Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The EVI1 gene, located at chromosome band 3q26, is overexpressed in some myeloid leukemia patients with breakpoints either 5' of the gene in the t(3;3)(q21;q26) or 3' of the gene in the inv(3)(q21q26). EVI1 is also expressed as part of a fusion transcript with the transcription factor AML1 in the t(3;21)(q26;q22), associated with myeloid leukemia. In cells with t(3;21), additional fusion transcripts are AML1-MDS1 and AML1-MDS1-EVI1. MDS1 is located at 3q26 170-400 kb upstream (telomeric) of EVI1 in the chromosomal region in which some of the breakpoints 5' of EVI1 have been mapped. MDS1 has been identified as a single gene as well as a previously unreported exon(s) of EVI1 We have analyzed the relationship between MDS1 and EVI1 to determine whether they are two separate genes. In this report, we present evidence indicating that MDS1 exists in normal tissues both as a unique transcript and as a normal fusion transcript with EVI1, with an additional 188 codons at the 5' end of the previously reported EVI1 open reading frame. This additional region has about 40% homology at the amino acid level with the PR domain of the retinoblastoma-interacting zinc-finger protein RIZ. These results are important in view of the fact that EVI1 and MDS1 are involved in leukemia associated with chromosomal translocation breakpoints in the region between these genes.
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PMID:Intergenic splicing of MDS1 and EVI1 occurs in normal tissues as well as in myeloid leukemia and produces a new member of the PR domain family. 864 84

The retinoblastoma interacting zinc finger gene RIZ is a member of the recently discovered PR domain family that includes the MDS1-EVI1 breakpoint gene involved in human leukemia. To help understand the role of RIZ in human diseases, we have determined the cytogenetic and physical localizations of the RIZ gene. Using fluorescence in situ hybridization, we determined that RIZ maps to 1p36. On the physical map, RIZ is adjacent to the polymorphic marker D1S228. We suggest that the RIZ gene may be a candidate target of 1p36 alterations that commonly occur in neuroendocrine, breast, liver, colon, and lymphoid tumors.
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PMID:Physical mapping of the retinoblastoma interacting zinc finger gene RIZ to D1S228 on chromosome 1p36. 866 Oct 32

The human PRDI-BF1 or BLIMP1 gene and its mouse homolog Blimp1 are members of the recently realized PR domain family that includes the retinoblastoma interacting zinc finger gene RIZ and the MDS1-EVI1 leukemia cancer gene. The specific high-level expression of Blimp1 in late B and plasma cells, its induction during B-cell differentiation, and its ability to drive B-cell maturation suggest that this gene may play a role in the differentiation and pathogenesis of B cells. We have now mapped the physical location of BLIMP1 near the marker D6S447 on human chromosome 6q21-q22.1; we have also mapped Blimp1 to mouse Chromosome 10 at 14 cM distal to the Myb locus and to a region homologous to the location of BLIMP1. Deletions of the 6q21-q22 region are common in several human malignancies, particularly in B-cell non-Hodgkin lymphoma (B-NHL). The data led us to suggest that BLIMP1 may be a candidate B-NHL tumor suppressor gene.
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PMID:The B-lymphocyte maturation promoting transcription factor BLIMP1/PRDI-BF1 maps to D6S447 on human chromosome 6q21-q22.1 and the syntenic region of mouse chromosome 10. 892 66

We have identified a novel gene, GR6, located within the leukemia breakpoint region of 3q21, that is normally expressed in early fetal development but not in adult peripheral blood. GR6 is activated in the UCSD-AML1 cell line and in a leukemic sample, both of which carry a t(3;3)(q21;q26). In UCSD-AML1, we have also identified fusion transcripts between the ecotropic viral insertion site I (EVI1) gene in 3q26 and GR6 and between EVI1 and Ribophorin I that maps 30 kb telomeric to GR6 in 3q21. All fusions splice the 5' ends of the 3q21 genes into exon 2 of the EVI1 gene, an event that is similar to the normal intergenic splicing of MDS1-EVI1 and to those previously documented in leukemias with t(3;21) and t(3;12), in which acute myelogenous leukemia 1-EVI1 fusions and ETV6-EVI1 fusions, respectively, occur. The Ribophorin I-EVI1 fusion in particular may be a common occurrence in t(3;3).
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PMID:Activation of a novel gene in 3q21 and identification of intergenic fusion transcripts with ecotropic viral insertion site I in leukemia. 930 71

Six patients with de novo acute myeloid leukemia (AML) and a t(2;3)(p15-21;q26-27) were identified among approximately 1000 cases enrolled in the GIMEMA trial. The t(2;3) was the sole anomaly in three patients, whereas in three cases monosomy 7, trisomy 15 and 22, and trisomy 14 represented additional aberrations. No cryptic chromosome deletions at 5q, 7q, 12p, and 20q were observed. One patient carried a FLT3 D835 mutation; FLT3 internal tandem duplication (ITD) was not detected in three patients tested. Characterization of the translocation breakpoints using a 3q26 BAC contig specific for the PRDM3 locus showed that the breakpoints were located 5' to EVIl as follows: within myelodysplatic syndrome (MDS) intron 1 (# 3), between MDS1 exons 2 and 3 in three patients (# 1, 2, 4) with a 170bp cryptic deletion distal to the breakpoint in one (# 2), and in a more centromeric position spanning from intron 2 to the 5' region of EVI1 (# 6, 5). A set of 2p16-21 BAC probes showed that the breakpoints on chromosome 2p were located within BCL11A in two separate regions (# 1, 4 and # 2-5), within the thyroid adenoma-associated (THADA) gene (# 6) or distal to the ZFP36L2 locus (# 3). Regulatory elements were present in proximity of these breakpoints. RACE PCR studies revealed a chimeric transcript in 1/6 patient analyzed, but no fusion protein. Quantitative PCR showed a 21-58-fold over-expression of the EVIl gene in all cases analyzed. The patients showed dysplasia of at least two myeloid cell lineages in all cases; they had a low-to-normal platelet count and displayed an immature CD34+ CD117+ immunophenotype. Despite intensive chemotherapy and a median age of 43 years (range 36-59), only two patients attained a short-lived response; one patient is alive with active disease at 12 months, five died at 4-14 months. We arrived at the following conclusions: (a) the t(2;3) is a recurrent translocation having an approximate 0.5% incidence in adult AML; (b) breakpoints involve the 5' region of EVIl at 3q26, and the BCL11A, the THADA gene or other regions at 2p16.1-21; (c) cryptic deletions distal to the 3q26 breakpoint may occur in some cases; (d) the juxtaposition of the 5' region of EVIl with regulatory elements normally located on chromosome 2 brings about EVI1 overexpression; (e) clinical outcome in these cases is severe.
Leukemia 2006 Jan
PMID:Characterization of a recurrent translocation t(2;3)(p15-22;q26) occurring in acute myeloid leukaemia. 1661 48

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

Gene therapy trials have been performed with virus-based vectors that have the ability to integrate permanently into genomic DNA and thus allow prolonged expression of corrective genes after transduction of hematopoietic stem and progenitor cells. Adverse events observed during the X-linked severe combined immunodeficiency gene therapy trial revealed a significant risk of genotoxicity related to retrovirus vector integration and activation of adjacent proto-oncogenes, with several cases of T-cell leukemia linked to vector activation of the LMO2 gene. In patients with chronic granulomatous disease (CGD), rhesus macaques, and mice receiving hematopoietic stem and progenitor cells transduced with retrovirus vectors, a highly non-random pattern of vector integration has been reported. The most striking finding has been overrepresentation of integrations in one specific genomic locus, a complex containing the MDS1 and the EVI1 genes. Most evidence suggests that this overrepresentation is primarily due to a modification of primitive myeloid cell behavior by overexpression of EVI1 or MDS1-EVI1, as opposed to a specific predilection for integration at this site. Three different proteins can be produced from this complex locus: MDS1, MDS1-EVI1, and EVI1. This review will summarize current knowledge regarding this locus and its gene products, with specific focus on issues with relevance to gene therapy, leukemogenesis, and hematopoiesis. Insights into the mechanisms that result in altered hematopoiesis and leukemogenesis when this locus is dysregulated could improve the safety of gene therapy in the future.
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PMID:The MDS1-EVI1 gene complex as a retrovirus integration site: impact on behavior of hematopoietic cells and implications for gene therapy. 1822 42

Acute promyelocytic leukemia (APL) is a subtype of acute myelogenous leukemia (AML) that is characterized by peculiar clinical and biologic features, including severe hemorrhagic diathesis, specific recurrent chromosomal aberration, and distinct morphologic features with predominant pathologic promyelocytes. A reciprocal translocation involving chromosomes 15 and 17, t(15;17)(q22;q21), is a characteristic feature of APL that represents approximately 5-8% of AML. The rearranged gene created by this translocation encodes a chimeric protein PML-RARA that is a transcriptional repressor. In contrast to other AML subtypes, APL is particularly sensitive to treatment with all trans-retinoic acid (ATRA) combined with chemotherapy, converting this once fatal leukemia to a highly curable disease. Nonetheless, therapy-related myelodysplastic syndrome-acute myelogenous leukemia (t-MDS/AML) has been reported as a rare complication of chemotherapy in APL. Of 30 APL cases described as t-MDS/AML in the literature, only 1 case relapsed as acute leukemia with t(3;21)(q26;q22). Here we describe a rare case of APL relapsing as secondary AML with t(3;21)(q26;q22) and clinically characterize this patient using the RUNX1 (previously AML1)-MDS1-EVI1 fusion transcript (with follow-up for 55 months), and review the relevant literature.
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PMID:Acute promyelocytic leukemia relapsing as secondary acute myelogenous leukemia with translocation t(3;21)(q26;q22) and RUNX1-MDS1-EVI1 fusion transcript. 1902 86

A subgroup of leukemogenic mixed-lineage leukemia (MLL) fusion proteins (MFPs) including MLL-AF9 activates the Mecom locus and exhibits extremely poor clinical prognosis. Mecom encodes EVI1 and MDS1-EVI1 (ME) proteins via alternative transcription start sites; these differ by the presence of a PRDI-BF1-RIZ1 (PR) domain with histone methyltransferase activity in the ME isoform. Using an ME-deficient mouse, we show that ME is required for MLL-AF9-induced transformation both in vitro and in vivo. And, although Nup98-HOXA9, MEIS1-HOXA9, and E2A-Hlf could transform ME-deficient cells, both MLL-AF9 and MLL-ENL were ineffective, indicating that the ME requirement is specific to MLL fusion leukemia. Further, we show that the PR domain is essential for MFP-induced transformation. These studies clearly indicate an essential role of PR-domain protein ME in MFP leukemia, suggesting that ME may be a novel target for therapeutic intervention for this group of leukemias.
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PMID:Essential role of PR-domain protein MDS1-EVI1 in MLL-AF9 leukemia. 2402 71