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

Progressive multifocal leukoencephalopathy, a slowly progressive papovavirus infection of the CNS, has been reported in more than 110 patients to date, over half of whom have had either leukemia or lymphoma. Our patient is the fourth case of PML occurring after long-term immunosuppression for renal transplantation. We believe that PML is emerging as a potentially serious problem in renal transplant recipients.
 ...
PMID:Progressive multifocal leukoencephalopathy in renal transplant recipients. 13 9

Recent investigations have clarified some of the molecular mechanisms underlying the t(15;17) translocation specific for acute promyelocytic leukaemia (APL). Together with providing new insights into the pathogenesis of the disease, the identification of breakpoints within the RAR-alpha and PML loci on chromosomes 17 and 15 has allowed a new relevant diagnostic tool for the recognition of this leukaemic form. We report the molecular characterization of 6 cases of acute myelogenous leukaemia (AML) in which a diagnosis of typical M3 by conventional morphocytochemistry (FAB criteria) was not accompanied by cytogenetic evidence of the specific t(15;17) aberration. DNA rearrangements were documented in all cases at the PML and RAR-alpha loci. Moreover, in 4 cases also analysed by Northern blot hybridization, we could detect aberrant RAR-alpha transcripts. These findings highlight the specificity of PML/RAR-alpha rearrangements in APL, whereas the lack of t(15;17) may be attributed to sub-microscopic translocations as well as to the presence of non-neoplastic cells undergoing mitosis in the samples examined for karyotype.
 ...
PMID:PML/RAR-alpha rearrangement in acute promyelocytic leukaemias apparently lacking the t(15;17) translocation. 131 68

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.
 ...
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

It has become apparent that a number of genes disrupted by chromosomal rearrangements during leukaemogenesis encode protein factors involved in transcriptional regulation (20-25) and PML may be another such gene. The replacement of the NH2-terminal transactivation domain in RAR alpha by the PML putative DNA binding and transactivation domains in the PML/RARA fusion produces a novel chimeric protein which may act to block normal myeloid differentiation through disregulation of the genes normally regulated by either or both of the normal proteins.
Leukemia 1992
PMID:A previously uncharacterized gene, PML, is fused to the retinoic acid receptor alpha gene in acute promyelocytic leukaemia. 131 62

APL (FAB M3) is a unique type of myeloid leukaemia characterized by specific clinical, morphological, cytogenetic and molecular features. An early and accurate diagnosis is necessary to initiate therapy and treat the life-threatening coagulopathy caused by release of procoagulants from the abundant promyelocytic granules. Cytogenetically the disease is characterized by a reciprocal translocation between the long arms of chromosomes 15 and 17, t(15;17)(q21;q22), which is seen in almost every patient with APL but in no other form of malignancy. The presence of this translocation, often as the only karyotypic change, suggests that potentially leukaemogenic sequences are located at the breakpoints and are activated by rearrangement. The recent cloning of the breakpoints by three groups has demonstrated that the retinoic acid receptor alpha gene (RARA) on chromosome 17 is fused to a previously undescribed transcription factor gene, PML, on chromosome 15. The DNA-binding motifs of both the RARA and PML proteins, together with the ligand-binding domain of RARA, are combined in a single fusion protein which may dysregulate either retinoic acid or PML-sensitive pathways. Identification of these dysregulated target genes has become the next molecular goal for research on APL. Intriguingly, some APLs not only express the PML-RARA fusion protein but also the reciprocal RARA-PML fusion protein, although the contribution of this product is unclear. The PML-RARA chimaeric protein is presumably the target during the striking differentiation therapy achieved with all-trans retinoic acid. This therapy induces the malignant promyelocytes to mature and die, rather than continue proliferating. Moreover, it represents the first direct connection between a genetic defect and clinical treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Molecular analysis of the t(15;17) translocation in acute promyelocytic leukaemia. 133 90

Human myeloid leukemia cells do not differentiate into functional end-cells but remain in the proliferation pool. Human cell lines can serve as model for hematopoietic cells arrested at different stages of myeloid differentiation and helps to dissect the cellular and molecular events involved in leukemogenesis. Furthermore, several agents have been identified as inducers of differentiation of leukemia cells. Exciting new clinical observation have shown that patients with APL respond well to the treatment with all-trans retinoic acid. RAR-alpha gene was proved to translocated from chromosome 17 to a locus PML on chromosome 15. This new chimeric gene, PML-RAR alpha is extremely important to understand the leukemogenesis of APL.
 ...
PMID:[Induction of differentiation of human leukemia cells]. 138 72

We report the isolation of a maturation-resistant acute promyelocytic leukemia (APL) cell line. This permanent cell line, derived from the same patient as the maturation inducible NB4 cell line, is the first retinoid-resistant cell line with a t(15;17) chromosomal translocation. Morphological, immunocytochemical and molecular features of the maturation responsive (NB4) and unresponsive (NB4-RAr) cells are compared. The isolation of the NB4-RAr cell line occurred through a two-step process requiring the continuous selective pressure of all-trans-retinoic acid. Cells are also resistant to 13-cis-retinoic acid. Karyotypic and Southern-blot analyses show that the two cell lines are similar with respect to the translocation. Northern-blot analyses show that the chimeric fusion transcript PML-RAR alpha and the normal allelic PML and RAR alpha transcripts are similarly expressed in both cell lines. The molecular basis for unresponsiveness to retinoic acid is not known. This resistant cell line offers a cellular model for molecular biology studies on the mechanism of induction of APL cell maturation, as well as a means to elucidate the molecular mechanisms of resistance. It also furnishes a unique tool for designing and/or screening new therapeutic drugs to avoid or relieve retinoid maturation blockage.
Leukemia 1992 Dec
PMID:A retinoid acid 'resistant' t(15;17) acute promyelocytic leukemia cell line: isolation, morphological, immunological, and molecular features. 145 73

The acute promyelocytic leukaemia (APL)-specific chromosome 15;17 translocation leads to the fusion of a newly identified putative transcription factor, PML, and the retinoic acid receptor alpha. We have characterized the structure of the PML genomic locus and preliminarily characterized its expression pattern. The PML locus spans a minimum of 35 kb and is subdivided into nine exons. The putative PML DNA binding site is encoded by exons 2 and 3. We isolated a large number of alternatively spliced PML transcripts that encode numerous PML isoforms. Two groups of isoforms were identified that differed either in their C-terminal region or in the length of their central region, but retained the putative DNA-binding and dimerization domains. RNAase protection experiments revealed that the different PML isoforms are equally expressed in established cell lines of different histological origin.
 ...
PMID:Alternative splicing of PML transcripts predicts coexpression of several carboxy-terminally different protein isoforms. 159 41

Acute promyelotic leukemia is characterized by a t(15;17) chromosomal translocation which results in fusion products between PML (chromosome 15) and RAR-alpha (chromosome 17). We describe 2 classes of patients which possess different PMLRAR and RARPML fusion transcripts. We then discuss the functional properties of PML and show that PMLRAR can interfere with both PML and RAR-alpha functions.
 ...
PMID:[Fusion proteins between PML and alpha-RAR in acute promyelocytic leukemia]. 166 21

This study comprises 187 patients aged over 15 years with acute leukaemia, diagnosed and treated between the years 1969 and 1978. Fourteen (7.5%) survived for more than 5 years after diagnosis. In this group of survivors there were 7 patients with AML and 6 with ALL--corresponding to 8.9 and 21.4% of each collective, respectively--and 1 patient with PML. Four patients (28.6%) died after a survival time exceeding 5 years, 1 patient with AML as a result of a gastric carcinoma and the 3 other patients (1 AML, 2 ALL) of the original disease. Hence, survival times over several years do not necessarily mean real cures. From an analysis of our data, no factor correlating with long-term survival was identifiable. In terms of clinical-diagnostic parameters the group of late relapses was also heterogeneous.
 ...
PMID:[Long-term survival and fatal late relapse in acute leukaemia in adults]. 661 32


1 2 3 4 5 6 7 8 9 10 Next >>