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)

Transforming growth factor beta (TGF-beta) is a pluripotent cytokine that controls key tumour suppressive functions, but cancer cells are often unresponsive to it. The promyelocytic leukaemia (PML) tumour suppressor of acute promyelocytic leukaemia (APL) accumulates in the PML nuclear body, but cytoplasmic PML isoforms of unknown function have also been described. Here we show that cytoplasmic Pml is an essential modulator of TGF-beta signalling. Pml-null primary cells are resistant to TGF-beta-dependent growth arrest, induction of cellular senescence and apoptosis. These cells also have impaired phosphorylation and nuclear translocation of the TGF-beta signalling proteins Smad2 and Smad3, as well as impaired induction of TGF-beta target genes. Expression of cytoplasmic Pml is induced by TGF-beta. Furthermore, cytoplasmic PML physically interacts with Smad2/3 and SARA (Smad anchor for receptor activation) and is required for association of Smad2/3 with SARA and for the accumulation of SARA and TGF-beta receptor in the early endosome. The PML-RARalpha oncoprotein of APL can antagonize cytoplasmic PML function and APL cells have defects in TGF-beta signalling similar to those observed in Pml-null cells. Our findings identify cytoplasmic PML as a critical TGF-beta regulator, and further implicate deregulated TGF-beta signalling in cancer pathogenesis.
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PMID:Cytoplasmic PML function in TGF-beta signalling. 1535 16

The MLL gene is a frequent target for leukemia-associated chromosomal translocations that generate dominant-acting chimeric oncoproteins. These invariably contain the amino-terminal 1,400 residues of MLL fused with one of a variety of over 30 distinct nuclear or cytoplasmic partner proteins. Despite the consistent inclusion of the MLL amino-terminal region in leukemia oncoproteins, little is known regarding its molecular contributions to MLL-dependent oncogenesis. Using high-resolution mutagenesis, we identified three MLL domains that are essential for in vitro myeloid transformation via mechanisms that do not compromise subnuclear localization. These include the CXXC/Basic domain and two novel domains of unknown function. Point mutations in the CXXC domain that eliminate myeloid transformation by an MLL fusion protein also abolished recognition and binding of nonmethylated CpG DNA sites in vitro and transactivation in vivo. Our results define a critical role for the CXXC DNA binding domain in MLL-associated oncogenesis, most likely via epigenetic recognition of CpG DNA sites within the regulatory elements of target genes.
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PMID:Binding to nonmethylated CpG DNA is essential for target recognition, transactivation, and myeloid transformation by an MLL oncoprotein. 1554 54

Resistance to imatinib mesylate (also known as Gleevec, Glivec, and STI571) often becomes a barrier to the treatment of chronic myelogenous leukemia (CML). In order to identify markers of the action of imatinib mesylate, we used a mass spectrometry approach to compare protein expression profiles in human leukemia cells (K562) and in imatinib mesylate-resistant human leukemia cells (K562-R) in the presence and absence of imatinib mesylate. We identified 118 differentially regulated proteins in these two leukemia cell-lines, with and without a 1 microM imatinib mesylate challenge. Nine proteins of unknown function were discovered. This is the first comprehensive report regarding differential protein expression in imatinib mesylate-treated CML cells.
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PMID:Identification of differentially expressed proteins in imatinib mesylate-resistant chronic myelogenous cells. 1633 89

Alemtuzumab is a humanized IgG1 kappa antibody directed against CD52, a glycosyl-phosphatidylinositol linked cell-membrane protein of unknown function. Herein, we demonstrate that alemtuzumab promotes rapid death of chronic lymphocytic leukemia (CLL) cells in vitro, in a complement and accessory cell free system. Using minimal detergent solubilization of CLL membranes, we found that CD52 colocalizes with ganglioside GM-1, a marker of membrane rafts. Fluorescence microscopy revealed that upon crosslinking CD52 with alemtuzumab+anti-Fc IgG, large patches, and in many cases caps, enriched in CD52 and GM-1 formed upon the CLL cell plasma membrane. Depletion of membrane cholesterol or inhibition of actin polymerization significantly diminished the formation of alemtuzumab-induced caps and reduced alemtuzumab-mediated CLL cell death. We compared alemtuzumab-induced direct cytotoxicity, effector cell-mediated toxicity and complement-mediated cytotoxicity of CLL cells to normal T cells. The direct cytotoxicity and observed capping was significantly greater for CLL cells as compared to normal T cells. Cell-mediated and complement-mediated cytotoxicity did not significantly differ between the two cell types. In summary, our data support the hypothesis that alemtuzumab can initiate CLL cell death by crosslinking CD52-enriched lipid rafts. Furthermore, the differential direct cytotoxic effect suggests that CD52 directed antibodies could possibly be engineered to more specifically target CLL cells.
Leukemia 2006 Feb
PMID:Alemtuzumab induces caspase-independent cell death in human chronic lymphocytic leukemia cells through a lipid raft-dependent mechanism. 1634 Oct 49

Shwachman-Diamond syndrome (SDS) is an autosomal recessive marrow failure syndrome associated with exocrine pancreatic insufficiency and leukemia predisposition. Bone marrow failure typically manifests with neutropenia, but anemia, thrombocytopenia, or aplastic anemia may also develop. Additional organ systems, such as liver or bone, may also be affected. Clonal cytogenetic abnormalities, particularly those involving chromosome 7 such as monosomy 7 or isochromosome 7, may develop. Mutations in the SBDS gene are found in approximately 90% of patients meeting clinical diagnostic criteria. SBDS is a highly conserved gene of unknown function. Studies of the yeast orthologue YLR022c and structurally related proteins suggest a role in RNA metabolism. In human cells, the SBDS protein localizes to both the cytoplasm and the nucleus, and shuttles in and out of the nucleolus in a cell cycle-dependent manner. A discussion of diagnostic workup, medical management, and treatment is presented.
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PMID:Shwachman-Diamond syndrome. 1682 60

Embryonic stem cells (ESCs) derived from the inner cell mass of blastocysts maintain their pluripotency through a complex interplay of different signaling pathways and transcription factors including Leukemia Inhibitory Factor (LIF), homeo-domain protein Nanog and POU-domain-containing transcription factor Oct3/4. LIF can maintain the self-renewal of mouse ESCs by activating the Jak/Stat3 pathway; however, it is dispensable for human ESCs. Nanog, a homeo-domain transcription factor alone is sufficient for sustaining the self-renewal of ESCs. Overexpression of Nanog by heterologous promoters can maintain self-renewal of human and mouse ESCs in the absence of LIF/Stat3 pathway. The mechanisms that control the expression of Nanog, however, remain poorly understood. In this report we demonstrate that retinol, the alcohol form of Vitamin A, can suppress the differentiation of ESCs by up-regulating the expression of Nanog. Retinol is mainly associated with differentiation through its active metabolite retinoic acid during early development of the embryo. The activation of Nanog by retinol is not mediated via retinoic acid signaling and appears to be independent of previously described LIF/Stat3, bone morphogenic proteins, Wnt/beta-catenin, and Oct3/4-Sox2 pathways. These studies therefore, reveal a previously unknown function of retinol and offer a model system to define alternate regulatory pathways that control the self-renewal of ESCs as well as to identify upstream "master" regulatory factors that are responsible for maintaining the integrity of stem cells.
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PMID:Suppression of ES cell differentiation by retinol (vitamin A) via the overexpression of Nanog. 1745 18

Although mitosis is a general physiologic process, cancer cells are unusually sensitive to mitotic inhibitors. Therefore, there is an interest in the identification of novel mitotic inhibitors. Here, we report the novel discovery of the SIL gene as a regulator of mitotic entry and cell survival. The SIL gene was cloned from leukemia-associated chromosomal translocation. It encodes a cytosolic protein with an unknown function and no homology to known proteins. Previously, we observed an increased expression of SIL in multiple cancers that correlated with the expression of mitotic spindle checkpoint genes and with increased metastatic potential. Here, we show that SIL is important for the transition from the G(2) to the M phases of the cell cycle. Inducible knockdown of SIL in cancer cells in vitro delayed entrance into mitosis, decreased activation of the CDK1 (CDC2)-cyclin B complex, and induced apoptosis in a p53-independent manner. SIL is also essential for the growth of tumor explants in mice. Thus, SIL is required for mitotic entry and cancer cell survival. Because increased expression of SIL has been noted in multiple types of cancers and correlates with metastatic spread, it may be a suitable target for novel anticancer therapy.
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PMID:The SIL gene is essential for mitotic entry and survival of cancer cells. 1745 84

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized by bone marrow failure, exocrine pancreatic dysfunction, and leukemia predisposition. Mutations in the SBDS gene are identified in most patients with SDS. SBDS encodes a highly conserved protein of unknown function. Data from SBDS orthologs suggest that SBDS may play a role in ribosome biogenesis or RNA processing. Human SBDS is enriched in the nucleolus, the major cellular site of ribosome biogenesis. Here we report that SBDS nucleolar localization is dependent on active rRNA transcription. Cells from patients with SDS or Diamond-Blackfan anemia are hypersensitive to low doses of actinomycin D, an inhibitor of rRNA transcription. The addition of wild-type SBDS complements the actinomycin D hypersensitivity of SDS patient cells. SBDS migrates together with the 60S large ribosomal subunit in sucrose gradients and coprecipitates with 28S ribosomal RNA (rRNA). Loss of SBDS is not associated with a discrete block in rRNA maturation or with decreased levels of the 60S ribosomal subunit. SBDS forms a protein complex with nucleophosmin, a multifunctional protein implicated in ribosome biogenesis and leukemogenesis. Our studies support the addition of SDS to the growing list of human bone marrow failure syndromes involving the ribosome.
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PMID:The human Shwachman-Diamond syndrome protein, SBDS, associates with ribosomal RNA. 1747 9

This study demonstrates the power of a genetic selection to identify a variant virus that uses a new retroviral receptor protein. We screened a random peptide library within the receptor-binding domain of a feline leukemia virus retroviral Envelope (FeLV Env) protein for productive infection of feline AH927 cells. One variant, A5, obtained with altered tropic properties acquired the ability to use the solute carrier protein family 35 member F2 (SLC35F2) as a receptor. The SLC35F2 protein is a presumed transporter of unknown function predicted to encode 8 to 10 transmembrane-spanning regions and is not homologous to any identified retroviral receptor. Expression of the feline SLC35F2 cDNA in nonpermissive cells renders the cells susceptible to infection by A5 virus, with remarkably high titers in the range of 10(5) infectious units per ml. The human SLC35F2 ORF also functioned as the retroviral receptor, albeit at lower efficiency than the feline homologue. The successful selection of a novel molecule, the SLC35F2 transporter/channel-type protein, as a receptor by the FeLV Env backbone suggests that multipass transmembrane proteins may be particularly suited for use in productive viral entry and fusion. The analysis of retroviral Env libraries randomized in the receptor-binding domain offers a viable means to develop viral vectors targeted to specific cell types in the absence of known targeting ligands.
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PMID:Identification of a retroviral receptor used by an envelope protein derived by peptide library screening. 1758 69

We describe the emerging role of Synovial Sarcoma X breakpoint 2 Interacting Protein (SSX2IP) in cancer and its still largely unknown function in human cells. In rodents, SSX2IP has been shown to play a role in adherens junctions and cell adhesion, while in chickens SSX2IP was identified by virtue of its regulation by the light cycle and circadian rhythms. In humans, SSX2IP was identified through its interaction with the cancer-testis gene SSX2. However SSX2IP is expressed in a range of normal and fetal tissues unlike SSX2. SSX2IP containing constructs indicated that SSX2IP could be expressed in the nucleus and cytoplasm of transfected human cells, however, SSX2IP expression has been subsequently shown to peak on the surface of myeloid leukaemia cells during mitosis. Here we discuss the current knowledge of SSX2IP function in several species and the growing evidence that SSX2IP may be a suitable target for leukaemia immunotherapy.
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PMID:SSX2IP: an emerging role in cancer. 1790 21


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