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)

PML is a protein associated with discrete spherical structures within the nucleus of normal cells. A defect in PML expression is observed in acute promyelocytic leukaemia as a consequence of a chromosomal translocation involving the genes encoding PML and the alpha retinoic acid receptor (RAR alpha). Disruption of PML bodies also occurs during herpes simplex virus infection after the immediate early protein Vmw110 has become associated with PML bodies. In this study, we followed the fate of PML bodies in human fibroblasts during the course of a human cytomegalovirus (CMV) infection. Disruption of PML bodies was observed to be dependent on de novo CMV gene expression and to occur within 4 h post-infection, concomitant with the onset of CMV IE gene expression. Although a transient increase in the number of PML bodies could be observed in some cells, PML exists predominantly as a diffuse nuclear protein during both the early and late stages of CMV infection. Although the function of PML bodies is still uncertain, their disruption may be important for efficient herpes virus replication.
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PMID:Disruption of PML-associated nuclear bodies during human cytomegalovirus infection. 759

Acute promyelocytic leukemia (APL) is characterized by a consistent chromosomal aberration that fuses the retinoic acid receptor alpha (RAR alpha) gene with the novel gene PML, resulting in the expression of a PML/RAR-alpha fusion protein. Immunohistochemical examination of APL cells shows a unique abnormal distribution of anti-PML and anti-RAR alpha antibody labeling. The PML labeling pattern observed in normal cells consists of 5 to 10 discrete spherical nuclear bodies called PODs (for "PML oncogenic domains"), whereas that of APL consists of a smaller and far more numerous speckled pattern. We examined malignant cells from patients with a variety of hematopoietic cancers by immunohistochemistry (IH) and found this abnormal PML pattern expressed in cells from patients with t(15;17)-associated leukemia but not in patients with other neoplastic disorders. IH results agreed with reverse transcription polymerase chain reaction for PML/RAR-alpha in 31 of 32 patients with acute myelogenous leukemia, including 5 of 5 patients in whom the initial clinical diagnosis of APL was not supported by cytogenetics, molecular tests, or response to all-trans retinoic acid (RA). Cells from patients with APL were examined during the course of retinoid therapy and at the time of complete remission and relapse. Reorganization of the PML labeling into PODs with normal appearance was observed in cells from patients who received RA. IH showed primarily normal PML staining during clinical remission, although the APL-specific labeling pattern was again seen in cells taken from patients at the time of relapse. Thus, IH provides an independent assay for the presence and expression of the molecular rearrangement of APL. The relative ease and speed of detecting the APL-specific PML labeling pattern should make IH a useful diagnostic tool to guide specific therapy of APL, and establish a direct assay for PML/RAR-alpha protein expression and localization in individual patient cells.
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PMID:Rapid diagnosis of acute promyelocytic leukemia by immunohistochemical localization of PML/RAR-alpha protein. 762 Jan 82

Promyelocyte Leukemia Zinc Finger (PLZF) is a Kruppel-like zinc finger gene previously identified in a unique case of acute promyelocytic leukemia (APL) as the counterpart of a reciprocal chromosomal translocation involving the retinoic acid receptor alpha gene (RAR alpha). PLZF is highly conserved throughout evolution from yeast to mammals. To elucidate its role, we isolated the murine PLZF gene and studied its expression during embryogenesis. PLZF is expressed in an extremely dynamic pattern with transcripts appearing at E 7.5 in the anterior neuroepithelium and quickly spreading to the entire neuroectoderm until E 10. At E 8.5, PLZF is transcribed in most of the endoderm. During mid to late gestation PLZF is expressed in restricted domains of the developing CNS as well as in specific organs and body structures. We have focused our attention on the developing forebrain where PLZF is transcribed in a transverse, segment-like domain corresponding to the anterior pretectum, in the alarmost part of the dorsal thalamus, in the epithalamus, and in the hypothalamus along a defined longitudinal subdomain. Furthermore, PLZF is expressed in several segmentary boundaries, among them, the zona limitans intrathalamica. Combined analysis with other regionally restricted genes, such as Orthopedia and Dlx1, indicates that in the hypothalamus the PLZF domain is contained within that of Orthopedia and both are complementary to that of Dlx1. Our data suggest a role for PLZF in the establishment and maintenance of transverse identities, longitudinal subdomains, and interneuromeric boundaries, providing additional evidences in favor of the neuromeric organization of the forebrain.
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PMID:Developmental analysis of murine Promyelocyte Leukemia Zinc Finger (PLZF) gene expression: implications for the neuromeric model of the forebrain organization. 762 23

The biological activity of a novel synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN) was investigated in human breast carcinoma (HBC) cells. Although capable of selective binding to the RAR gamma nuclear receptor, AHPN inhibited the growth of a number of HBC cell lines via RAR- or RXR-independent pathways. AHPN also inhibited the growth of the human leukemia cell line HL-60R which does not possess functional RARs. RA significantly inhibited AP-1 mediated gene activation in MCF-7 cells while AHPN displayed no such anti-AP-1 activity. Retinoids normally are cytostatic in their inhibition of breast carcinoma growth and permit cell proliferation upon their removal, wher as AHPN induced G0/G1 arrest within 6h followed by apoptosis. In MCF-7 cells that harbor wild type p53, AHPN-induced G0/G1 arrest and apoptosis was accompanied by p53-independent regulation of WAF1/CIP1 as well as bax mRNA levels while bcl-2 mRNA levels were decreased. In MDA-MB-231 cells which possess a mutant p53, AHPN-mediated G0/G1 arrest and apoptosis was also associated with a concomitant up regulation of WAF1/CIP1 mRNA while these cells did not express bax or bcl-2 messages. Thus AHPN represents a novel retinoid that induces G0/G1 arrest and apoptosis via a unique pathway which appears to involve activation of known downstream effectors of p53 in a p53-independent manner.
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PMID:p53 independent G0/G1 arrest and apoptosis induced by a novel retinoid in human breast cancer cells. 763 Jun 33

Acute promyelocytic leukaemia (APL) is characterized by t(15;17), which results in the formation of two chimaeric genes, PML-RAR alpha and RAR alpha-PML. PML-RAR alpha transcripts have been detected in all cases of APL whilst those of RAR alpha-PML have been detected in only about 67% of cases. We have used reverse transcriptase polymerase chain reaction (RT-PCR) to detect both fusion transcripts serially in 18 patients in remission of APL after chemotherapy and bone marrow transplantation. All patients were negative for PML-RAR alpha, whereas in six patients (remission 3-9 years) RAR alpha-PML was consistently detected. Only one patient at remission showed the 5' breakpoint RAR alpha-PML, with the rest showing the 3' breakpoint 144 bp RAR alpha-PML. The level of sensitivity for detecting RAR alpha-PML was some 10-fold higher than that for PML-RAR alpha. Serial negative tests for PML-RAR alpha have been correlated with durable remissions, suggesting possible eradication of residual leukaemia in APL. Our results, however, show persistence of t(15;17) cells expressing RAR alpha-PML fusion mRNA in patients in long-term remission of APL. They indicate that patients considered clinically 'cured' of APL still have molecular evidence of minimal residual disease and also provide further insight into the biology of acute myeloid leukaemia.
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PMID:Persistence of RAR alpha-PML fusion mRNA detected by reverse transcriptase polymerase chain reaction in patients in long-term remission of acute promyelocytic leukaemia. 764 2

The very rapid development of techniques based on use of the polymerase chain reaction (PCR) for characterizing molecular lesions in leukaemia and lymphoma mow offers the opportunity for monitoring residual disease at a sensitivity of one malignant cell in 10(5) or 10(6) normal cells. Maximal specificity is achieved when the DNA sequences amplified are truly leukaemia-specific (i.e. BCR/ABL in CML, PML/RAR-alfa in APL, AML1/ETO in t(8; 21) AML and CBFB/MYH1 in inv(16) AML). A good level of sensitivity may also be achieved by using immunoglobin heavy chain (IGH) and T-cell receptor (TCR) gene rearrangements if a clonospecific probe can be generated. For clinical purposes the crucial issues are the following: can PCR techniques be used for confirmation of diagnosis and evaluation of extent of disease? Can PCR data obtained be developed to quantitate the PCR product and thereby increase its predictive value? These and other issues are still a matter of debate and several studies are presently in progress to address these points.
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PMID:Minimal residual disease detection in human leukemias: biologic and clinical significance. 765 31

Retinoic acid (RA) is a vitamin A derivative with striking effects on development and cell differentiation. The identification of three RA receptors (RAR alpha, beta and gamma) as members of the nuclear receptor superfamily led to important insights into the molecular mechanism of action of retinoids. The nuclear receptors, that also include receptors for steroid hormone, vitamin D3 and thyroid hormone act as ligand-inducible transcription factors and are characterized by the presence of two well conserved DNA- and hormone-binding domains. One of the most intriguing properties of RA is its ability to induce in vivo differentiation of acute promyelocytic leukaemia (APL) cells into mature granulocytes, leading to morphological complete remissions. We and others have shown that the t(15;17) translocation specifically associated with APL fuses an as yet unidentified gene, named PML, to the retinoic acid receptor alpha locus. The resulting PML-RAR alpha hybrid protein that retains most of the functional domains of parental proteins exhibits altered transactivating functions when compared to the wild-type receptor; however the biological significance of this property in the transforming phenotype is still obscure. PML, whose function is unknown, belongs to a novel family of nuclear proteins characterized by the presence of a Cys/His-rich motif, named a RING finger, that include RNA-binding proteins, transcription factors and oncoproteins. A dimerization domain within PML is able to mediate the formation of PML-RAR alpha homodimers that can bind to target sequences with distinct DNA binding properties if compared with RAR alpha.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The t(15;17) translocation in acute promyelocytic leukemia. 767 45

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
PMID:The retinoid receptors. 780 17

Secondary leukaemia following treatment of M3 acute promyelocytic leukaemia (APL) is a rare event. We describe a patient in remission following chemotherapy for APL who relapsed with M2 acute non-lymphoblastic leukaemia (ANLL). The original t(15;17) (q22;q21) chromosome translocation was lost and replaced by a clone containing a dic(5;17) (q11;p11) abnormality. Southern genomic analysis demonstrated re-arrangements of the retinoic acid receptor varies; is directly proportional to (RAR varies; is directly proportional to) and PML genes in the APL blasts at presentation but not in the M2 ANLL marrow at relapse. The significance of unbalanced 5;17 translocations as markers for therapy-related secondary leukaemia is discussed.
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PMID:Acute promyelocytic leukaemia (M3): relapse with acute myeloblastic leukaemia (M2) and dic(5;17) (q11;p11). 783 90

We report a patient with acute promyelocytic leukaemia who developed marked basophilia during all-trans retinoic acid treatment. We studied genomic DNA and RNA extracted from the patient's peripheral leucocytes in order to determine the origin of the basophils. The RAR alpha rearranged band in the Southern blot analysis and a chimaeric product of PML-RAR alpha by polymerase chain reaction were strongly visible before ATRA treatment, but at the time of maximal basophilia both of them were markedly diminished. These findings suggest that the basophils which appeared during the ATRA treatment are reactive in nature rather than a leukaemic clone.
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PMID:Marked basophilia in acute promyelocytic leukaemia treated with all-trans retinoic acid: molecular analysis of the cell origin of the basophils. 791 86


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