Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0598766 (leukemogenesis)
4,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The accuracy of cytogenetic diagnosis in the management of hematological malignancies has improved significantly over the past 10 years. Fluorescence in situ hybridization (FISH), a technique of molecular cytogenetics, has played a pivotal role in the detection of unique sub-microscopic chromosomal rearrangements that helped in the identification of chromosomal loci, which contain genes involved in leukemogenesis. We studied the feasibility and sensitivity of the FISH technique for molecular analysis of translocations markers, t(9;22) and t(15;17) for accurate molecular diagnosis and for monitoring the disease in 21 patients with chronic myeloid leukemia (CML) who received interferon-alpha and/or chemotherapy (7 patients), bone marrow transplantation (14 patients), and 14 patients with acute promyelocytic leukemia (APL) who received all-trans-retinoic acid (ATRA) and/or chemotherapy. We also applied conventional karyotyping (CK) for identification of t(9;22) and t(15;17) at diagnosis. All CML cases had a Ph; t(9;22) and except for two cases all APL had t(15;17). The FISH studies on CML marrows in complete cytogenetic remission (CCR) (100% Ph- by CK) achieved by IFN-alpha, showed 0-2.5% of cells with BCR-ABL fusion in first cytogenetic remission (Controls, range 0.5-1.5%). Repeat follow-up FISH studies could be done in two cases in remission, which demonstrated 0-10% of cells with BCR-ABL fusion. Evaluation of Ph positive status of CML marrow at diagnosis by CK (100% Ph+ cells) and FISH (80-92% BCR-ABL fusion) pointed the existence of dormant clone of normal residual hematopoietic cells along with actively proliferating clones of Ph positive cells. Fluorescence in situ hybridization analysis of post-BMT CML marrows in CCR (0% Ph+ mitoses) could detect MRD with range of 1-6%. Among 14 patients, 9 who showed percentage of BCR-ABL positive cells (0.0-1.5%) almost similar to normal controls, 6 patients had comparatively good prognosis (disease-free survival 7-14 months). Of five patients with residual leukemic cells in the range of 2-6%, 4 relapsed within a period of 3-24 months. Fourteen APL patients in CCR [100% t(15;17) negative cells by CK] were evaluated by FISH to check the presence of residual leukemic cells. In these patients FISH could efficiently detect 1-14.5% of residual cells with PML-RARA (patients mean MRD 5%, controls mean MRD 3.5%, P=.02). Since the time of FISH analysis, 5 to 7 patients with higher fraction of leukemic cells (5-11%) relapsed within a short period (1-7 months). On the contrary, 5 of 7 patients with either absence or low percentage of PML-RARA positive cells remained in complete remission for 11-24 months. Our data show that FISH has a potential to detect and measure the fraction of aberrant malignant cells in remission marrows, induced by BMT in CML and chemotherapy in APL. These findings encourage the investigations on a large scale to merit its potential for identification of patients at high risk. In the present studies, FISH on interphase cells also demonstrated its efficiency in the molecular diagnosis by its ability to detect BCR-ABL and PML-RARA fusion in CML with masked/variant Ph and t(15;17) negative APL, respectively. The efficiency of technique in molecular diagnosis was also proved in one of the CML patients who progressed to myeloid blastic phase where interphase FISH could identify an extra BCR-ABL fusion on both chromosomes 9 indicating insertion of BCR into ABL and its duplication.
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PMID:Fluorescence in situ hybridization: a highly efficient technique of molecular diagnosis and predication for disease course in patients with myeloid leukemias. 1175 52

Arsenic trioxide (As2O3) has recently been identified as an effective drug in the treatment of newly diagnosed and relapsed acute promyelocytic leukemia (APL) without cross-resistance to all-trans retinoic acid and achieved complete remission rates of 80-90% according to most reports. With intravenous infusion at a dose of 0.08-0.16 mg/kg daily, a course of 28-42 days is required to induce remission. As2O3 in combination with chemotherapy as postremission therapy results in longer survival than arsenic alone. In vitro, As2O3 exerts dose-dependent dual effect; triggering apoptosis at relatively high concentration (0.5-2.0 micromol/l), which is associated with the disruption of mitochondrial transmembrane potentials, while inducing partial differentiation at low concentration (0.1-0.5 micromol/l), which might be related to retinoic acid signaling pathway. Importantly, at both concentrations, As2O3 can degrade PML (promyelocytic leukemia) -RAR alpha (retinoic acid receptor), an oncoprotein that has a central role in leukemogenesis.
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PMID:Treatment of acute promyelocytic leukemia with arsenic trioxide: clinical and basic studies. 1191 7

We identified two patients with atypical PML-RAR(alpha) rearrangements, 53 and 13 base pairs longer than the typical bcr1 transcript. Sequence analysis revealed a new PML breakpoint at the end of exon 7a in patient 1, and a PML exon 6 breakpoint in patient 2, with an insertion of 35 nucleotides of RAR(alpha) intron 2. Patient 1 did not express RAR(alpha)-PML and patient 2 showed the RAR(alpha)-PML transcript, which corresponded to the typical bcr1. These results emphasize on the relevance of the correct identification of atypical PML-RAR(alpha) rearrangements because of the potential implications in leukemogenesis, in the response to treatment, and for the correct monitoring of minimal residual disease.
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PMID:Identification of two atypical PML-RAR(alpha) transcripts in two patients with acute promyelocytic leukemia. 1191 15

Acute promyelocytic leukemia (APL) is characterized by the t(15;17)(q22;q11.2), which results in the PML-RARA fusion gene. In previous studies, we demonstrated that expression of a human PML-RARA complementary DNA in murine granulocyte precursor cells initiated the development of leukemia. However, leukemogenesis by PML-RARA required additional genetic alterations. To identify genetic changes that cooperate with PML-RARA in leukemogenesis, we performed spectral karyotyping analysis of myeloid leukemias from hMRP8-PML-RARA mice (11 cases) and from mice coexpressing PML-RARA and BCL2 (8 cases). Clonal abnormalities were detected in 18 of 19 cases (95%). Recurring numerical abnormalities identified in these murine leukemias included +15 (15 cases, 79%); loss of a sex chromosome (12 cases, 63%); +8 (10 cases, 53%); +10 (9 cases, 47%); +4, +7, or +14 (8 cases each, 42%); +16 (7 cases, 37%); and +6 (5 cases, 26%). In a series of 965 patients with APL, we identified secondary abnormalities in 368 (38%). The most common recurring abnormalities were +8 or partial trisomy of 8q (120 patients, 12.4%) and ider(17) t(15;17) (42 patients, 4.4%). The critical consequence of +8 in human leukemias appears to be the gain of 8q24, which is syntenic to mouse 15. Thus, our results suggest that PML-RARA-initiated murine leukemia is associated with a defined spectrum of genetic changes, and that these secondary mutations recapitulate, in part, the cytogenetic abnormalities found in human APL.
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PMID:Recurring chromosomal abnormalities in leukemia in PML-RARA transgenic mice parallel human acute promyelocytic leukemia. 1192 90

Homeobox genes encode transcription factors known to be important morphogenic regulators during embryonic development. An increasing body of work implies a role for homeobox genes in both hematopoiesis and leukemogenesis. In the present study we have analyzed the role of the homeobox gene, HOXB6, in the program of differentiation of the myeloid cell lines, NB4 and HL60. HOXB6 expression is transiently induced during normal granulocytopoiesis and monocytopoiesis, with an initial induction during the early phases of differentiation, followed by a blockade of expression at early maturation. The enforced expression of HOXB6 in promyelocytic NB4 cells or in myeloblastic HL60 cells elicited inhibition of the granulocytic or monocytic maturation, respectively. Furthermore, HOXB6 was frequently expressed (18 out of 49 cases) in AMLs lacking major translocations while it was expressed at very low frequency (two out of 47 cases) in AMLs characterized by PML/RAR-alpha, AML-1/ETO, CBFbeta/MYH11 fusion and rearrangements of the MLL gene at 11q23. According to these observations, we suggest that a regulated pattern of HOXB6 expression is required for normal granulopoiesis and monocytopoiesis. Abnormalities of the HOXB6 expression may contribute to the development of the leukemic phenotype.
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PMID:Expression pattern of HOXB6 homeobox gene in myelomonocytic differentiation and acute myeloid leukemia. 1209 53

PML is the most frequent fusion partner of the RARalpha in the specific translocations associated with acute promyelocytic leukemia (APL). Models to explain the origin of this leukemia propose a block in cell differentiation due to aberrant repression of retinoic acid responsive genes and/or disruption of the function of the PML-containing nuclear bodies. Recently, PML has been identified as a regulator of replicative senescence and the premature senescence that occurs in response to oncogenic ras. This review discusses the idea that senescence is a general tumor suppressor mechanism related to terminal differentiation and disrupted during the establishment of APL and other cancers. According to this idea the PML-RARalpha fusion protein promotes leukemogenesis not only through repression of retinoic acid responsive genes, but also by way of interfering with several tumor suppressor proteins that cooperate to establish senescence. Retinoids and other drugs effective against APL do so by re-establishment of the senescence program, which also includes features of cell differentiation.
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PMID:PML a target of translocations in APL is a regulator of cellular senescence. 1235 43

Although transcription factors are still the main focus to understanding leukemogenesis, recent results strongly suggest that alteration of a receptor and/or subsequent signaling plays a critical and co-operative role in the pathogenesis of acute myeloid leukemia (AML). The t(15;17) translocation, found in 95% of APL, encodes a PML-RARalpha fusion protein. A main model proposed for acute promyelocytic leukemia (APL) is that PML-RARalpha exerts its oncogenic effects by repressing retinoic acid-inducible genes critical to myeloid differentiation. Dysregulation of these genes may result in abnormal signaling, thereby freeing pre-leukemic cells from controls which normally induce the onset of differentiation. It is also likely that treatment of APL cells by retinoic acid induces de novo up-regulation of the same genes which are dominantly repressed by PML-RARalpha and whose expression is required for reactivation of the differentiation program. Identification of such genes together with the signaling pathways interrupted at the early stages of leukemia transformation and reactivated during retinoic acid-induced differentiation in APL cells will contribute to the development of new molecular targets for treatment of leukemia.
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PMID:Signaling revisited in acute promyelocytic leukemia. 1235 45

Acute promyelocytic leukemia (APL) is associated with a reciprocal and balanced translocation involving the retinoic acid receptor-alpha (RARalpha). All-trans retinoic acid (ATRA) is used to treat APL and is a potent morphogen that regulates HOX gene expression in embryogenesis and organogenesis. HOX genes are also involved in hematopoiesis and leukemogenesis. Thirty-nine mammalian HOX genes have been identified and classified into 13 paralogous groups clustered on 4 chromosomes. They encode a complex network of transcription regulatory proteins whose precise targets remain poorly understood. The overall function of the network appears to be dictated by gene dosage. To investigate the mechanisms involved in HOX gene regulation in hematopoiesis and leukemogenesis by precise measurement of individual HOX genes, a small-array real-time HOX (SMART-HOX) quantitative polymerase chain reaction (PCR) platform was designed and validated. Application of SMART-HOX to 16 APL bone marrow samples revealed a global down-regulation of 26 HOX genes compared with normal controls. HOX gene expression was also altered during differentiation induced by ATRA in the PML-RARalpha(+) NB4 cell line. PML-RARalpha fusion proteins have been reported to act as part of a repressor complex during myeloid cell differentiation, and a model linking HOX gene expression to this PML-RARalpha repressor complex is now proposed.
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PMID:Global down-regulation of HOX gene expression in PML-RARalpha + acute promyelocytic leukemia identified by small-array real-time PCR. 1256 Feb 42

To investigate the leukemogenic potential of PML-RARalpha fusion protein in vivo, hCG-PML-RARalpha transgene was constructed using molecular cloning technique and hCG-PML-RARalpha transgenic mice were generated. The genotype and phenotype of hCG-PML-RARalpha transgenic mice were analyzed by PCR, RT-PCR, morphology of peripheral blood and bone marrow cells, and pathological examination of spleen, liver and bone marrow. As a result, acute promyelocytic leukemia was developed in 3 hCG-PML-RARalpha transgenic mice in 1 - 5 months. The results demonstrated that PML-RARalpha fusion protein plays a crucial role in leukemogenesis.
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PMID:[Development of Acute Promyelocytic Leukemia in PML-RARalpha Transgenic Mice] 1257 97

Fluorescence in situ hybridization analysis was carried out in five patients with acute myeloblastic leukemia of various French-American-British subtypes and with double trisomy of chromosomes 8 and 21. PML-RARA fusion was detected with appropriate molecular probes in one patient with acute promyelocytic leukemia without t(15;17). Two PAC probes covering the 5' and 3' part of the RUNX1 gene were used in the four other patients. While three copies were present in three patients, as expected from conventional karyotype analysis, only two hybridization signals were present in the fifth patient. This was due to the apparent loss of the 3' part of RUNX1. Since chromosome number abnormalities may be associated with submicroscopic gene rearrangements, it should be important to search for them for a better understanding of mechanisms of leukemogenesis, and to understand the prognostic heterogeneity in leukemic patients with aneusomies without apparent chromosome structure rearrangements.
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PMID:Double trisomy 8 and 21 in acute myelocytic leukemias, one with rearrangement of the RUNX1 gene. 1269 96


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