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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Variants of the t(15;17)(q22;q12-q21) chromosomal rearrangement associated with acute promyelocytic leukemia (APL) have been previously described and they frequently involve either chromosome 15 and/or 17. Previously we reported a rare variant t(11;17). We now describe two patients with myelodysplastic syndrome (MDS) that transformed to APL-like leukemia. Both had trisomy 11 at the diagnosis of APL-like leukemia. Following treatment for APL, patient 1 reverted to MDS and showed a normal karyotype. When leukemia recurred, his bone marrow karyotype was 47,XY,t(4;11), +11,der(22)t(1;22). Both patients were treated with all-trans retinoic acid (ATRA) for APL for 5 weeks, but failed to respond. The karyotype of patient 1 after ATRA treatment was 46,XY,t(4;11); the trisomy 11 had been lost and the bone marrow was replaced with immature myeloblasts without promyelocytes. In patient 2, the karyotype remained the same as at diagnosis, i.e., 47,X,-Y,dir ins(4;7),del(5), +6,del(7), +8, + 11,-18. Molecular analysis by reverse transcriptase PCR analysis showed the presence of wild type retinoic acid receptor alpha (RARA) and the absence of the PML-RARA chimeric gene associated with t(15;17). Additional analysis of PLZF, a new zinc finger gene associated with t(11;17), also showed the absence of this hybrid gene. These data support the concept that APL is a heterogeneous disorder and that variants with chromosome 11 rearrangement exist that do not respond to ATRA.
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PMID:Myelodysplastic syndrome transforming to acute promyelocytic-like leukemia with trisomy and rearrangement of chromosome 11. 751 69

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 WT 1 gene has been isolated as a tumor suppressor gene of Wilms' tumor. Using reverse transcriptase-polymerase chain reaction (RT-PCR), relative levels of the WT 1 gene expression was examined in 87 patients with acute leukemia, 25 with chronic myelogenous leukemia (CML), and 24 with non-Hodgkin's lymphoma (NHL). Significant levels of the WT 1 gene were expressed in all leukemia patients, and for CML the levels increased as the clinical phase progressed. No point mutations were found in the WT 1 gene when samples from 15 acute leukemia patients were subjected to PCR single-strand conformation polymorphism analysis. In striking contrast to acute leukemia, the levels of WT1 gene expression for NHL were significantly low or even undetectable. The levels of WT 1 gene expression inversely correlated with the prognosis of acute leukemia. The quantification of the WT 1 gene expression made it possible to detect minimal residual disease (MRD) in acute leukemia regardless of the presence of absence of tumor-specific DNA markers. Simultaneous monitoring of MRD by RT-PCR using primers for specific DNA markers in four patients (two AML-M3 with PML/RAR-alpha, one AML-M2 with AML1/ETO, and one CML with bcr/abl) detected MRD comparable to that obtained from quantitation of WT 1 gene expression. In a patient with acute promyelocytic leukemia, the limits of leukemic cell detection by RT-PCR using either WT 1 or PML/RAR-alpha gene primers were 10(-3)-10(-4) and 10(-4) for bone marrow, and 10(-5) and 10(-4) for peripheral blood, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[WT 1 and leukemia]. 764 50

In the t(15;17) translocation of acute promyelocytic leukemia (APL) at least three regions of the PML gene are involved in the reciprocal translocation between the PML and the RAR-alpha loci. The chimeric PML/RAR-alpha fusion transcripts can be demonstrated in all cases of APL, by a specific reverse-transcription PCR (RT-PCR). Previous studies found a correlation between expression of CD2 and involvement of the PML bcr3. In this study, we assessed this association in 43 children and adults with APL. A blind morphologic review of all smears was performed by four experienced hemopathologists who agreed the diagnosis of M3 vs M3v APL. CD2 expression on APL was detected by using different monoclonal antibodies (MoAbs) directed against specific CD2 epitopes by flow cytometry and in selected cases by Northern blot by the use of a specific CD2 cDNA probe. Nineteen of 43 cases displayed the typical microgranular features consistent with the diagnosis of M3v. Of these, 12 had the bcr3 breakpoint on chromosome 15, while seven had the bcr1 type. In 16 of the 19 patients, leukemic cells expressed both CD2 protein and the corresponding mRNA. Similarly, in the negative cases, Northern blot analysis failed to demonstrate the presence of specific mRNA. The remaining 24 patients, with the classic morphologic features of M3, were CD3 negative. These results point out that CD2 expression correlates with the FAB M3v and not with the PML breakpoints. During the course of all-trans retinoic treatment a down-modulation of CD2 expression was observed in three M3v cases. Overall, our findings might suggest a role of CD2 epitopes in the regulation of adhesion properties of APL blast cells.
Leukemia 1995 Sep
PMID:CD2 expression in acute promyelocytic leukemia is associated with microgranular morphology (FAB M3v) but not with any PML gene breakpoint. 765 12

All-trans retinoic acid (ATRA) has been used as a potent differentiation drug for acute promyelocytic leukemia (APL). Although the mechanism of its effectiveness upon APL remains unclear, the PML-retinoic acid receptor alpha (RARA) chimeric protein produced by t(15;17) is assumed to underlie the sensitivity of APL cells to ATRA. There are two major isoforms of PML-RARA transcripts; short (S) and long (L), according to the breakpoints in the PML gene. We therefore compared the clinical variables, the response to ATRA and the prognosis between 28 patients with type S and 68 patients with type L. Patients were treated in multi-institutional trials with ATRA, and chemotherapy was combined when peripheral blasts and leukocyte counts increased during the therapy. The clinical features at diagnosis were similar between the two molecular subtypes, and there was no significant difference in remission induction rates; 86% for the type S group and 90% for the type L group. There was no statistical difference in overall survival and CR duration as well as disease-free survival (DFS). In newly diagnosed patients, predicted 2-year DFS was 66% for the type S group and 67% for the type L group. In refractory or relapsed patients, it was 19 and 23%, respectively. These data indicated that isoforms of PML-RARA fused transcripts affect neither the clinical features of APL nor the prognosis after treatment with ATRA.
Leukemia 1995 Sep
PMID:Isoforms of PML-retinoic acid receptor alpha fused transcripts affect neither clinical features of acute promyelocytic leukemia nor prognosis after treatment with all-trans retinoic acid. The Leukemia Study Group of the Ministry of Health and Welfare (Kohseisho). 765 15

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 purpose of this work was to assess the re-arrangement of RAR-alpha and pml genes in a group of patients with acute promyelocytic leukaemia (APL) in different stages of the disease. Twenty-two patients with APL were studied. Of them, 17 were at the onset and 5 had achieved already complete haematological remission (CR). Evolutive post-remission studies were performed in 8 cases. The cytogenetic analysis was carried out at diagnosis by means of the G-band technique in 14 patients. The molecular study of RAR-alpha and pml genes was made with the Southern method. The common anomaly, t(15;17) was present in 7 of the 9 cases with evaluable metaphases (78%), in one case a 17q+ was the only cytogenetic alteration and another patient had normal karyotype. The molecular study showed re-arrangement of one or both genes involved in the translocation in the 17 patients studied at the onset of the APL. Those patients studied only in CR showed a germinal configuration. Rearrangement bands reappeared in 3 of the 8 patients evaluated along their clinical course. These results are in concordance with previous studies, in which re-arrangement of RAR-alpha and pml genes had been found in APL, despite there are instances in which no cytogenetic anomalies are found; this confirms the interest of molecular studies in the diagnosis and follow-up of APL patients.
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PMID:[Rearrangement of the alpha RAR and pml genes in promyelocytic leukemia]. 771 76

Minimal residual disease (MRD) was prospectively monitored at the 10(-5) level by the reverse transcriptase-polymerase chain reaction (RT-PCR) of PML-retinoic acid receptor alpha (RARA) transcripts from 27 acute promyelocytic leukemia (APL) patients who achieved complete remission (CR) with all-trans retinoic acid and chemotherapy (previously untreated patients, 15; refractory to chemotherapy or relapsed, 12). The RNA quality from bone marrow cells was firstly assessed by gel electrophoresis to avoid false negativity because of the fragility of the APL cells and the PML-RARA transcripts. In 12 of 15 untreated patients, RT-PCR became negative during consolidation and intensification therapy 4-16 months after the initiation of therapy, whereas it remained positive in nine of 12 refractory patients. At the end of therapy, RT-PCR was negative in 14 patients and positive in 13 patients. The former patients remained in CR at median follow-up of 9 months after the end of therapy. In the latter, however, 10 patients relapsed at a median of 5 months after the end of therapy. These results suggest that the RT-PCR assay can evaluate the quality of CR in APL and predict subsequent relapse.
Leukemia 1995 Apr
PMID:Prognostic significance of the RT-PCR assay of PML-RARA transcripts in acute promyelocytic leukemia. The Leukemia Study Group of the Ministry of Health and Welfare (Kouseisho). 772 89

Retinoic acids exert a wide range of biological activities following binding to the cognate nuclear receptors, which has several members (RAR-alpha, beta, gamma and RXR-alpha, beta, gamma). Retinoic acids lead to several different effects on tumor cells and include cell differentiation, inhibition of cell proliferation and apoptosis. The expression and abundance of each receptor type, and the distinct role of each receptor type related to biologic effect is under investigation. Similarly the mechanism(s) responsible for favorable responses in certain tumor types (skin, cervical) needs to be understood to best utilize this family of compounds, either alone or in various combinations. The significancer of drug-drug interaction in regard to their effects on pharmacokinetics, receptor modulation and regulation of cytoplasmic retinoic acid receptor binding proteins (CRABPs) should be carefully evaluated in pre-clinical and clinical trials. Furthermore, appropriate models to study combinations of RAs with other biological response modifiers are needed.
Leukemia 1994
PMID:Solid tumor treatment workshop summary. 780 33


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