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)

We have isolated a novel cDNA clone encoding interferon (IFN) consensus sequence-binding protein in adult T-cell leukemia cell line or activated T cells (ICSAT); this protein is the human homolog of the recently cloned Pip/LSIRF. ICSAT is structurally most closely related to the previously cloned ICSBP, a member of the IFN regulatory factor (IRF) family of proteins that binds to interferon consensus sequences (ICSs) found in many promoters of the IFN-regulated genes. Among T-cell lines investigated, ICSAT was abundantly expressed in human T-cell leukemia virus type 1 (HTLV-1)-infected T cells. When the HTLV-1 tax gene was expressed or phorbol myristake acetate-A23187 stimulation was used, ICSAT expression was induced in Jurkat cells which otherwise do not express ICSAT. When the binding of ICSAT to four different ICSs was tested, the relative differences in binding affinities for those ICSs were determined. To study the functional role of ICSAT, we performed cotransfection experiments with the human embryonal carcinoma cell line N-Tera2. ICSAT was demonstrated to possess repressive function over the gene activation induced by IFN stimulation or by IRF-1 cotransfection. Such repressive function is similar to that seen in IRF-2 or ICSBP. However, we have found that ICSAT has a different repressive effect from that of IRF-2 or ICSBP in some IFN-responsive reporter constructs. These results suggest that a novel mechanism of gene regulation by "differential repression" is used by multiple members of repressor proteins with different repressive effects on the IFN-responsive genes.
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PMID:A novel interferon regulatory factor family transcription factor, ICSAT/Pip/LSIRF, that negatively regulates the activity of interferon-regulated genes. 865 1

Hematopoietic neoplasms developing in AKXD recombinant inbred, NFS.V(+) and ICSBP knockout mice were assessed using morphologic, cytologic and molecular criteria that relate these disorders to human lymphoma and leukemia. Lymphoma types included precursor T-cell and B-cell lymphoblastic, small lymphocytic, splenic marginal zone, follicular, and diffuse large cell (DLCL). In addition to previously defined subtypes of DLCL composed of centroblasts or immunoblasts, two additional subtypes are defined here: lymphoblastic lymphoma like (LL) and lymphoma characterized by a histiocytic reaction (HS). DLCL(HS) were distinguished from true histiocytic lymphomas by the presence of clonal Ig gene rearrangements.
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PMID:Combined histologic and molecular features reveal previously unappreciated subsets of lymphoma in AKXD recombinant inbred mice. 1159 41

IFN consensus sequence binding protein (ICSBP; IFN regulatory factor-8) is a transcription factor of the IFN regulatory factor family. Disruption of this gene results in a leukemia-like disease in mice. To investigate the role of ICSBP in myeloid cell development, lineage marker-negative (Lin(-)) bone marrow progenitor cells were purified from ICSBP(+/+) and ICSBP(-/-) mice and tested for gene expression and colony-forming ability. ICSBP was expressed in Lin(-) progenitor cells, and its levels were markedly increased by IFN-gamma. The colony-forming potential of ICSBP(-/-) progenitor cells was grossly abnormal, as they gave rise to a disproportionately high number of granulocyte colonies and many fewer macrophage colonies. IFN-gamma inhibited colony formation, while promoting macrophage maturation in ICSBP(+/+) cells. In contrast, the effects of IFN-gamma were completely absent in ICSBP(-/-) progenitors. By retrovirus transduction we tested whether reintroduction of ICSBP restores a normal colony-forming potential in -/- progenitor cells. The wild-type ICSBP, but not transcriptionally defective mutants, corrected abnormal colony formation by increasing macrophage colonies and decreasing granulocyte colonies. Taken together, ICSBP plays a critical role in myeloid cell development by controlling lineage selection and is indispensable for IFN-gamma-dependent modulation of progenitor cell maturation.
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PMID:IFN consensus sequence binding protein/IFN regulatory factor-8 guides bone marrow progenitor cells toward the macrophage lineage. 1213 47

The E2a-Pbx1 oncoprotein of human pre-B cell leukemia prevents differentiation and maintains continued cell division in cultured myeloid progenitors. Previously, estrogen-dependent forms of E2a-Pbx1 were generated that immortalized neutrophil (ECoM-G cells) or monocyte (ECoM-M cells) progenitors and that permitted their terminal differentiation upon estrogen withdrawal. Here, representational difference analysis (RDA) and Affymetrix array analysis are used to identify changes in gene expression that accompany the early differentiation of these cells. The promoters of these genes, whose expression changes upon E2a-Pbx1 inactivation, integrate the biochemical mechanism through which E2a-Pbx1 arrests differentiation and maintains cell division. Inactivation of E2a-Pbx1 caused the 10- to 80-fold up regulation of a small subset of myeloid differentiation genes (MRP8, Cnlp, NB1, Bactenecin, YM1, Stefin 1, Lipocortin, Lactoferrin, gp91 phox and Ly6-G) and a 10-fold down regulation of the TLE1 corepressor gene, as well as of a group of genes expressed in dividing cells (c-Myc, Nucleophosmin, Spermidine synthase, NOP56, Hnrpa1). Transcription of 97% of cellular genes, including 300 other transcription factor genes (21 Hox genes) and other myeloid genes, varied less than 3-fold, with most varying less than 50%. Therefore, E2a-Pbx1 prevents transcription and maintains the cell cycle by a specific rather than a global transcriptional mechanism. Monocyte progenitors were distinguished by persistent expression of IRF8 and of a category of other genes characterized as "interferon-stimulated" (ISG15, ISG20, Ifit1, Ifi202a, Ifi203, IfiS204, Ifi204-related, IRF7 and Ly6-E.1), as well as by the upregulation of the Lrg21 bZip transcription factor gene during late differentiation. The synchronous expression of stage-specific and cell cycle genes regulated by E2a-Pbx1 in these cell lines comprises a model system in which analysis of their promoters can be used as a starting point to backtrack to the transcriptional mechanisms of oncogenesis by E2a-Pbx1.
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PMID:Transcriptional profiling during the early differentiation of granulocyte and monocyte progenitors controlled by conditional versions of the E2a-Pbx1 oncoprotein. 1291 72

BXH-2 mice develop a fatal myeloid leukemia by a two-step mutagenic process. First, a BXH-2-specific recessive mutation causes a myeloproliferative syndrome. Second, retroviral insertions alter oncogenes or tumor suppressors, resulting in clonal expansion of leukemic cells. We have identified a recessive locus on chromosome 8 (Myls) that is responsible for myeloproliferation in BXH-2. This Myls interval has been narrowed down to 2 Mb and found to contain several positional candidates, including the interferon consensus sequence-binding protein 1 gene (Icsbp, also known as interferon regulatory factor 8 [IRF8]). We show that BXH-2 mice carry a mutation (915 C to T) resulting in an arginine-to-cysteine substitution at position 294 within the predicted IRF association domain of the protein. Although expression of Icsbp1 mRNA transcripts is normal in BXH-2 splenocytes, these cells are unable to produce interleukin 12 and interferon-gamma in response to activating stimuli, confirming that R294C behaves as a loss-of-function mutation. Myeloproliferation in BXH-2 mice is concomitant to increased susceptibility to Mycobacterium bovis (BCG) despite the presence of resistance alleles at the Nramp1 locus. These results suggest a two-step model for chronic myeloid leukemia in BXH-2, in which inactivation of Icsbp1 predisposes to myeloproliferation and immunodeficiency. This event is required for retroviral replication, and subsequent insertional mutagenesis that causes leukemia in BXH-2 mice.
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PMID:A mutation in the Icsbp1 gene causes susceptibility to infection and a chronic myeloid leukemia-like syndrome in BXH-2 mice. 1578 80

ICSBP (interferon consensus sequence binding protein)/IRF8 (interferon regulatory factor 8) is an interferon gamma-inducible transcription factor expressed predominantly in hematopoietic cells, and down-regulation of this factor has been observed in chronic myelogenous leukemia and acute myeloid leukemia in man. By screening about 1200 murine leukemia virus (MLV)-induced lymphomas, we found proviral insertions at the Icsbp locus in 14 tumors, 13 of which were mature B-cell lymphomas or plasmacytomas. Only one was a T-cell lymphoma, although such tumors constituted about half of the samples screened. This indicates that the Icsbp locus can play a specific role in the development of mature B-lineage malignancies. Two proviral insertions in the last Icsbp exon were found to act by a poly(A)-insertion mechanism. The remaining insertions were found within or outside Icsbp. Since our results showed expression of Icsbp RNA and protein in all end-stage tumor samples, a simple tumor suppressor function of ICSBP is not likely. Interestingly, proviral insertions at Icsbp have not been reported from previous extensive screenings of mature B-cell lymphomas induced by endogenous MLVs. We propose that ICSBP might be involved in an early modulation of an immune response to exogenous MLVs that might also play a role in proliferation of the mature B-cell lymphomas.
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PMID:The Icsbp locus is a common proviral insertion site in mature B-cell lymphomas/plasmacytomas induced by exogenous murine leukemia virus. 1678 Sep 17

In this study, we provide a molecular signature of highly enriched CD34+ cells from bone marrow of untreated patients with chronic myelogenous leukemia (CML) in chronic phase in comparison with normal CD34+ cells using microarrays covering 8746 genes. Expression data reflected several BCR-ABL-induced effects in primary CML progenitors, such as transcriptional activation of the classical mitogen-activated protein kinase pathway and the phosphoinositide-3 kinase/AKT pathway as well as downregulation of the proapoptotic gene IRF8. Moreover, novel transcriptional changes in comparison with normal CD34+ cells were identified. These include upregulation of genes involved in the transforming growth factorbeta pathway, fetal hemoglobin genes, leptin receptor, sorcin, tissue inhibitor of metalloproteinase 1, the neuroepithelial cell transforming gene 1 and downregulation of selenoprotein P. Additionally, genes associated with early hematopoietic stem cells (HSC) and leukemogenesis such as HoxA9 and MEIS1 were transcriptionally activated. Differential expression of differentiation-associated genes suggested an altered composition of the CD34+ cell population in CML. This was confirmed by subset analyses of chronic phase CML CD34+ cells showing an increase of the proportion of megakaryocyte-erythroid progenitors, whereas the proportion of HSC and granulocyte-macrophage progenitors was decreased in CML. In conclusion, our results give novel insights into the biology of CML and could provide the basis for identification of new therapeutic targets.
Leukemia 2007 Mar
PMID:Molecular signature of CD34(+) hematopoietic stem and progenitor cells of patients with CML in chronic phase. 1725 12

Zoledronic acid (ZA) is a nitrogen-containing bisphosphonate with antitumor activity used to treat patients with malignant diseases. ZA treatment induces, as a side effect, inflammatory responses, which are accompanied by expansion of gammadelta T cells. In our study, we analyzed the function and differentiation of monocyte-derived immature and lipopolysaccharide (LPS)-stimulated dendritic cells (moDCs) treated with different ZA concentrations, which are achieved in patients. We found that moDC activation with TLR4 ligand LPS is modulated by ZA. The expression of maturation markers was diminished with increasing ZA levels upon LPS activation. The migratory capacity, interleukin-12 secretion and generation of cytotoxic- T-cell responses were reduced at higher ZA levels. Increasing ZA concentrations downregulated nuclear factor-kappaB family members and interferon-regulatory factor (IRF)-3. Surprisingly, in immature moDCs, low ZA concentrations caused upregulation of RelB, c-Rel, IRF-3 and IRF-8. We conclude that ZA concentrations used to treat patients have inhibitory effects on DC activation. This might lead to immunosuppression or result in infectious complications.
Leukemia 2007 Apr
PMID:Zoledronic acid inhibits the function of Toll-like receptor 4 ligand activated monocyte-derived dendritic cells. 1730 19

The IFN consensus sequence-binding protein (ICSBP; also referred to as IFN regulatory factor 8) is a transcription factor which is expressed in myeloid and B cells. In previous studies, we found that ICSBP activated transcription of the gene encoding gp91(PHOX) (the CYBB gene), a rate-limiting component of the phagocyte respiratory burst oxidase expressed exclusively after the promyelocyte stage of myelopoiesis. Previously, we found that CYBB transcription was dependent on phosphorylation of specific ICSBP tyrosine residues. Since ICSBP is tyrosine-phosphorylated during myelopoiesis, this provided a mechanism of differentiation stage-specific CYBB transcription. In the current studies, we found that ICSBP was a substrate for Src homology-containing tyrosine phosphatase 2 (SHP2-PTP) in immature myeloid cells but not during myelopoiesis. Therefore, SHP2-PTP inhibited CYBB transcription and respiratory burst activity in myeloid progenitor cells by dephosphorylating ICSBP. In contrast, we found that ICSBP was a substrate for a leukemia-associated, constitutively active mutant form of SHP2, described previously, throughout differentiation. Consistent with this, constitutive SHP2 activation blocked ICSBP-induced CYBB transcription and respiratory burst activity in differentiating myeloid cells. ICSBP-deficiency and constitutive SHP2 activation have been described in human myelodysplastic syndromes. As these two abnormalities may coexist, our results identified a potential molecular mechanism for impaired phagocyte function in this malignant myeloid disease.
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PMID:Constitutive activation of SHP2 protein tyrosine phosphatase inhibits ICSBP-induced transcription of the gene encoding gp91PHOX during myeloid differentiation. 1808 53

Plasmacytoid dendritic cells (pDCs) are involved in innate immunity (eg, by secreting interferons) and also give rise to CD4+CD56+ hematodermic neoplasms. We report extensive characterization of human pDCs in routine tissue samples, documenting the expression of 19 immunohistologic markers, including signaling molecules (eg, BLNK), transcription factors (eg, ICSBP/IRF8 and PU.1), and Toll-like receptors (TLR7, TLR9). Many of these molecules are expressed in other cell types (principally B cells), but the adaptor protein CD2AP was essentially restricted to pDCs, and is therefore a novel immunohistologic marker for use in tissue biopsies. We found little evidence for activation-associated morphologic or phenotypic changes in conditions where pDCs are greatly increased (eg, Kikuchi disease). Most of the molecules were retained in the majority of pDC neoplasms, and 3 (BCL11A, CD2AP, and ICSBP/IRF8) were also commonly negative in leukemia cutis (acute myeloid leukemia in the skin), a tumor that may mimic pDC neoplasia. In summary, we have documented a range of molecules (notably those associated with B cells) expressed by pDCs in tissues and peripheral blood (where pDCs were detectable in cytospins at a frequency of <1% of mononuclear cells) and also defined potential new markers (in particular CD2AP) for the diagnosis of pDC tumors.
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PMID:Novel markers of normal and neoplastic human plasmacytoid dendritic cells. 1821 51


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