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

---

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

Because previous PCR-based methodologies for detection of minimal residual disease (MRD) in leukemia patients have been too cumbersome to allow for widespread clinical usefulness, we have employed a real-time quantitative PCR (RQ-PCR) system to develop an MRD assay for t(12;21). We initially determined the expression of the different alternatively spliced TEL-AML1 mRNAs found in t(12;21) breakpoint variants I and II. We then optimized PCR primers for the RQ-PCR system and, using the t(12;21)+ REH cell line in spiking experiments, found a linear detection of TEL-AML1 over at least five logs. Moreover, 1 malignant cell in a background of 1,000,000 normal cells could be detected. The expression of the GAPDH, ABL, and beta(2)-microglobulin (beta2M) housekeeping genes were then compared in normal donors and in leukemic patients, and the very stably expressed beta2M was selected as an internal reference gene, allowing us to compensate for variation in RNA quality and day-to-day variation. In 12 samples from t(12;21)-positive patients at diagnosis, the levels of the TEL-AML1 fusion transcripts were found to vary up to 14-fold after normalization to beta2M. Interestingly, in samples obtained from seven patients at diagnosis, during induction chemotherapy, or relapse, the level of TEL-AML1 in peripheral blood (PB) and bone marrow (BM) was found to differ only by threefold, suggesting that MRD may be evaluated in PB samples in most patients. We conclude that this assay could set new standards for t(12;21) MRD detection with its accuracy, its high throughput, and its short turnover time for samples. Genes Chromosomes Cancer 26:355-365, 1999.
...
PMID:Rapid and sensitive minimal residual disease detection in acute leukemia by quantitative real-time RT-PCR exemplified by t(12;21) TEL-AML1 fusion transcript. 1053 71

The bleeding diathesis associated with congenital deficiency of factor XI (FXI) is variable and correlates poorly with standard coagulation assays. Platelets are reported to contain FXI activity that may substitute for the plasma protein. The presence of this platelet activity in some patients deficient in plasma FXI could partly explain the variable bleeding associated with the deficiency state. Polyclonal antibodies to plasma FXI recognize a 220 kD platelet membrane protein distinct in structure from plasma FXI. The messenger RNA (mRNA) coding for this protein has been postulated to be an alternatively spliced FXI message lacking the fifth exon found in the liver (wild type) message. We analyzed RNA from platelets, leukocytes, and bone marrow for FXI mRNA by reverse transcription polymerase chain reaction (RT-PCR) technology. Single FXI mRNA species were identified by RT-PCR in platelet and bone marrow RNA, but not leukocyte RNA, that are the same size as the message from liver RNA. Sequencing of PCR products confirmed that the FXI mRNA species in platelets is identical to the one in liver. Wild-type FXI mRNA was also identified in three leukemia cell lines with megakaryocyte features (MEG-01, HEL 92.1.7, and CHRF-288-11). The data show that platelets contain wild-type FXI mRNA. FXI protein, therefore, may be present in platelets and may be released during platelet activation. The data do not support the premise that the 220 kD platelet protein that cross-reacts with FXI antibodies is a product of an alternatively spliced mRNA from the FXI gene.
...
PMID:Factor XI messenger RNA in human platelets. 1055 49

The Philadelphia chromosome translocation t(9;22)(q34;q11) may give rise to different BCR/ABL fusion mRNAs due to different genomic breakpoints and alternative splicing. The e1a2, b2a2 or b3a2 and c3a2 fusion mRNAs encode distinct fusion proteins (p190, p210 and p230, respectively), which are associated with different forms of leukemogenesis in humans and animal models. Our patient presented with acute pre-B cell lymphoblastic leukemia (ALL) with normal cytogenetics. After 3 years of standard ALL therapy, he relapsed with t(9;22)-positive chronic myelogenous leukemia (CML). Retrospective molecular analyses of the pre-treatment pre-B cell ALL sample showed the b3a2 (p210) and e1a2 (p190) BCR/ABL fusion transcripts. Only the b3a2 (p210) transcript was detected at relapse. Southern and immunoglobulin heavy chain (IgH) analyses of the presentation and relapse samples revealed an identical BCR rearrangement in both samples. However, only the ALL sample harbored an IgH gene rearrangement. These findings show a clonal relationship between the more differentiated pre-B cell and less differentiated CML clones and that the p210 and p190 fusion mRNAs were alternatively spliced from a single genomic breakpoint. Our patient's unusual molecular findings provide circumstantial evidence that the p190 protein may promote a more differentiated phenotype in a comparatively less differentiated p210-transformed precursor cell.
Leukemia 1999 Dec
PMID:Pre-B acute lymphoblastic leukemia with b3a2 (p210) and e1a2 (p190) BCR-ABL fusion transcripts relapsing as chronic myelogenous leukemia with a less differentiated b3a2 (p210) clone. 1060 22

Human CEM-7A cells established by gradual deprivation of leucovorin from the growth medium, display 100-fold overexpression of methotrexate transport activity. We found that this was associated with 10-fold reduced folate carrier gene amplification and 50-fold overexpression of both the principal 3 kb reduced folate carrier transcript and, surprisingly, a novel truncated 2 kb reduced folate carrier mRNA poorly expressed in parental CEM cells. The molecular basis for the generation of this truncated reduced folate carrier transcript and its potential functional role in folate accumulation were studied. Reduced folate carrier genomic and cDNA sequencing revealed that the truncated transcript had an internal deletion of 987 nucleotides which was a result of an alternative splicing utilizing a cryptic acceptor splice site within exon 6. This deletion consisted of the 3'-most 480 nucleotides of the reduced folate carrier ORF and the following 507 nucleotides of the 3'-UTR. These resulted in a truncated reduced folate carrier protein, which lacks the C-terminal 160 amino acids, but instead contains 58 new C-terminal amino acids obtained from reading through the 3'-UTR. Consequently, a truncated reduced folate carrier protein is generated that lacks the 12th transmembrane domain and contains a new and much shorter C-terminus predicted to reside at the extracellular face. Western analysis with plasma-membrane fraction from CEM-7A cells revealed marked overexpression of both a broadly migrating approximately 65-90 kDa native reduced folate carrier and a approximately 40-45 kDa truncated reduced folate carrier, the core molecular masses of which were confirmed by in vitro translation. However, unlike the native reduced folate carrier, the truncated reduced folate carrier protein failed to bind the affinity labels NHS-[3H]MTX and NHS-[3H]folic acid. Stable transfection of the truncated reduced folate carrier cDNA into mouse L1210 leukemia cells: increased folate accumulation, decreased their leucovorin and folic acid growth requirements, and increased their sensitivity to methotrexate. This constitutes the first documentation of an expressed alternatively spliced truncated reduced folate carrier that, when coexpressed along with the native carrier, augments folate accumulation and consequently decreases the cellular folate growth requirement. The possible mechanisms by which the truncated reduced folate carrier may increase folate accumulation and/or metabolism in cells coexpressing the truncated and native reduced folate carrier are discussed.
...
PMID:Characterization of a human alternatively spliced truncated reduced folate carrier increasing folate accumulation in parental leukemia cells. 1065 5

Fas antigen, a cell surface molecule, directly mediates apoptosis, and is expressed on a limited number of human tissues. Blood or bone marrow samples from patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL) and mixed leukemia were examined qualitatively and quantitatively for the expression of Fas as well as its function using flow cytometry and the annexin V staining method. Fas expression was flow cytometrically unimodal with heterogeneous density, and showed quantitatively characteristic features in different diseases: undetectable in mixed leukemia, faint to weak in ALL, low in M0 and M1, and variable (low to strong) in M2, M3, M4, and M5. Both the full-length and the alternatively spliced truncated mRNAs were detected constitutively even in acute leukemia cells with qualitatively negative and quantitatively faint Fas, and the band density of the former transcripts detected by RT-PCR was correlated with the level of expression of the Fas protein. Short-term culturing of freshly isolated leukemia cells gave rise to an increase of Fas density. In acute leukemia cells, the apoptosis induced by anti-Fas MoAb was compared with that induced by etoposide (a topoisomerase II inhibitor). We found that fresh ALL and AML cells were resistant to the anti-Fas IgM antibody, while etoposide could trigger apoptosis in all types of leukemia tested. The combined effects of the anti-Fas MoAb and etoposide were not always synergistic. These results suggest that Fas is a biological marker for characterizing ALL and AML cells, and provide insight into creating a new therapeutic modality using cytotoxic drugs and cytokines together with modulation of Fas.
...
PMID:Qualitative and quantitative characterization of Fas (CD95) expression and its role in primary human acute leukemia cells. 1078 66

The BCR/ABL fusion gene is pathognomonic for chronic myelogenous leukaemia (CML). We have previously reported alternative splicing of BCR/ABL, as indicated by the detection of both p190- and p210-encoding transcripts, in about 60% of CML patient samples. These exon-skipping events involved the joining of ABL exon 2 to variable upstream BCR exons. Similarly, ABL exon 2 is alternatively spliced to either of two upstream ABL exons (1a or 1b) in c-ABL. We have constructed BCR and BCR/ABL minigenes to study this phenomenon in more detail. These constructs were transfected into various cell types and splicing was assessed by reverse transcriptase PCR. Whereas the basic BCR minigene expressed exon-inclusive transcripts only, insertion of genomic DNA spanning ABL exon 2 induced exon-skipping but only when expressed in the CML cell lines K562 and EM3. In this study we localized the required sequence element to ABL exon 2 itself. These results mimic the splicing phenotype displayed by most CML patients. We propose a model where a trans-factor present in some CML cells interacts with ABL exon 2 pre-mRNA to promote skipping of upstream BCR exons.
...
PMID:Exon-skipping in BCR/ABL is induced by ABL exon 2. 1079 14

In the family of cytokines and cytokine receptors, alternative splicing of pre-mRNA is a frequently observed process that generates different protein isoforms from a single genetic locus. The splicing-derived cytokine receptor protein isoforms are mostly soluble receptors or show alterations in their cytoplasmic domain. It is possible that receptor abnormalities or a pathological ratio of different isoforms may contribute to leukaemia by circumventing normal growth factor control or altering the balance of proliferation and differentiation. IL-7 plays a critical role in early stages of both B and T cell maturation. Moreover, it stimulates the expansion of mature T cells including anti-tumour reactive cells as well as a number of T and B cell malignancies underlining its potential importance for deregulated lymphoid proliferation and leukaemogenesis. Here, we present detailed data on the expression of the interleukin 7 receptor alpha chain (IL-7Ralpha) in leukaemic cells from 210 children with acute lymphoblastic leukaemia (ALL) and describe two novel alternatively spliced transcripts of human IL-7Ralpha coding for truncated receptor proteins which are still capable of binding IL-7. IL-7Ralpha mRNA expression was more frequent in more mature pre-B ALL [91% (30/33)] than in common [81% (81/100)] or pro-B ALL [64% (18/28)], or even in T ALL [64% (29/45)]. These results are in concordance with flow cytometric analyses on the proportion of IL-7Ralpha bearing cells among total blast cell population. Our results lead us to assume that splicing derived IL-7Ralpha isoforms play a potential role in modulating IL-7 signal transduction and might be important for the pathogenesis of leukaemia.
...
PMID:Expression analysis and characterization of alternatively spliced transcripts of human IL-7Ralpha chain encoding two truncated receptor proteins in relapsed childhood all. 1105 10

The partner gene of MLL was identified in a patient with treatment-related acute myeloid leukemia in which the karyotype suggested t(3;11)(q25;q23). Prior therapy included the DNA topoisomerase II inhibitors, teniposide and doxorubicin. Southern blot analysis indicated that the MLL gene was involved in the translocation. cDNA panhandle polymerase chain reaction (PCR) was used, which does not require partner gene-specific primers, to identify the chimeric transcript. Reverse-transcription of first-strand cDNAs with oligonucleotides containing known MLL sequence at the 5' ends and random hexamers at the 3' ends generated templates with an intra-strand loop for PCR. In-frame fusions of either MLL exon 7 or exon 8 with the GMPS (GUANOSINE 5'-MONOPHOSPHATE SYNTHETASE) gene from chromosome band 3q24 were detected. The fusion transcript was alternatively spliced. Guanosine monophosphate synthetase is essential for de novo purine synthesis. GMPS is the first partner gene of MLL on chromosome 3q and the first gene of this type in leukemia-associated translocations. (Blood. 2000;96:4360-4362)
...
PMID:t(3;11) translocation in treatment-related acute myeloid leukemia fuses MLL with the GMPS (GUANOSINE 5' MONOPHOSPHATE SYNTHETASE) gene. 1111 Jul 14

A novel full-length cDNA was cloned from human dendritic cells (DC) by subtractive cloning and RACE. The deduced protein is a type II lectin-like membrane protein that contains an ITIM proximal to N terminal and is designated as lectin-like immunoreceptor (LLIR). The gene of LLIR is located in a region of chromosomal 12p13 and shows highest homologous with ASGPR. Two alternatively spliced transmembraneless variants of LLIR were identified by RT-PCR and named as LLIRv1 and LLIRv2. RT-PCR and immunoblotting analysis revealed that LLIR was expressed with much higher level in immature DC than in mature DC. The ITIM in LLIR was demonstrated to bind SHP-1 in HL-60 cell after the tyrosine had been phosphorylated. In addition, the mRNA expression level of LLIRv2 was raised when leukemia cells were induced to differentiate by PMA.
...
PMID:Cloning and characterization of a novel ITIM containing lectin-like immunoreceptor LLIR and its two transmembrane region deletion variants. 1117 71

The RUNX1 gene on human chromosome 21q22.12 belongs to the 'runt domain' gene family of transcription factors (also known as AML/CBFA/PEBP2alpha). RUNX1 is a key regulator of hematopoiesis and a frequent target of leukemia associated chromosomal translocations. Here we present a detailed analysis of the RUNX1 locus based on its complete genomic sequence. RUNX1 spans 260 kb and its expression is regulated through two distinct promoter regions, that are 160 kb apart. A very large CpG island complex marks the proximal promoter (promoter-2), and an additional CpG island is located at the 3' end of the gene. Hitherto, 12 different alternatively spliced RUNX1 cDNAs have been identified. Genomic sequence analysis of intron/exon boundaries of these cDNAs has shown that all consist of properly spliced authentic coding regions. This indicates that the large repertoire of RUNX1 proteins, ranging in size between 20-52 kDa, are generated through usage of alternatively spliced exons some of which contain in frame stop codons. The gene's introns are largely depleted of repetitive sequences, especially of the LINE1 family. The RUNX1 locus marks the transition from a ~1 Mb of gene-poor region containing only pseudogenes, to a gene-rich region containing several functional genes. A search for RUNX1 sequences that may be involved in the high frequency of chromosomal translocations revealed that a 555 bp long segment originating in chromosome 11 FLI1 gene was transposed into RUNX1 intron 4.1. This intron harbors the t(8;21) and t(3;21) chromosomal breakpoints involved in acute myeloid leukemia. Interestingly, the FLI1 homologous sequence contains a breakpoint of the t(11;22) translocation associated with Ewing's tumors, and may have a similar function in RUNX1.
...
PMID:Architecture and anatomy of the genomic locus encoding the human leukemia-associated transcription factor RUNX1/AML1. 1117 64


<< Previous 1 2 3 4 5 6 7 8 9 Next >>

---