UMLS:C0598766 - FACTA Search

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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

Signal transducer and activator of transcription (STAT) 5b-retinoic acid receptor (RAR) alpha is the fifth fusion protein identified in acute promyelocytic leukemia (APL). Initially described in a patient with all-trans retinoic acid (ATRA)-unresponsive disease, STAT5b-RARalpha resulted from an interstitial deletion on chromosome 17. To determine the molecular mechanisms of myeloid leukemogenesis and maturation arrest in STAT5b-RARalpha(+) APL and its unresponsiveness to ATRA, we examined the effect of STAT5b-RARalpha on the activity of myeloid transcription factors including RARalpha/retinoid X receptor (RXR) alpha, STAT3, and STAT5 as well as its molecular interactions with the nuclear receptor corepressor, SMRT, and nuclear receptor coactivator, TRAM-1. STAT5b-RARalpha bound to retinoic acid response elements (RAREs) both as a homodimer and as a heterodimer with RXRalpha and inhibited wild-type RARalpha/RXRalpha transactivation. Although STAT5b-RARalpha had no effect on ligand-induced STAT5b activation, it enhanced interleukin 6-induced STAT3-dependent reporter activity, an effect shared by other APL fusion proteins including promyelocytic leukemia-RARalpha and promyelocytic leukemia zinc finger (PLZF)-RARalpha. SMRT was released from STAT5b-RARalpha/SMRT complexes by ATRA at 10(-6) M, whereas TRAM-1 became associated with STAT5b-RARalpha at 10(-7) M. The coiled-coil domain of STAT5b was required for formation of STAT5b-RARalpha homodimers, for the inhibition of RARalpha/RXRalpha transcriptional activity, and for stability of the STAT5b-RARalpha/SMRT complex. Thus, STAT5b-RARalpha contributes to myeloid maturation arrest by binding to RARE as either a homodimer or as a heterodimer with RXRalpha resulting in the recruitment of SMRT and inhibition of RARalpha/RXRalpha transcriptional activity. In addition, STAT5b-RARalpha and other APL fusion proteins may contribute to leukemogenesis by interaction with the STAT3 oncogene pathway.
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PMID:Interactions of STAT5b-RARalpha, a novel acute promyelocytic leukemia fusion protein, with retinoic acid receptor and STAT3 signaling pathways. 1192 48

Loss of the inhibition of apoptosis is important in leukemogenesis and may influence the prognosis. Survivin is an inhibitor of apoptosis that shows selective expression during fetal development and in human malignancies. Survivin expression was examined in human leukemias using the reverse transcriptase-polymerase chain reaction. Survivin gene expression was detected in 17 of 31 patients with acute myelocytic leukemia and 11 of 16 patients with acute lymphocytic leukemia but was not identified in normal bone marrow cells. Survivin expression was lower in patients with M3 acute myelocytic leukemia than in patients with other types of acute leukemia. Survivin was not detected in the chronic phase of chronic myelocytic leukemia but was observed in 5 of 7 patients with chronic myelocytic leukemia in blastic crisis. These findings suggest a relationship between survivin gene expression and hematopoietic cell differentiation. In fact, survivin gene expression was down-regulated during the differentiation of HL-60 cells after treatment with dimethyl sulfoxide or all-trans-retinoic acid. Moreover, the disease-free survival rates of patients with survivin expression were lower than in patients without survivin expression. Accordingly, survivin may have a role in leukemogenesis as well as in other malignancies. Detecting survivin may also provide prognostic information.
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PMID:Expression of the antiapoptosis gene survivin in human leukemia. 1193 62

The effect of all-trans retinoid acid (ATRA) on the expression of Notch1 gene by real-time reverse transcriptase polymerase chain reaction (RT-PCR) in acute promyelocytic leukemia cells (APL), NB4, and HL-60 lacking t(15;17) was studied. The cells were treated with ATRA 0.5 microM for up to 96 hours. The increased transcript level of Notch1 was in concert with that of CD11b in NB4 cells, but not in HL-60 cells. The expression of Notch1 gene might be specific for APL cells. As Notch1 gene is involved in the differentiation and leukemogenesis in lymphoid neoplasm, observations suggest that Notch1 is involved in ATRA-modulated differentiation process in APL.
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PMID:All-trans retinoid acid increases Notch1 transcript expression in acute promyelocytic leukemia. 1505 51

The granulocyte colony-stimulating factor (G-CSF) plays an important role in normal granulopoiesis. Its functions are mediated by specific receptors on the surface of responsive cells and, upon ligand binding, several cytoplasmic tyrosine kinases are activated. The cytoplasmic region proximal to the membrane of the G-CSF receptor (G-CSF-R) transduces proliferative and survival signals, whereas the distal carboxy-terminal region transduces maturation signals and suppresses the receptor's proliferative signals. Mutations in the G-CSF-R gene resulting in truncation of the carboxy-terminal region have been detected in a subset of patients with severe congenital neutropenia who developed acute myelogenous leukemia (AML). In addition, the AML1-ETO fusion protein, expressed in leukemic cells harboring the t(8;21), disrupt the physiological function of transcription factors such as C/EBPalpha and C/EBPepsilon, which in turn deregulate G-CSF-R expression. The resulting high levels of G-CSF-R and G-CSF-dependent cell proliferation may be associated with pathogenesis of AML with t(8;21). Moreover, in vitro and in vivo studies demonstrated that G-CSF may act as a co-stimulus augmenting the response of PML-RARalpha acute promyelocytic leukemia cells to all-trans-retinoic acid treatment. Finally, in the PLZF-RARalpha acute promyelocytic leukemia transgenic model, G-CSF deficiency suppressed leukemia development. Altogether, these data suggest that the G-CSF signaling pathway may play a role in leukemogenesis.
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PMID:Granulocyte colony-stimulating factor and leukemogenesis. 1522 4

Chemoprevention is the use of noncytotoxic therapeutic intervention at the early stages of carcinogenesis against the development and progression of mutant clones to invasive cancer. Retinoids are the most extensively studied and one of the most prominent groups of chemopreventive agents to reach clinical trials. Acute promyelocytic leukemia is the first human malignancy that is successfully treated with all-trans retinoic acid. The t(15;17)(q22;q21) gene rearrangement and PML/RARalpha fusion product in acute promyelocytic leukemia played the key role to leukemogenesis and to sensitivity to differentiation-inducing therapy of all-trans retinoic acid. This review focuses on retinoid-based chemoprevention and therapy of cancer, and use acute promyelocytic leukemia as a model to illustrate the molecular mechanisms of retinoid signaling pathway.
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PMID:Molecular mechanisms of chemoprevention and therapy of cancer by retinoids. 1535 89

In the last twenty years, using all-trans retinoic acid (ATRA) as a differentiation inducer, Shanghai Institute of Hematology has achieved an important breakthrough in the treatment of acute promyelocytic leukemia (APL), which realized the theory of reversing phenotype of cells and provided a successful model of differentiation therapy in cancers. Our group first discovered in the world the variant chromosome translocation t(11;17)(q23;q21) of APL, and cloned the PML-RAR alpha, PLZF-RAR alpha and NPM-RAR alpha fusion genes corresponding to the characterized chromosome translocations t(15;17); t(11;17) and t(5;17) in APL. Moreover, establishment of transgenic mice model of APL proved their effects on leukemogenesis. The ability of ATRA to modify the recruitment of nuclear receptor co-repressor with PML-RAR alpha but not PLZF-RAR alpha caused by the variant chromosome translocation elucidated the therapeutic mechanism of ATRA from the molecular level and provides new insight into transcription-modulating therapy. Since 1994, our group has successfully applied arsenic trioxide (As(2)O(3)) in treating relapsed APL patients, with the complete remission rate of 70% - 80%. The molecular mechanism study revealed that As(2)O(3) exerts a dose-dependent dual effect on APL. Low-dose As(2)O(3) induced partial differentiation of APL cells, while the higher dose induced apoptosis. As(2)O(3) binds ubiquitin like SUMO-1 through the lysine 160 of PML, resulting in the degradation of PML-RAR alpha. Taken together, ATRA and As(2)O(3) target the transcription factor PML-RAR alpha, the former by retinoic acid receptor and the latter by PML sumolization, both induce PML-RAR alpha degradation and APL cells differentiation and apoptosis. Because of the different acting pathways, ATRA and As(2)O(3) have no cross-resistance and can be used as combination therapy. Clinical trial in newly diagnosed APL patients showed that ATRA/As(2)O(3) in combination yields a longer disease-free survival time. With the median survival of 18 months, none of the 20 cases in combination treatment relapsed, whereas 7 relapsed in 37 cases in mono-treatment. This is the best clinical effect achieved in treating adult acute leukemia to this day, possibly making APL the first adult curable leukemia. Based on the great success of the pathogenetic gene target therapy in APL, this strategy may extend to other leukemias. Combination of Gleevec and arsenic agents in treating chronic myeloid leukemia has already make a figure both in clinical and laboratory research, aiming at counteracting the abnormal tyrosine kinase activity of ABL and the degradating BCR-ABL fusion protein. In acute myeloid leukemia M(2b), using new target therapy degradating AML1-ETO fusion protein and reducing the abnormal tyrosine kinase activity of c-kit will also lead to new therapeutic management in acute leukemias.
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PMID:[Basic and clinical studies of the gene product-targeting therapy based on leukemogenesis--editorial]. 1574 26

Acute promyelocytic leukemia (APL) is characterized by the t(15;17)(q22;q21), which results in the fusion of the promyelocytic leukemia (PML) gene at 15q22 with the retinoic acid alpha-receptor (RARalpha) at 17q21. The 2 chimeric genes PML/RARalpha and RARalpha/PML are thought to play a role in leukemogenesis. We report a case of APL in a patient carrying an apparently complex variant translocation identified as t(6;15;17) by R-banding and whole chromosome 15 and 17 painting. However, FISH analysis with a PML/RARalpha dual-color kit showed a more complex translocation, resulting presumably from a two-step rearrangement, with PML-RARalpha fusion gene located as expected on the der(15) but the residual 5'-RARalpha signal located on the der(6). The patient achieved complete remission with all-trans retinoic acid treatment associated with chemotherapy. This case illustrates the usefulness of combined cytogenetics, FISH, and molecular biology to evidence the PML/RARalpha fusion gene in complex cases.
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PMID:A new variant t(6;15;17)(q25;q22;q21) in acute promyelocytic leukemia: fluorescence in situ hybridization confirmation. 1586 Mar 61

The EVI1 gene plays important roles in development and leukemogenesis. Recently, human EVI1 has been shown to give rise to at least six different mRNA variants with alternative 5'-ends, only some of which are conserved in mice. In order to gain a basic understanding of the regulation and potential biological importance of these alternative transcripts, we confirmed their expression by Northern blot, and, using real time quantitative RT-PCR, compared their abundance and stability under different conditions. The general expression patterns of the EVI1 5'-end variants in a panel of 20 human tissues were similar, but particularly high or low levels of some of them were noted in certain tissues. Pronounced differences in the expression of the 5'-end variants were noted in response to all-trans retinoic acid: in a human teratocarcinoma cell line, only the EVI1 transcript variants containing alternative exons 1a and 1b were upregulated in response to this agent. This induction required transcriptional activity of RNA polymerase, but was also associated with a substantial increase in the stability of these mRNA variants.
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PMID:Regulation of the expression of the oncogene EVI1 through the use of alternative mRNA 5'-ends. 1601 22

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