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)

Chromosome abnormalities influence prognosis and tumour progression in B-cell Chronic Lymphocytic Leukaemia (CLL). This study sought to determine whether these different disease subgroups were associated with unique gene expression patterns. Thirty-four cases of CLL were screened for the 11q23, 13q14, 17p13 deletions, and trisomy 12 by fluorescence in situ hybridization (FISH). Expression of 205 cell signalling and apoptosis genes were compared by cDNA array among cases with different chromosome abnormalities. A majority of the statistically differentially expressed genes were present in the 11q23 deletion group by hierarchical clustering. CDC2, a serine/threonine kinase, was overexpressed in the 11q23 deletion group (P = 0.0004) and confirmed by Taqman real-time polymerase chain reaction. Several other genes associated with cell signalling were overexpressed in the 11q23 deletion group. A strong overall correlation existed between the presence of different chromosome abnormalities and a number of prognostic factors including immunoglobulin heavy chain variable region mutation status (P = 0.011), time to treatment (P = 0.025) and lymphocyte doubling time (P = 0.034). This study confirmed the prognostic impact of chromosome abnormalities identified by FISH in CLL, particularly the 11q23 deletion and trisomy 12. In addition, the 11q23 deletion group was associated with a unique gene expression pattern involving cell signalling and apoptosis genes.
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PMID:Unique gene expression and clinical characteristics are associated with the 11q23 deletion in chronic lymphocytic leukaemia. 1568 53

The serine/threonine kinase Akt, a downstream effector of phosphatidylinositol 3-kinase (PI3K), is known to play an important role in antiapoptotic signaling and has been implicated in the aggressiveness of a number of different human cancers including acute myeloid leukemia (AML). The progression of myelodysplastic syndromes (MDSs) to AML is thought to be associated with abrogation of apoptotic control mechanisms. However, little is known about signal transduction pathways which may be involved in enhanced survival of MDS cells. In this report, we have performed immunocytochemical and flow cytometric analysis to evaluate the levels of activated Akt in bone marrow or peripheral blood mononuclear cells from patients diagnosed with MDS. We observed high levels of Ser473 phosphorylated Akt (p-Akt) staining in 90% of the cases (n=22) diagnosed as high-risk MDS, whereas mononuclear cells from normal bone marrow or low-risk MDS patients showed low or absent Ser473 p-Akt staining. Furthermore, all high-risk MDS patients also demonstrated high expression of the Class I PI3K p110delta catalytic subunit and a decreased expression of PTEN. Taken together, our results suggest that Akt activation might be one of the factors contributing to the decreased apoptosis rate observed in patients with high-risk MDS.
Leukemia 2006 Feb
PMID:Frequent elevation of Akt kinase phosphorylation in blood marrow and peripheral blood mononuclear cells from high-risk myelodysplastic syndrome patients. 1634 Oct 40

The serine/threonine kinase Akt, a downstream effector of phosphatidylinositol 3-kinase (PI3K), is known to play an important role in antiapoptotic signaling and has been implicated in the aggressiveness of a number of different human cancers including acute myelogenous leukemia (AML). We have investigated the therapeutic potential of the novel Akt inhibitor, perifosine, on human AML cells. Perifosine is a synthetic alkylphospholipid, a new class of antitumor agents, which target plasma membrane and inhibit signal transduction networks. Perifosine was tested on THP-1 and MV 4-11 cell lines, as well as primary leukemia cells. Perifosine treatment induced cell death by apoptosis in AML cell lines. Perifosine caused Akt and ERK 1/2 dephosphorylation as well as caspase activation. In THP-1 cells, the proapoptotic effect of perifosine was partly dependent on the Fas/FasL system and c-jun-N-kinase activation. In MV 4-11 cells, perifosine downregulated phosphorylated Akt, but not phosphorylated FLT3. Moreover, perifosine reduced the clonogenic activity of AML, but not normal, CD34(+) cells, and markedly increased blast cell sensitivity to etoposide. Our findings indicate that perifosine, either alone or in combination with existing drugs, might be a promising therapeutic agent for the treatment of those AML cases characterized by upregulation of the PI3K-Akt survival pathway.
Leukemia 2008 Jan
PMID:Proapoptotic activity and chemosensitizing effect of the novel Akt inhibitor perifosine in acute myelogenous leukemia cells. 1792 81

Pim2 is a serine/threonine kinase expressed at high levels in several malignancies including acute leukemia. Pim2 protein is induced by oncogenic Fms-like tyrosine kinase-3 (Flt3)-internal tandem duplications (ITD), but not by Flt3 wild-type receptor (Flt3-Wt) in response to Flt3 ligand (FL). Here we show that Pim2 can complement Flt3-Wt signaling and induce transformation similar to Flt3-ITD in myeloid cells. Our data demonstrate that Pim2 is necessary but not sufficient for Flt3-ITD-induced transformation of 32D cells and primary bone marrow cells as assessed by colony assays. Pim2-induced clonogenic growth of FL-treated 32D-Flt3-Wt cells. Proliferation of 32D-Flt3-Wt cells was significantly enhanced in FL-treated Pim2-overexpressing cells. This increase was associated with enhanced S-phase cell cycle progression. Pim2-overexpressing cells were resistant to apoptosis induced by growth factor deprivation or treatment with tyrosine kinase inhibitor (PKC412). The Flt3 point mutant D835Y, which is not able to support colony growth of myeloid cells, also induced clonogenic growth in the presence of Pim2. In conclusion, Pim2 is an important target of Flt3-ITD-induced transformation, and overexpression of Pim2 together with Flt3-Wt or D835Y receptor mimics Flt3-ITD-mediated transformation. Pim2 complements with Flt3-Wt signaling to induce proliferation by enhancing G(1)/S-phase progression of the cell cycle.
Leukemia 2008 Jan
PMID:Pim2 complements Flt3 wild-type receptor in hematopoietic progenitor cell transformation. 1794 65

Glycogen synthase kinase 3 (GSK3) is a multifunctional serine/threonine kinase that participates in numerous signalling pathways involved in diverse physiological processes. Several of these pathways are implicated in disease pathogenesis, which has prompted efforts to develop GSK3-specific inhibitors for therapeutic applications. However, before now, there has been no strong rationale for targeting GSK3 in malignancies. Here we report pharmacological, physiological and genetic studies that demonstrate an oncogenic requirement for GSK3 in the maintenance of a specific subtype of poor prognosis human leukaemia, genetically defined by mutations of the MLL proto-oncogene. In contrast to its previously characterized roles in suppression of neoplasia-associated signalling pathways, GSK3 paradoxically supports MLL leukaemia cell proliferation and transformation by a mechanism that ultimately involves destabilization of the cyclin-dependent kinase inhibitor p27(Kip1). Inhibition of GSK3 in a preclinical murine model of MLL leukaemia provides promising evidence of efficacy and earmarks GSK3 as a candidate cancer drug target.
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PMID:Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy. 1880 75

Aurora-A kinase (Aur-A) is a member of the serine/threonine kinase family that regulates the cell division process, and has recently been implicated in tumorigenesis. In this study, we identified an antigenic 9-amino-acid epitope (Aur-A(207-215): YLILEYAPL) derived from Aur-A capable of generating leukemia-reactive cytotoxic T lymphocytes (CTLs) in the context of HLA-A*0201. The synthetic peptide of this epitope appeared to be capable of binding to HLA-A*2402 as well as HLA-A*0201 molecules. Leukemia cell lines and freshly isolated leukemia cells, particularly chronic myelogenous leukemia (CML) cells, appeared to express Aur-A abundantly. Aur-A-specific CTLs were able to lyse human leukemia cell lines and freshly isolated leukemia cells, but not normal cells, in an HLA-A*0201-restricted manner. Importantly, Aur-A-specific CTLs were able to lyse CD34+ CML progenitor cells but did not show any cytotoxicity against normal CD34+ hematopoietic stem cells. The tetramer assay revealed that the Aur-A(207-215) epitope-specific CTL precursors are present in peripheral blood of HLA-A*0201-positive and HLA-A*2402-positive patients with leukemia, but not in healthy individuals. Our results indicate that cellular immunotherapy targeting Aur-A is a promising strategy for treatment of leukemia.
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PMID:Aurora-A kinase: a novel target of cellular immunotherapy for leukemia. 1882 Jan 30

Human T-cell leukemia virus type I (HTLV-I) is an oncogenic retrovirus that causes adult T-cell leukemia/lymphoma (ATLL). The virus encodes an oncoprotein, Tax, which functions in transcriptional regulation, cell cycle control, and transformation. Through its pleiotropic actions, Tax plays critical roles in leukemogenesis. We have previously reported that PTEN and SHIP-1, PIP3 inositol phosphatases that negatively regulate the phosphatidylinositol (PI) 3-kinase signaling cascade, are disrupted in ATLL neoplasias. Overactivation of PI3-kinase signaling has an essential role in both development of ATLL-specific nuclear polymorphisms and onset of ATLL. We report here that both PTEN and SHIP-1 are down-regulated by HTLV-I Tax through the NF-kappaB signaling pathway. Tax expression up-regulated phosphorylated Akt, a downstream serine/threonine kinase in the PI3-kinase signaling cascade. Transduction of NF-kappaB p65, which mimics the activation of NF-kappaB signaling, also suppressed these phosphatases. An IkappaBDeltaN mutant that inhibits the activation of NF-kappaB prevented PIP3 phosphatase down-regulation by Tax. The underlying mechanism of NF-kappaB-mediated suppression of PIP3 phosphatases involved sequestration of the coactivator p300 by p65. These down-regulations of PIP3 phosphatases were found to be essential for the Tax-induced cell proliferation. Thus, our results suggest that HTLV-I Tax down-regulates PIP3 phosphatases through the NF-kappaB pathway, resulting in increased activation of the PI3-kinase signaling cascade in human T-cells and contributing to leukemogenesis.
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PMID:Human T-cell leukemia virus type I tax down-regulates the expression of phosphatidylinositol 3,4,5-trisphosphate inositol phosphatases via the NF-kappaB pathway. 2224 17

Provirus integration site for Moloney murine leukemia virus (PIM1) is a proto-oncogene that encodes a serine/threonine kinase with multiple cellular functions. Overexpression of PIM-1 plays a critical role in progression of prostatic and hematopoietic malignancies. Here we describe the generation of a mAb specific for GST-PIM-1, which reacted strongly with most human and mouse cancer tissues and cell lines of prostate, breast, and colon origin but only weakly (if at all) with normal tissues. The mAb binds to PIM-1 in the cytosol and nucleus as well as to PIM-1 on the surface of human and murine cancer cells. Treatment of human and mouse prostate cancer cell lines with the PIM-1-specific mAb resulted in disruption of PIM-1/Hsp90 complexes, decreased PIM-1 and Hsp90 levels, reduced Akt phosphorylation at Ser473, reduced phosphorylation of Bad at Ser112 and Ser136, and increased cleavage of caspase-9, an indicator of activation of the mitochondrial cell death pathway. The mAb induced cancer cell apoptosis and synergistically enhanced antitumor activity when used in combination with cisplatin and epirubicin. In tumor models, the PIM-1-specific mAb substantially inhibited growth of the human prostate cancer cell line DU145 in SCID mice and the mouse prostate cancer cell TRAMP-C1 in C57BL/6 mice. These findings are important because they provide what we believe to be the first in vivo evidence that treatment of prostate cancer may be possible by targeting PIM-1 using an Ab-based therapy.
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PMID:PIM-1-specific mAb suppresses human and mouse tumor growth by decreasing PIM-1 levels, reducing Akt phosphorylation, and activating apoptosis. 1914 83

Azurin and Laz are bacterial proteins that have been shown to exert anticancer effects against a variety of solid tumors. Their effects on liquid cancers have never been studied. We now show that they are also effective against liquid-borne cancers such as leukemia. Azurin and Laz can each enter in two leukemia cell lines but Laz exerts a greater cytotoxic effect on both K562 and HL60 cells, while having little effect on peripheral blood mononuclear cells, where they have very limited entry. In addition to Azurin and Laz, we have recently identified another protein, Pa-CARD, from Pseudomonas aeruginosa that carries a caspase recruitment domain (CARD)-like domain. This CARD domain polypeptide, called Pa-CARD, demonstrates cytotoxic activity against leukemia cells. In the leukemia cell lines, HL60 and K562, the anticancer activity of Laz and Pa-CARD is mediated through cell cycle arrest at the G2/M phase involving the Wee1 protein stabilization and the depletion of phosphorylated AKT-Ser-473, the active form of a serine/threonine kinase that is often dysregulated in many cancer types.
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PMID:Bacterial proteins as potential drugs in the treatment of leukemia. 1925 Jun 73

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that functions as a key regulator of cell growth, protein synthesis, and cell-cycle progression through interactions with a number of signalling pathways, including PI3K/AKT, ras, TCL1, and BCR/ABL. Many haematological malignancies have aberrant activation of the mTOR and related signalling pathways. Accordingly, mTOR inhibitors, a class of signal transduction inhibitors that were originally developed as immunosuppressive agents, are being investigated in preclinical models and clinical trials for a number of haematological malignancies. Sirolimus and second-generation mTOR inhibitors, such as temsirolimus and everolimus, are safe and relatively well-tolerated, making them potentially attractive as single agents or in combination with conventional cytotoxics and other targeted therapies. Promising early clinical data suggests activity of mTOR inhibitors in a number of haematological diseases, including acute lymphoblastic leukaemia, chronic myeloid leukaemia, mantle cell lymphoma, anaplastic large cell lymphoma, and lymphoproliferative disorders. This review describes the rationale for using mTOR inhibitors in a variety of haematological diseases with a focus on their use in leukaemia.
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PMID:Mammalian target of rapamycin inhibitors and their potential role in therapy in leukaemia and other haematological malignancies. 1934 92


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