Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiplex reverse transcription-polymerase chain reaction (M-RT-PCR) has been proved to possess great clinical potential for simultaneous screening of 29 chromosomal translocations in acute leukemia. To evaluate the clinical value of M-RT-PCR in hematologic malignancies, bone marrow samples from 90 patients with various hematologic malignancies, including 25 acute myelogenous leukemia (AML), 22 acute lymphoblastic leukemia (ALL), 27 chronic myelogenous leukemia (CML), 4 myeloproliferative diseases (MPD), 3 chronic lymphoblastic leukemia (CLL), 3 non-Hodgkin's lymphoma (NHL), 3 myelodysplastic syndrome (MDS), 2 multiple myeloma (MM) and 1 malignant histiocytosis (MH) were subjected to both M-RT-PCR and chromosome karyotypic analysis. Some of cases were subjected to follow-up examination of M-RT-PCR during the period of clinical complete remission (CR) for detection of minimal residual leukemia. In our hand, 12 of 29 chromosomal translocation transcripts including TEL/PDGFR, DEK/CAN, MLL/AF6, AML1/ETO, MLL/AF9, BCR/ABL, MLL/MLL, PML/RARu, TLS/ERG, E2A/HLF, EVI1 and HOXI1 were detected in 57 cases (63.3 %) of the 90 samples, which were in consistency with the results of karyotypic analysis. Furthermore, M-RT-PCR had also shown good clinical relevance when used as an approach to detect minimal residual leukemia. We concluded that M-RT-PCR could be used as an efficient and fast diagnostic tool not only in the initial diagnosis of hematologic malignancies but also in subsequent monitor of minimal residual leukemia.
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PMID:Multiplex reverse transcription-polymerase chain reaction for simultaneous screening of 29 chromosomal translocation in hematologic malignancies. 1735 82

To establish an additional marker for polymerase chain reaction (PCR)-based measurement of minimal residual disease (MRD) detection in acute myeloid leukemia (AML), the expression level of the combined MDS1-EVI1 and EVI1 gene was quantified by real-time reverse transcription PCR (RT-PCR) in four AML cases at initial presentation and as a follow-up marker during anti-leukemic therapy. Quantification of the MDS1-EVI1/EVI1 gene expression correlated closely to the clinical course of the disease in all four cases. A hematologic complete remission was accompanied by a reduction of MDS1-EVI1/ EVI1 expression levels of at least 2 log while persistent leukemia was reflected by an MDS1-EVI1/ EVI1 expression in the range of the primary diagnostic sample. After achieving a complete cytomorphologic remission, three patients relapsed after 154, 210, and 280 days, respectively. Molecular relapse was detected on the basis of increasing expression levels of MDS1-EVI/EVI 29, 36, and 93 days before hematologic manifestation. In conclusion, the combined MDS-EVI1/EVI1 gene may serve as an alternative MRD marker in AML, especially in samples where other specific markers are lacking.
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PMID:Feasibility of using the combined MDS-EVI1/EVI1 gene expression as an alternative molecular marker in acute myeloid leukemia: a report of four cases. 1769 94

EVI1 is an oncoprotein inappropriately expressed in acute myeloid leukemia and myelodysplastic syndrome cells. In vitro studies indicate that diverse biological properties can be attributed to this protein. Its role in leukemogenesis is still unclear but it is thought that overall EVI1 can act mostly as a transcription repressor through its interaction with a subset of histone deacetylases. Studies with histone deacetylase inhibitors have however indicated that EVI1-mediated repression can be only partially rescued by deacetylase inhibitor drugs, suggesting that additional chromosomal modifications might occur to induce gene repression by EVI1. To investigate whether histone methylation contributes to the repressive potential of EVI1, we examined a potential association between EVI1, the histone methyltransferase (HMT) SUV39H1, and methyltransferase activity in vitro. We find that EVI1 directly interacts with SUV39H1 and that the proteins form an active complex with methyltransferase activity in vitro. Our data indicate that SUV39H1 enhances the transcription repressive potential of EVI1 in vivo. We suggest that EVI1 affects promoters' activity in two different pathways, by association with histone deacetylases and by recruiting chromatin-modifying enzymes to impose a heterochromatin-like structure establishing a lasting transcription repression.
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PMID:EVI1 recruits the histone methyltransferase SUV39H1 for transcription repression. 1865 52

RUNX1-EVI1 is a chimeric gene generated by t(3;21)(q26;q22) observed in patients with aggressive transformation of myelodysplastic syndrome or chronic myelogenous leukemia. RUNX1-EVI1 has oncogenic potentials through dominant-negative effect over wild-type RUNX1, inhibition of Jun kinase (JNK) pathway, stimulation of cell growth via AP-1, suppression of TGF-beta-mediated growth inhibition and repression of C/EBPalpha. Runx1-EVI1 heterozygous knock-in mice die in uteri due to central nervous system (CNS) hemorrhage and severe defects in definitive hematopoiesis as Runx1-/- mice do, indicating that RUNX1-EVI1 dominantly suppresses functions of wild-type RUNX1 in vivo. Acute myelogenous leukemia is induced in mice transplanted with bone marrow cells expressing RUNX1-EVI1, and a Runx1-EVI1 knock-in chimera mouse developed acute megakaryoblastic leukemia. These results suggest that RUNX1-EVI1 plays indispensable roles in leukemogenesis of t(3;21)-positive leukemia. Major leukemogenic effect of RUNX1-EVI1 is mainly through histone deacetyltransferase recruitment via C-terminal binding protein. Histone deacetyltransferase could be a target in molecular therapy of RUNX1-EVI1-expressing leukemia.
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PMID:Role of the RUNX1-EVI1 fusion gene in leukemogenesis. 1901 45

EVI1 is an oncogene inappropriately expressed in the bone marrow (BM) of approximately 10% of myelodysplastic syndrome (MDS) patients. This disease is characterized by severe anemia and multilineage myeloid dysplasia that are thought to be a major cause of mortality in MDS patients. We earlier reported on a mouse model that constitutive expression of EVI1 in the BM led to fatal anemia and myeloid dysplasia, as observed in MDS patients, and we subsequently showed that EVI1 interaction with GATA1 blocks proper erythropoiesis. Whereas this interaction could provide the basis for the erythroid defects in EVI1-positive MDS, it does not explain the alteration of myeloid differentiation. Here, we have examined the expression of several genes activated during terminal myelopoiesis in BM cells and identified a group of them that are altered by EVI1. A common feature of these genes is their regulation by the transcription factor PU.1. We report here that EVI1 interacts with PU.1 and represses the PU.1-dependent activation of a myeloid promoter. EVI1 does not seem to inhibit PU.1 binding to DNA, but rather to block its association with the coactivator c-Jun. After mapping the PU.1-EVI1 interaction sites, we show that an EVI1 point mutant, unable to bind PU.1, restores the activation of PU.1-regulated genes and allows a normal differentiation of BM progenitors in vitro.
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PMID:EVI1 Impairs myelopoiesis by deregulation of PU.1 function. 1920 46

The oncogene EVI1 has been implicated in the etiology of AML and MDS. Although AML cells are characterized by accelerated proliferation and differentiation arrest, MDS cells hyperproliferate when immature but fail to differentiate later and die instead. In agreement with its roles in AML and in immature MDS cells, EVI1 was found to stimulate cell proliferation and inhibit differentiation in several experimental systems. In contrast, the variant protein MDS1/EVI1 caused the opposite effect in some of these assays. In the present study, we expressed EVI1 and MDS1/EVI1 in a tetracycline-regulable manner in the human myeloid cell line U937. Induction of either of these proteins caused cells to accumulate in the G(0)/G(1)-phase of the cell cycle and moderately increased the rate of spontaneous apoptosis. However, when EVI1- or MDS1/EVI1-expressing cells were induced to differentiate, they massively succumbed to apoptosis, as reflected by the accumulation of phosphatidylserine in the outer leaflet of the plasma membrane and increased rates of DNA fragmentation. In summary, these data show that inducible expression of EVI1 in U937 cells causes phenotypes that may be relevant for its role in MDS and provides a basis for further investigation of its contribution to this fatal disease.
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PMID:Inducible expression of EVI1 in human myeloid cells causes phenotypes consistent with its role in myelodysplastic syndromes. 1960

We previously reported a recurrent t(3;8)(q26;q24) translocation involving EVI1 in five patients with myelodysplastic syndrome or acute myeloid leukemia. Here we report the same structural abnormality in a case of chronic myeloid leukemia in blast phase. The t(3;8)(q26;q24) occurred several months after the initial diagnosis of chronic myeloid leukemia, while the patient was being treated with a tyrosine kinase inhibitor. We confirmed rearrangement of EVI1 by fluorescence in situ hybridization assay using a dual-color break-apart probe set that spans the EVI1 region. Our findings demonstrate that, similar to other recurrent translocations involving 3q26, such as t(3;3) and t(3;21), the t(3;8)(q26;q24) is implicated not only in myelodysplastic syndrome and acute myeloid leukemia, but also in progression of chronic myeloid leukemia. These findings extend the known disease spectrum associated with this cytogenetic aberration.
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PMID:Chronic myeloid leukemia in blast phase associated with t(3;8)(q26;q24). 1966 75

Myeloid leukemia in this series corresponds to the myeloid neoplasms of the 4th WHO classification of pathology and genetics of tumor of haematopoietic and lymphoid tissue. The myeloid neoplasms are composed of six categories, which are 1) myeloproliferative neoplasms (MPN), a new category of 2) myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1, 3) myelodysplastic syndrome (MDS)/MPN, 4) MDS, 5) acute myeloid leukemia (AML) and related precursor neoplasms, and 6) acute leukemias of ambiguous lineage. In MPNs without chronic myelogenous leukemia, the genetic marker of JAK2 V617F is added to the diagnostic criteria for polycythemia vera, essential thrombocythemia and primary myelofibrosis. MDS has the new subtype of refractory cytopenia with unilineage dysplasia composed of refractory anemia, refractory neutropenia and refractory thrombocytopenia. AML with t(9; 11) (p22;q23); MLLT3-MLL, AML with t(6;9) (p23; q34); DEK-NUP214, AML with inv(3) (q21q26.2) or t(3; 3) (q21 ; q26.2); RPN1-EVI1 and AML (megakaryoblastic) with t(1; 22) (p13; q13); RBM15-MKL1 are added to the subtype of AML with recurrent genetic abnormalities, and AML with gene mutations of NPM1 and CEBPA are also added as provisional entities of it. The myeloid neoplasms of the 4th WHO classification are comprehensive and seem to be dynamic by incorporating the results of leukemia researches.
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PMID:[Classification of myeloid leukemias]. 1986 Jan 79

Therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/t-AML) are late complications of cytotoxic therapy used in the treatment of malignant diseases. The most common subtype of t-AML ( approximately 75% of cases) develops after exposure to alkylating agents, and is characterized by loss or deletion of chromosome 5 and/or 7 [-5/del(5q), -7/del(7q)], and a poor outcome (median survival 8 months). In the University of Chicago's series of 386 patients with t-MDS/t-AML, 79 (20%) patients had abnormalities of chromosome 5, 95 (25%) patients had abnormalities of chromosome 7, and 85 (22%) patients had abnormalities of both chromosomes 5 and 7. t-MDS/t-AML with a -5/del(5q) is associated with a complex karyotype, characterized by trisomy 8, as well as loss of 12p, 13q, 16q22, 17p (TP53 locus), chromosome 18, and 20q. In addition, this subtype of t-AML is characterized by a unique expression profile (higher expression of genes) involved in cell cycle control (CCNA2, CCNE2, CDC2), checkpoints (BUB1), or growth (MYC), loss of expression of IRF8, and overexpression of FHL2. Haploinsufficiency of the RPS14, EGR1, APC, NPM1, and CTNNA1 genes on 5q has been implicated in the pathogenesis of MDS/AML. In previous studies, we determined that Egr1 acts by haploinsufficiency and cooperates with mutations induced by alkylating agents to induce myeloid leukemias in the mouse. To identify mutations that cooperate with Egr1 haploinsufficiency, we used retroviral insertional mutagenesis. To date, we have identified two common integration sites involving genes encoding transcription factors that play a critical role in hematopoiesis (Evi1 and Gfi1b loci). Of note is that the EVI1 transcription factor gene is deregulated in human AMLs, particularly those with -7, and abnormalities of 3q. Identifying the genetic pathways leading to t-AML will provide new insights into the underlying biology of this disease, and may facilitate the identification of new therapeutic targets.
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PMID:Cytogenetic and genetic pathways in therapy-related acute myeloid leukemia. 1995 52

Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases characterized by ineffective hematopoiesis presenting with peripheral cytopenias in combination with a hyperplastic bone marrow. MDS patients have an increased risk of disease evolution to acute leukemia. Strong efforts have been made to gain further insights into the pathobiology of MDS. Development and progression of MDS to acute myeloid leukemia is suggested to be a multistep alteration to hematopoietic stem cells consisting of class I and class II alterations: the former targeting genes that are involved in signal transduction (e.g., FLT3, RAS and KIT), whereas the latter affect transcription factors (e.g., RUNX, RARA, EVI1 and WT1). These alterations consist of not only genomic mutations but also epigenetic aberrations, which can lead to reversible gene silencing. However, whether numerical and structural alterations of chromosomes and/or single genes or epigenetic changes represent the initiating event or, more likely, secondary events remains part of the discussion. Accumulation of such defects may finally cause the leukemic transformation of MDS.
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PMID:Molecular mechanisms involved in the progression of myelodysplastic syndrome. 2022


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