotypes. In cases with ambiguous morphology, molecular diagnosis may therefore enable the prompt administration of APL-specific therapies, such as all-trans retinoic acid. Significantly, clinical response to this differentiating agent is predictable based on the presence of the specific PML/RAR-a rearrangement. Appropriate oligoprimers complementary to PML and RAR-a sequences nearby the DNA breakpoints may be successfully used in PCR experiments to amplify the PML/RAR-a hybrid gene and sensitively detect minimal residual disease. Preliminary PCR studies indicate that this approach might indeed prove a very important and reliable prognostic indicator in the follow up monitoring of APL patients. Early identification of impending relapse by PCR may suggest the use of additional treatment in patients at risk and significantly increase the probability of cure of the disease.
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PMID:Clinical relevance of the PML/RAR-a gene rearrangement in acute promyelocytic leukaemia. 818 May 96

A basis for differentiation therapy of leukemias is provided by knowledge of agents which induce specific lineage maturation. All-trans retinoic acid (RA) induces differentiation of HL60 cells to neutrophils and is used to treat acute promyelocytic leukemia. We observed that RA did not induced neutrophil differentiation in serum-free grown HL60 cells whereas 50 nM 1 alpha,25-dihydroxyvitamin D3 (D3) induced maximal monocyte differentiation. Increasing RA concentrations reduced the D3 concentration required for monocyte differentiation. Cells treated with 5 nM D3 showed little response, but differentiated maximally with 5 nM D3 and 10 nM RA. The D3 analogs MC903, EB1089 and KH1060 were more potent inducers of monocyte differentiation. The extent to which analog activity was increased after cotreatment with RA was inversely related to potency. Twenty-four hour treatment with 10 nM RA primed cells for response to 5 nM D3; the reverse sequence being ineffective. Priming with 10 nM RA, or subsequent treatment with D3 (5 nM), did not alter expression of mRNAs encoding receptors for D3 (VDR), RA (RAR alpha) or 9-CIS RA (RXR alpha, beta, gamma). That RA promotes both neutrophil and monocyte differentiation has implications for the use of RA and D3 in treatment of leukemias and provides insight into mechanisms whereby RAR, VDR and RXR facilitate monocyte differentiation.
Leukemia 1994 May
PMID:All-trans retinoic acid and 1 alpha,25-dihydroxyvitamin D3 co-operate to promote differentiation of the human promyeloid leukemia cell line HL60 to monocytes. 818 38


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