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)

Following gene therapy of SCID-X1 using murine leukemia virus (MLV) derived vector, two patients developed leukemia owing to an activating vector integration near the LMO2 gene. We found that these integrations reside within FRA11E, a common fragile site known to correlate with chromosomal breakpoints in tumors. Further analysis showed that fragile sites attract a nonrandom number of MLV integrations, shedding light on its integration mechanism and risk-to-benefit ratio in gene therapy.
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PMID:Fragile sites are preferential targets for integrations of MLV vectors in gene therapy. 1651 18

Childhood T-cell precursor acute lymphoblastic leukemia (TCP ALL) is an aggressive disease with a presumably short latency that differs in many biologic respects from B-cell precursor (BCP) ALL. We therefore addressed the issue of in utero origin of this particular type of leukemia by tracing oncogenic mutations and clone-specific molecular markers back to birth. These markers included various first- and second-hit genetic alterations (TCRD-LMO2 breakpoint regions, n = 2; TAL1 deletions, n = 3; Notch1 mutations, n = 1) and nononcogenic T-cell receptor rearrangements (n = 13) that were derived from leukemias of 16 children who were 1.5 to 11.2 years old at diagnosis of leukemia. Despite highly sensitive polymerase chain reaction (PCR) approaches (1 cell with a specific marker among 100,000 normal cells), we identified the leukemic clone in the neonatal blood spots in only 1 young child. These data suggest that in contrast to BCP ALL most TCP ALL cases are initiated after birth.
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PMID:Screening for leukemia- and clone-specific markers at birth in children with T-cell precursor ALL suggests a predominantly postnatal origin. 1755 95

Gene expression programs are established by networks of interacting transcription factors. The basic helix-loop-helix factor SCL and the LIM-only protein LMO2 are components of transcription factor complexes that are essential for hematopoiesis. Here we show that LMO2 and SCL are predominant interaction partners in hematopoietic cells and that this interaction occurs through a conserved interface residing in the loop and helix 2 of SCL. This interaction nucleates the assembly of SCL complexes on DNA and is required for target gene induction and for the stimulation of erythroid and megakaryocytic differentiation. We also demonstrate that SCL determines LMO2 protein levels in hematopoietic cells and reveal that interaction with SCL prevents LMO2 degradation by the proteasome. We propose that the SCL-LMO2 interaction couples protein stabilization with higher order protein complex assembly, thus providing a powerful means of modulating the stoichiometry and spatiotemporal activity of SCL complexes. This interaction likely provides a rate-limiting step in the transcriptional control of hematopoiesis and leukemia, and similar mechanisms may operate to control the assembly of diverse protein modules.
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PMID:Protein stability and transcription factor complex assembly determined by the SCL-LMO2 interaction. 1787 55

The nuclear proteins TAL1 (T-cell acute leukaemia protein 1) and LMO2 (LIM-only protein 2) have critical roles in haematopoietic development, but are also often aberrantly activated in T-cell acute lymphoblastic leukaemia. TAL1 and LMO2 operate within multifactorial protein-DNA complexes that regulate gene expression in the developing blood cell. TAL1 is a tissue-specific basic helix-loop-helix (bHLH) protein that binds bHLH domains of ubiquitous E-proteins, (E12 and E47), to bind E-box (CANNTG) DNA motifs. TAL1(bHLH) also interacts specifically with the LIM domains of LMO2, which in turn bind Ldb1 (LIM-domain binding protein 1). Here we used biophysical methods to characterize the assembly of a five-component complex containing TAL1, LMO2, Ldb1, E12, and DNA. The bHLH domains of TAL1 and E12 alone primarily formed helical homodimers, but together preferentially formed heterodimers, to which LMO2 bound with high affinity (K(A) approximately 10(8) M(-1)). The resulting TAL1/E12/LMO2 complex formed in the presence or absence of DNA, but the different complexes preferentially bound different Ebox-sequences. Our data provide biophysical evidence for a mechanism, by which LMO2 and TAL1 both regulate transcription in normal blood cell development, and synergistically disrupt E2A function in T-cells to promote the onset of leukaemia.
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PMID:Assembly of the oncogenic DNA-binding complex LMO2-Ldb1-TAL1-E12. 1791 69

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

The LIM-domain protein LMO2 is a T-cell oncogenic protein first recognized by gene activation through chromosomal translocations, but it is also responsible for leukaemias arising as secondary, adverse effects in an X-SCID gene therapy trial. There are no specific reagents currently available to analyse the LMO2 multiprotein complex or to combat LMO2-dependent leukaemias. Accordingly, we have isolated an anti-LMO2 single chain Fv antibody fragment to determine if intracellular interference with LMO2-protein complexes can avert LMO2-dependent functions in normal and cancer settings. The anti-LMO2 single chain Fv, obtained using Intracellular Antibody Capture (IAC) technology, is specific for LMO2 among the LIM-only protein family and binds LMO2 through the third and fourth LIM fingers. Using vector-mediated expression of anti-LMO2 scFv, we show inhibition of Lmo2-dependent erythropoiesis but not endothelial development. We also demonstrate inhibition of Lmo2-dependent leukaemia in a mouse T-cell tumourigenesis transplantation assay with retroviral-mediated expression of anti-LMO2 scFv. Our studies establish that interference with the LMO2 multiprotein complex inhibits both normal and tumourigenic roles. The antibody fragment is a tool for dissecting LMO2 function in haematopoiesis and leukaemia and is a lead for development of therapeutics against LMO2-dependent T-ALL.
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PMID:An antibody inhibitor of the LMO2-protein complex blocks its normal and tumorigenic functions. 1843 27

Leukemia caused by retroviral insertional mutagenesis after stem cell gene transfer has been reported in several experimental animals and in patients treated for X-linked severe combined immunodeficiency. Here, we analyzed whether gene transfer into mature T cells bears the same genotoxic risk. To address this issue in an experimental "worst case scenario," we transduced mature T cells and hematopoietic progenitor cells from C57BL/6 (Ly5.1) donor mice with high copy numbers of gamma retroviral vectors encoding the potent T-cell oncogenes LMO2, TCL1, or DeltaTrkA, a constitutively active mutant of TrkA. After transplantation into RAG-1-deficient recipients (Ly5.2), animals that received stem cell transplants developed T-cell lymphoma/leukemia for all investigated oncogenes with a characteristic phenotype and after characteristic latency periods. Ligation-mediated polymerase chain reaction analysis revealed monoclonality or oligoclonality of the malignancies. In striking contrast, none of the mice that received T-cell transplants transduced with the same vectors developed leukemia/lymphoma despite persistence of gene-modified cells. Thus, our data provide direct evidence that mature T cells are less prone to transformation than hematopoietic progenitor cells.
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PMID:Resistance of mature T cells to oncogene transformation. 1877 97

Gene expression profiles have been associated with clinical outcome in patients with diffuse large B-cell lymphoma (DLBCL) treated with anthracycline-containing chemotherapy. Using Affymetrix HU133A microarrays, we analyzed the lymphoma transcriptional profile of 30 patients treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and 23 patients treated with rituximab (R)-CHOP in the Groupe d'Etude des Lymphomes de l'Adulte clinical centers. We used this data set to select transcripts showing an association with progression-free survival in all patients or showing a differential effect in the two treatment groups. We performed real-time quantitative reverse transcription-PCR in the 23 R-CHOP samples of the screening set and an additional 44 R-CHOP samples set to evaluate the prognostic significance of these transcripts. In these 67 patients, the level of expression of 16 genes and the cell-of-origin classification were significantly associated with overall survival, independently of the International Prognostic Index. A multivariate model comprising four genes of the cell-of-origin signature (LMO2, MME, LPP and FOXP1) and two genes related to immune response, identified for their differential effects in R-CHOP patients (APOBEC3G and RAB33A), demonstrated a high predictive efficiency in this set of patients, suggesting that both features affect outcome in DLBCL patients receiving immunochemotherapy.
Leukemia 2008 Oct
PMID:The expression of 16 genes related to the cell of origin and immune response predicts survival in elderly patients with diffuse large B-cell lymphoma treated with CHOP and rituximab. 1861 1

Blood and endothelium arise in close association during development, possibly from a common precursor, the hemangioblast [1-4]. Genes essential for blood and endothelial development contain functional ETS binding sites, and binding and expression data implicate the transcription factor, friend leukaemia integration 1 (Fli1) [5-10]. However, loss-of-function phenotypes in mice, although suffering both blood and endothelial defects, have thus far precluded the conclusion that Fli1 is essential for these two lineages [11, 12]. By using Xenopus and zebrafish embryos, we show that loss of Fli1 function results in a substantial reduction or absence of hemangioblasts, revealing an absolute requirement. TUNEL assays show that the cells are eventually lost by apoptosis, but only after the regulatory circuit has been disrupted by loss of Fli1. In addition, a constitutively active form of Fli1 is sufficient to induce expression of key hemangioblast genes, such as Scl/Tal1, Lmo2, Gata2, Etsrp, and Flk1. Epistasis assays show that Fli1 expression is induced by Bmp signaling or Cloche, depending on the hemangioblast population, and in both cases Fli1 acts upstream of Gata2, Scl, Lmo2, and Etsrp. Taken together, these results place Fli1 at the top of the transcriptional regulatory hierarchy for hemangioblast specification in vertebrate embryos.
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PMID:Fli1 acts at the top of the transcriptional network driving blood and endothelial development. 1871 62

Lmo2 is a T cell leukemia-related proto-oncogene, which belongs to the LIM protein family. Previous work has established its key role in yolk sac erythropoiesis and adult hematopoiesis, and it is also necessary for regulating angiogenesis. It has been demonstrated that this gene encodes a protein of 158 amino acids, consisting of two tandem cysteine-rich LIM domains, but the detailed mechanism of its transcriptional regulation remains to be elucidated. To further investigate the mechanism of transcriptional regulation of Lmo2, we combined SMART PCR technology with 5'RACE and found a novel post-transcriptional splicing form of Lmo2 in adult human kidney. This alternative transcript contains only two exons, encoding a smaller protein of 151 amino acids. Interestingly, it shares the same reading frame as the original Lmo2, but differs in 7 amino acids at the N-terminus. A genomic DNA fragment (from -294 nts to +180 nts) containing the putative promoter region has been inserted into the luciferase reporter gene vector pGL3-basic and showed stable promoter activity when transfected into COS7. RT-PCR analysis revealed that this variant transcript was expressed widely in human tissues and cell lines, suggesting its potential basic functional importance.
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PMID:A novel post-transcriptional splicing form of the acute T cell leukemia proto-oncogene Lmo2. 1876 96


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