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 purpose of the present study was to characterize the human Helios gene products expressed in leukemia cells. A 3.5 kb human Helios cDNA clone was isolated from a human T-cell cDNA library derived from the human T-acute lymphoblastic leukemia (ALL) cell line JURKAT. This cDNA clone had a unique open reading frame (ORF) encoding a novel 304 amino acid (AA) peptide, which was designated as Helios 3. The sequence of the 289 AA C-terminal portion of Helios 3 downstream of V-16 is identical to the corresponding sequence found in Helios 1 and 2 and contains two zinc fingers. By contrast, the 15 AA N-terminal portion of Helios 3 is unique and does not contain the N-terminal zinc finger motifs that are conserved in Helios 1 and 2 as well as other previously identified members of the Ikaros family. Southern blot analysis of genomic DNA fragments of the human Helios gene locus showed that Helios 3 is encoded by the same genomic locus as Helios 1 and 2. The expression of Helios 3 mRNA was not restricted to T-lineage ALL cells or another immunophenotypically distinct subset of leukemias. Helios 3 mRNA was expressed in freshly obtained primary leukemic cells from six of 15 children with newly diagnosed ALL. Helios 3 exhibited a unique protein interaction profile via its N-terminal portion, which may have biological significance in pathogenesis of human leukemias.
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PMID:Expression of a unique helios isoform in human leukemia cells. 1215 74

In previous studies, we demonstrated an over-expression of the dominant-negative isoform of the transcription factor Ikaros in patients with blast crisis of both chronic myelogenous leukaemia and B-cell acute lymphoblastic leukaemia (ALL). Recently, we reported an over-expression of the short isoforms of Helios, which is one of the members of the Ikaros gene family, in a patient with T-cell ALL. In the present study, we found over-expression of short isoforms of Helios in human T lymphotropic virus-I (HTLV1)-infected patients who had developed chronic and acute forms of adult T-cell leukaemia/lymphoma. In contrast, we could not detect any over-expression of short isoforms of Helios in healthy HTLV1 carriers. By Southern blotting, we detected a small deletion in the Helios gene locus of adult T-cell leukaemia/lymphoma patients. The present results suggest that Helios gene abnormalities might be one of the important mechanisms in the disease progression of HTLV1 infection.
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PMID:Over-expression of short isoforms of Helios in patients with adult T-cell leukaemia/lymphoma. 1264 68

In previous studies, we demonstrated an over-expression of the dominant-negative isoform of the transcription factor Ikaros, Ik-6, in patients with B-cell malignancies, including blast crisis of chronic myelogenous leukaemia and acute lymphoblastic leukaemia. To investigate the consequence of over-expression of Ik-6 in B cells, we constructed Ik-6 transfectants of the FDH-1 and Ramos cell lines. FDH-1, which was established from a patient with early pre-B acute lymphoblastic leukaemia, undergoes apoptosis with dexamethasone treatment, whereas Ramos undergoes apoptosis following anti-IgM antibody treatment. Compared with the wild type, the over-expression of Ik-6 rendered the FDH-1 and Ramos transfectants resistant to dexamethasone-induced and anti-IgM-induced apoptosis respectively. An immunoblotting study demonstrated bcl-2 upregulation in anti-IgM-induced Ramos Ik-6 transfectants, but not in FDH-1 Ik-6 transfectants. Further investigations of the mechanism of leukaemogenesis associated with the over-expression of Ik-6 are warranted.
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PMID:Over-expression of the dominant-negative isoform of Ikaros confers resistance to dexamethasone-induced and anti-IgM-induced apoptosis. 1267 Mar 48

The chromosomal translocation t(7;9)(q34;q34.3) in human T cell acute lymphoblastic leukemia (T-ALL) results in the aberrant expression of the intracellular domain of Notch (N(ic)). Consistent with the current multistep model for tumorigenesis, mice that express N(ic) in T cell progenitors develop a T-ALL-like disease with a lengthened latency. Proviral insertional mutagenesis greatly accelerated the onset of leukemia in N(ic) transgenic mice. We demonstrate that the Ikaros (Ik) locus is a common target of proviral integration in N(ic) transgenic mice, which results in the loss of Ik DNA binding activity through altered isoform expression. We propose that cooperative leukemogenesis occurs in cells that have constitutive N(ic) and altered Ik isoform expression because genes normally repressed by Ik become activated by N(ic)/CSL.
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PMID:Perturbation of Ikaros isoform selection by MLV integration is a cooperative event in Notch(IC)-induced T cell leukemogenesis. 1284 84

The Ikaros transcription factor has been shown to play an important role in the differentiation of both myeloid and lymphoid lineages. Mice heterozygous for a dominant negative (DN) ikaros isoform develop T-cell leukaemia and lymphoma with 100% penetrance. Overexpression of DN Ikaros isoforms has been reported in some forms of leukaemia, such as childhood acute myelomonocytic and monocytic leukaemias, adult B-cell acute lymphoblastic leukaemias (B ALL) and in childhood and adult pre-B ALL. In this study, the expression of Ikaros isoforms in 49 infant and childhood leukaemia patients was analysed by reverse transcription polymerase chain reaction and Western blot analysis. We found overexpression of the DN Ikaros 6 (Ik6) isoform in a subset of leukaemia patients harbouring t(4;11) translocations. To further study the consequences of Ik6 overexpression in B ALL, we inducibly expressed Ik6 in BaF3 cells and found that Ik6 overexpression delayed cell death after interleukin-3 withdrawal, suggesting that overexpression of Ik6 found in t(4;11) B cells could contribute to leukaemogenesis by preventing the apoptosis of cells in an environment with reduced survival factors.
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PMID:Overexpression of the Ikaros 6 isoform is restricted to t(4;11) acute lymphoblastic leukaemia in children and infants and has a role in B-cell survival. 1501 65

Ikaros is a key regulator of lymphocyte proliferative responses. Inactivating mutations in Ikaros cause antigen-mediated lymphocyte hyperproliferation and the rapid development of leukemia and lymphoma. Here we show that Ikaros's ability to negatively regulate the G(1)-S transition can be modulated by phosphorylation of a serine/threonine-rich conserved region (p1) in exon 8. Ikaros phosphorylation in p1 is induced during the G(1)-S transition. Mutations that prevent phosphorylation in p1 increase Ikaros's ability to impede cell cycle progression and its affinity for DNA. Casein kinase II, whose increased activity in lymphocytes leads to transformation, is a key player in Ikaros p1 phosphorylation. We thus propose that Ikaros's activity as a regulator of the G(1)-S transition is controlled by phosphorylation in response to signaling events that down-modulate its DNA binding activity.
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PMID:Phosphorylation controls Ikaros's ability to negatively regulate the G(1)-S transition. 1502 69

Notch signaling is required for normal T cell development. However, Notch expression must be precisely regulated as constitutive Notch signaling leads to T cell lymphomas. Recent evidence has provided insights into potential mechanisms of Notch-mediated lymphomagenesis and its relationship to T cell development. The evidence suggests that Notch likely interacts with several important cellular pathways and can cooperate with other oncogenes during lymphomagenesis. In particular, Notch appears to modulate pre-TCR signaling, inhibit the E2A pathway, and in murine leukemia models, frequently cooperates with Myc, E2A-PBX and dominant negative Ikaros dysregulation. This review will present current knowledge in these areas and explore theories on Notch-mediated T cell lymphomagenesis.
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PMID:Notch and T cell malignancy. 1528 58

Ikaros is a hematopoietic cell-specific zinc finger DNA binding protein that plays an important role in lymphocyte development. Genetic disruption of Ikaros results in T-cell transformation. Ikaros null mice develop leukemia with 100% penetrance. It has been hypothesized that Ikaros controls gene expression through its association with chromatin remodeling complexes. The development of leukemia in Ikaros null mice suggests that Ikaros has the characteristics of a tumor suppressor gene. In this report, we show that the introduction of Ikaros into an established mouse Ikaros null T leukemia cell line leads to growth arrest at the G0/G1 stage of the cell cycle. This arrest is associated with up-regulation of the cell cycle-dependent kinase inhibitor p27kip1, the induction of expression of T-cell differentiation markers, and a global and specific increase in histone H3 acetylation status. These studies provide strong evidence that Ikaros possesses the properties of a bona fide tumor suppressor gene for the T-cell lineage and offer insight into the mechanism of Ikaros's tumor suppressive activity.
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PMID:Ikaros induces quiescence and T-cell differentiation in a leukemia cell line. 1571 24

A number of transcription factors (TFs) have been reported that play crucial roles in hematopoiesis. However, only little is known about how these factors are involved in the mechanisms of hematopoietic development and lineage commitment. To investigate the roles of TFs in human B-cell precursors (BCPs), the present study analyzed the expression of the following 16 hematopoietic TFs: AML1, C/EBPalpha, C/EBPbeta, C/EBPgamma, C/EBPepsilon, E2A, Ets-1, GATA-1, GATA-2, GATA-3, Ikaros, IRF-1, Pax5, PU.1, T-bet and TCF-1 in 30 human BCP-leukemia cell lines. All BCP-leukemia cell lines were found to be positive for the expression of AML1, C/EBPgamma, E2A, Ets-1, IRF-1, Pax5 and PU.1 at the mRNA level. The mRNA expression of C/EBPalpha, C/EBPbeta, C/EBPepsilon, GATA-2, Ikaros, T-bet and TCF-1 was detected in 2 to 29 of the cell lines. Eight BCP-cell lines showed positivity for the dominant negative Ikaros isoform Ik6, while others were positive for expression of Ik1, 2, 3 and 4. GATA-1 and GATA-3 were universally negative. The expression of C/EBPalpha, PU.1 and T-bet was positive at the protein level in five, 29 and four out of 30 BCP-cell lines, respectively. Cell lines were stimulated with interleukin (IL)-7 and/or interferon (IFN)-gamma to investigate the regulation of TF expression. T-bet was clearly induced in the two cell lines NALM-19 and NALM-29 after stimulation. C/EBPbeta and IRF-1 were up-regulated in both cell lines and TCF-1 was down-regulated in NALM-19. No significant changes were observed for the other 12 TFs. The present report could provide useful information in the study of the role of TFs on normal and malignant human BCPs.
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PMID:Transcription factor expression in B-cell precursor-leukemia cell lines: preferential expression of T-bet. 1592 79

Hematological changes induced by various stress stimuli are accompanied by replacement of the primary acetylcholinesterase (AChE) 3' splice variant acetylcholinesterase-S (AChE-S) with the myelopoietic acetylcholinesterase-R (AChE-R) variant. To search for putative acetylcholinesterase-S interactions with hematopoietic pathways, we employed a yeast two-hybrid screen. The transcriptional co-repressor C-terminal binding protein (CtBP) was identified as a protein partner of the AChE-S C terminus. In erythroleukemic K562 cells, AChE-S displayed nuclear colocalization and physical interaction with CtBP. Furthermore, co-transfected AChE-S reduced the co-repressive effect of CtBP over the hematopoietic transcription factor, Ikaros. In transgenic mice, overexpressed human (h) AChE-S mRNA induced selective bone marrow upregulation of Ikaros while suppressing FOG, another transcriptional partner of CtBP. Transgenic bone marrow cells showed a correspondingly elevated potential for producing progenitor colonies, compared with controls, while peripheral blood showed increased erythrocyte counts as opposed to reduced platelets, granulocytes and T lymphocytes. AChE's 3' alternative splicing, and the corresponding changes in AChE-S/CtBP interactions, thus emerge as being actively involved in controlling hematopoiesis and the potential for modulating immune functions, supporting reports on malfunctioning immune reactions under impaired splice site selection.
Leukemia 2007 Jul
PMID:Acetylcholinesterase/C terminal binding protein interactions modify Ikaros functions, causing T lymphopenia. 1747 78


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