Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0598766 (leukemogenesis)
 4,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

All-trans-retinoic acid (ATRA), a vitamin A derivative, is a safe and effective drug in the obtention of complete remission in acute promyelocytic leukemia (APL). ATRA is able to activate the maturation of malignant cells from patients with APL either in vitro or in vivo. Complete remission was obtained without any feature of aplastic phase and the severe bleeding diathesis rapidly disappeared. The major adverse effect is the occurrence of hyperleukocytosis which is prevented by the addition of chemotherapy. A progressive acquired resistance appears during ATRA treatment and prolonged event free survival time is obtained after consolidation with cytotoxic drugs. In APL the retinoic acid receptor alpha gene is rearranged and fused with a novel gene called PML. The hybrid PML-RAR product could have a role in the leukemogenesis blocking the effect of the normal RAR on target genes. Retinoic acid exerts a differentiating effect either by the induction of a normal activity of the aberrant product in the presence of pharmacological concentration, or by an over-expression of the normal allele. The results obtained by cellular and molecular biology gave opportunities to confirm the diagnosis, to follow the assessment of the minimal residual disease and to understand the acquired resistance.
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PMID:All-trans-retinoic acid treatment and retinoic acid receptor alpha gene rearrangement in acute promyelocytic leukemia: a model for differentiation therapy. 131 9

Acute promyelocytic leukemia is a clonal expansion of malignant cells blocked at a specific stage of myeloid differentiation. The disease is associated with a specific translocation between chromosome 17 and chromosome 15 [t(15;17)] and with a bleeding diathesis previously attributed to disseminated intravascular coagulation, which has recently also been related to primary fibrinolysis. The high percentage of early deaths, about 20%, experienced by acute promyelocytic leukemia patients, is generally due to the hemorrhagic syndrome. A new finding is the high effectiveness of treatment with all-trans retinoic acid, a vitamin A derivative, for inducing complete remission. The induction of cellular maturation by this agent represents the first model of differentiation therapy. Furthermore, recent molecular studies revealed that the breakpoints of the t(15;17) translocation are clustered in the gene of retinoic acid receptor-alpha, generating a hybrid gene product. Gene transfection experiments disclosed the impairment of gene transactivation due to the hybrid gene products, opening new concepts for understanding leukemogenesis. Understanding the mechanisms of action of retinoic acid could extend differentiation therapy to other malignancies with aberrant gene transcription.
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PMID:Retinoic acid in acute promyelocytic leukemia: a model for differentiation therapy. 131 15

To investigate leukemogenesis of acute promyelocytic leukemia (APL), we studied the involvements of retinoic acid receptor alpha (RAR alpha) and myl genes, and also the frequency of N-RAS, K-RAS, H-RAS, and FMS point mutations in sixteen patients with APL. By Southern blot analysis, the rearrangements of RAR alpha gene were detected in 13 patients (81.2%), and myl gene in 14 (87.5%). Either RAR alpha or myl gene rearrangements were found in all patients including one with normal karyotype. Breakpoints of both genes were clustered. By direct sequencing, no point mutations were found at codons 12, 13, and 61 of N-, K-, and H-RAS genes, and at codons 301 and 969 of FMS gene. These data indicate that myl-RAR alpha translocation occurs frequently in APL, whereas RAS and FMS mutations are rare in APL. It may be suggested that leukemogenesis of APL is different from other subtypes of acute myelogenous leukemia, and multistep leukemogenesis may not be a prevalent feature in APL.
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PMID:Frequent rearrangements of retinoic acid receptor alpha gene and myl gene, and rare mutations of RAS and FMS genes in acute promyelocytic leukemia. 132 28

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.
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PMID:[Induction of differentiation of human leukemia cells]. 138 72

This is the first report in Israel of the successful treatment of acute promyelocytic leukemia (APL; M3) with an active metabolite of vitamin A. In a 42-year-old woman with APL all-trans-retinoic acid (ATRA; tretinoin), 45 mg/m2/day was given per os for 90 days. APL is associated with a distinct cytogenetic abnormality: translocation of a portion of the long arm chromosome 17 onto the long arm chromosome 15t (15; 17) with a breakpoint on chromosome 17 in the region of the retinoic acid receptor-alpha (RAR-alpha), playing a crucial role in the leukemogenesis of APL. In man, the drug induces myeloid and mainly promyelocytic leukemic cells to differentiate, without the development of bone marrow hypoplasia. In our patient it caused complete remission and the disappearance of intravascular disseminated coagulation. The only side-effects were a transient macular rash, gastrointestinal symptoms and mild hypertriglyceridemia. Other principal adverse effects reported in the literature are relatively not very serious and consist of dryness of the skin, occasional headaches and intracranial hypertension, nasal congestion, lymphadenopathy, respiratory distress with infiltrates in the lung, bone pain and increased hepatic aminotransferase. A hyperleukocytosis syndrome seems to be more problematic. ATRA appears to be superior to conventional chemotherapeutic regimens. It is safe and highly effective in inducing clinical, morphologic and karyotypic remission with a marked decrease in the expression of the abnormal RAR-message in APL. There is a possible molecular link between the pathogenesis and treatment of this severe and often fatal coagulopathic disease. This therapy of course does not eradicate the leukemic clone, and consolidation chemotherapy or bone marrow transplantation is necessary.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Remission of acute promyelocytic leukemia after all-trans-retinoic acid]. 148 98

We have previously shown that the t(15;17) translocation specifically associated with acute promyelocytic leukemia (APL) fuses the retinoic acid receptor alpha (RAR alpha) locus to an as yet unknown gene, initially called myl and now renamed PML. We report here that this gene product contains a novel zinc finger motif common to several DNA-binding proteins. The PML-RAR alpha mRNA encodes a predicted 106 kd chimeric protein containing most of the PML sequences fused to a large part of RAR alpha, including its DNA- and hormone-binding domains. In transient expression assays, the hybrid protein exhibits altered transactivating properties if compared with the wild-type RAR alpha progenitor. Identical PML-RAR alpha fusion points are found in several patients. These observations suggest that in APL, the t(15;17) translocation generates an RAR mutant that could contribute to leukemogenesis through interference with promyelocytic differentiation.
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PMID:The PML-RAR alpha fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. 165 69

We have recently demonstrated that all-trans retinoic acid (RA), the active metabolite of vitamin A, is an efficient alternative to chemotherapy in the treatment of acute promyelocytic leukemia (AML3). We have further shown that, in these AML3 cells, the gene of the retinoic acid receptor-alpha (RAR alpha) is translocated from chromosome 17 to chromosome 15, and fused to a new gene, PLM. This results in the expression of both normal and chimeric RAR alpha transcripts in AML3 cells. The PLM-RAR alpha protein may account for the impairment of differentiation and thus leukemogenesis, but not for the paradoxical efficacy of RA in these cells. In an attempt to elucidate RA's differentiative effect in AML3 patients, the present work examined the in vitro and in vivo modulation of the normal RAR alpha transcripts by all-trans RA in seven cases of AML3. In all samples, Northern blot analysis revealed a low expression of the two normal RAR alpha transcripts compared with other human myeloid leukemic cells. No modulation was observed after 4-8 d of in vivo therapy with all-trans RA 45 mg/m2 per d. In vitro incubation with all-trans RA, however, increased the level of expression of the normal RAR alpha transcripts in AML3 cells but not in other AML leukemic subtypes. This modulation of the two normal RAR alpha transcripts appeared to be an early and primary event of RA's differentiating effect. We therefore suggest that up-regulation of the normal RAR alpha gene expression by pharmacological concentrations of all-trans RA may restore the normal differentiation pathway in these cells.
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PMID:All-trans retinoic acid modulates the retinoic acid receptor-alpha in promyelocytic cells. 166 1

Acute promyelocytic leukemias (APLs) are characterized by a reciprocal balanced translocation that involves chromosomes 15 and 17 [t(15;17)]. We report the isolation and characterization of one of the two reciprocal break sites and demonstrate that the chromosome 17 breakpoint lies within the retinoic acid receptor alpha locus. Nucleotide sequencing of the 15;17 cross-over junction on 15q+ showed that the retinoic acid receptor alpha gene is truncated within its first intron, 370 base pairs upstream from the splicing donor site of exon II. Such a recombination would be expected to generate abnormal RAR alpha mRNA and protein. Southern blot analysis of a number of APLs with chromosome 15- and 17-derived DNA probes revealed similar 15;17 recombinations in the majority of other APLs. Our data are strong evidence that the retinoic acid receptor alpha gene plays a crucial role in the leukemogenesis of APL.
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PMID:Translocation breakpoint of acute promyelocytic leukemia lies within the retinoic acid receptor alpha locus. 184 17

All-trans retinoic acid (RA), the active metabolite of vitamin A, has recently been demonstrated to be an efficient alternative to chemotherapy in the treatment of acute promyelocytic leukemia (M3 subtype of the French-American-British cytological classification). Complete remission is obtained by inducing terminal granulocytic differentiation of the leukemic cells. To elucidate whether the effect of retinoic acid on the differentiation of M3 leukemic cells was related to any specific characteristics of its receptor, we analyzed the structure and expression of retinoic acid receptor (RAR) genes in 16 M3 patients. Abnormal RAR alpha transcripts were detected in 13 cases. In nine patients, the genomic DNA was analyzed by Southern blotting and evidence for a rearranged RAR alpha gene was found generated in four cases. Normal RAR transcripts and germline restriction fragments were found in samples from normal or other leukemic cells, suggesting that this alteration of the RAR alpha gene is specifically seen in M3 leukemias. These results suggest that alteration of the retinoic acid receptor alpha may be implicated in M3 leukemogenesis.
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PMID:The retinoic acid receptor alpha gene is rearranged in retinoic acid-sensitive promyelocytic leukemias. 217 2

Although acute promyelocytic leukemias (APLs) are consistently associated with a reciprocal chromosome 15;17 translocation, the gene(s) directly affected by the breakpoints have never been isolated. The chromosome 17 breakpoint maps to near the retinoic acid receptor alpha (RAR alpha) locus. Investigation of 20 APLs and a large series of other neoplastic patients and normal controls revealed RAR alpha gene rearrangements and aberrant transcripts only in the APL cases. These findings suggest that the RAR alpha gene is involved in the APL chromosome 17 breakpoint, is implicated in leukemogenesis, and could be used as a marker for identifying leukemic promyelocytes.
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PMID:Rearrangements and aberrant expression of the retinoic acid receptor alpha gene in acute promyelocytic leukemias. 217 43


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