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 PTEN (phosphatase and tensin homolog deleted on chromosome ten) tumor suppressor gene is mutated in a wide range of malignancies and recent studies have demonstrated that PTEN prevents tumorigenesis through multiple mechanisms. PTEN functions as a plasma-membrane lipid phosphatase that antagonizes the PI3K (phosphoinositide 3 kinase)-AKT pathway. PTEN physically and genetically interacts with the central genome guardian p53. PTEN also associates with the centromeric protein CENP-C to maintain centromere integrity and suppresses chromosomal instability from DNA double-strand breaks (DSBs) through transcriptional regulation of Rad51 (radiosensitive yeast mutant 51). Moreover PTEN controls the growth and proliferation of haematopoietic stem cells (HSC) and restrains cells from leukemia in an mTOR (mammalian target of rapamycin) dependent manner. Thus, restoring PTEN functions in cancer cells directly or indirectly holds great promise for cancer therapy.
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PMID:PTEN mutation: many birds with one stone in tumorigenesis. 1918 42

Despite advances in the treatment of acute lymphoblastic leukemia (ALL), the majority of children who relapse still die of ALL. Therefore, the development of more potent but less toxic drugs for the treatment of ALL is imperative. We investigated the effects of the mammalian target of rapamycin inhibitor, RAD001 (Everolimus), in a nonobese diabetic/severe combined immunodeficiency model of human childhood B-cell progenitor ALL. RAD001 treatment of established disease increased the median survival of mice from 21.3 days to 42.3 days (P < .02). RAD001 together with vincristine significantly increased survival compared with either treatment alone (P < .02). RAD001 induced a cell-cycle arrest in the G(0/1) phase with associated dephosphorylation of the retinoblastoma protein, and reduced levels of cyclin-dependent kinases 4 and 6. Ultrastructure analysis demonstrated the presence of autophagy and limited apoptosis in cells of RAD001-treated animals. In contrast, cleaved poly(ADP-ribose) polymerase suggested apoptosis in cells from animals treated with vincristine or the combination of RAD001 and vincristine, but not in those receiving RAD001 alone. In conclusion, we have demonstrated activity of RAD001 in an in vivo leukemia model supporting further clinical development of target of rapamycin inhibitors for the treatment of patients with ALL.
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PMID:Potentiating effects of RAD001 (Everolimus) on vincristine therapy in childhood acute lymphoblastic leukemia. 1919 56

Mantle cell lymphoma (MCL) is a clinically aggressive B-cell non-Hodgkin lymphoma characterized by the t(11;14)(q13;q32) and overexpression of cyclin D1. A high proportion of MCL tumors harbor wild-type (wt) and potentially functional p53 gene. We show here that stabilization and activation of wt-p53 using a recently developed potent MDM2 inhibitor, nutlin 3A, results in significant p53-dependent G1-S cell cycle arrest and apoptosis in MCL cells through regulation of p53 target genes. As mTOR signaling is activated in MCL and may control cyclin D1 levels, we show that p53 activation may downregulate the AKT/mTOR pathway through a mechanism involving AMP kinase (AMPK). Despite the non-genotoxic mode of nutlin 3A treatment, we show evidence that stabilization of p53 is associated with its phosphorylation at serine 15 residue and activation of AMPK. Stimulation of AMPK kinase activity using AICAR inhibits phosphorylation of critical downstream effectors of mTOR signaling, such as 4E-BP1 and rpS6. Pharmacologic inhibition of AMPK using compound C in nutlin-3A-treated MCL cells harboring wt-p53 did not affect the level of (ser15)p-p53, suggesting that the (ser15)p-p53 --> AMPK is the direction involved in the p53/AMPK/mTOR cross talk. These data establish a p53 --> AMPK --> mTOR mechanism in MCL and uncover a novel biologic effect of potent MDM2 inhibitors in preclinical models of MCL.
Leukemia 2009 Apr
PMID:Stabilization and activation of p53 downregulates mTOR signaling through AMPK in mantle cell lymphoma. 1922 36

The cyclic AMP-responsive element binding protein (CREB) is documented to be overexpressed in leukemia, but the underlying mechanism remains unknown. Here, microRNAs (miRNA), which act as negative regulators of gene expression principally through translational repression, are investigated for the mediation of high CREB protein levels. A series of miRNAs that target CREB were identified. Real-time quantitative PCR revealed that miR-34b was expressed significantly less in myeloid cell lines, previously known for high CREB protein levels. Exogenous miR-34b expression was induced, and results revealed a direct interaction with the CREB 3'-untranslated region, with the consequent reduction of the CREB protein levels in vitro. miR-34b restored expression caused cell cycle abnormalities, reduced anchorage-independent growth, and altered CREB target gene expression, suggesting its suppressor potential. Using reverse-phase protein array, CREB target proteins (BCL-2, cyclin A1, cyclin B1, cyclin D, nuclear factor-kappaB, Janus-activated kinase 1, and signal transducer and activator of transcription 3), as well as many downstream protein kinases and cell survival signaling pathways (AKT/mammalian target of rapamycin and extracellular signal-regulated kinase) usually elicited by CREB, were observed to have decreased. The miR-34b/miR-34c promoter was shown to be methylated in the leukemia cell lines used. This epigenetic regulation should control the observed miR-34b expression levels to maintain the CREB protein overexpressed. In addition, the inverse correlation between miR-34b and CREB expression was found in a cohort of 78 pediatric patients at diagnosis of acute myeloid leukemia, supporting this relationship in vivo. Our results identify a direct miR-34b target gene, provide a possible mechanism for CREB overexpression, and provide new information about myeloid transformation and therapeutic strategies.
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PMID:miR-34b targets cyclic AMP-responsive element binding protein in acute myeloid leukemia. 1925 99

To evaluate the effect of deferasirox in human myeloid leukemia cells, and to identify the molecular pathways responsible for antiproliferative effects on leukemia cells during chelation therapy, we performed gene expression profiling to focus on the pathway involved in the anticancer effect of deferasirox. The inhibitory concentration (IC50) of deferasirox was 17-50 microM in three human myeloid cell lines (K562, U937, and HL60), while those in fresh leukemia cells obtained from four patients it varied from 88 to 172 microM. Gene expression profiling using Affymerix GeneChips (U133 Plus 2.0) revealed up-regulation of cyclin-dependent kinase inhibitor 1A (CDKN1A) encoding p21CIP, genes regulating interferon (i.e. IFIT1). Pathways related to iron metabolism and hypoxia such as growth differentiation factor 15 (GDF-15) and Regulated in development and DNA damage response (REDD1) were also prominent. Based on the results obtained from gene expression profiling, we particularly focused on the REDD1/mTOR (mammalian target of rapamycin) pathway in deferasirox-treated K562 cells, and found an enhanced expression of REDD1 and its down-stream protein, tuberin (TSC2). Notably, S6 ribosomal protein as well as phosphorylated S6, which is known to be a target of mTOR, was significantly repressed in deferasirox-treated K562 cells, and REDD1 small interfering RNA restored phosphorylation of S6. Although iron chelation may affect multiple signaling pathways related to cell survival, our data support the conclusion that REDD1 functions up-stream of tuberin to down-regulate the mTOR pathway in response to deferasirox. Deferasirox might not only have benefit for iron chelation but also may be an antiproliferative agent in some myeloid leukemias, especially patients who need both iron chelation and reduction of leukemia cells.
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PMID:The oral iron chelator deferasirox represses signaling through the mTOR in myeloid leukemia cells by enhancing expression of REDD1. 1929 23

We explored the impact of mutations in the NOTCH1, FBW7 and PTEN genes on prognosis and downstream signaling in a well-defined cohort of 47 patients with pediatric T-cell acute lymphoblastic leukemia (T-ALL). In T-ALL lymphoblasts, we identified high-frequency mutations in NOTCH1 (n=16), FBW7 (n=5) and PTEN (n=26). NOTCH1 mutations resulted in 1.3- to 3.3-fold increased transactivation of an HES1 reporter construct over wild-type NOTCH1; mutant FBW7 resulted in further augmentation of reporter gene activity. NOTCH1 and FBW7 mutations were accompanied by increased median transcripts for NOTCH1 target genes (HES1, DELTEX1 and cMYC). However, none of these mutations were associated with treatment outcome. Elevated HES1, DELTEX1 and cMYC transcripts were associated with significant increases in transcript levels of several chemotherapy relevant genes, including MDR1, ABCC5, reduced folate carrier, asparagine synthetase, thiopurine methyltransferase, BCL2 and dihydrofolate reductase. PTEN transcripts positively correlated with HES1 and cMYC transcript levels. Our results suggest that (1) multiple factors should be considered with attempting to identify molecular-based prognostic factors for pediatric T-ALL, and (2) depending on the NOTCH1 signaling status, modifications in the types or dosing of standard chemotherapy drugs for T-ALL, or combinations of agents capable of targeting NOTCH1, AKT and/or mTOR with standard chemotherapy agents may be warranted.
Leukemia 2009 Aug
PMID:The impact of NOTCH1, FBW7 and PTEN mutations on prognosis and downstream signaling in pediatric T-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group. 1934 1

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

The elimination of tumor cells by apoptosis is the main mechanism of action of chemotherapeutic drugs used in current treatment protocols of acute lymphoblastic leukemia (ALL). Despite the rapid cytoreduction achieved, serious acute and late complications are frequent, and resistance to chemotherapy develops. During the past decade, new strategies to kill cancer cells by nonapoptotic mechanisms have flourished and many mediators of alternate cell death pathways have been identified. In the present study we have evaluated the efficacy of an mTOR inhibitor, RAD001 (Everolimus), to induce autophagy in an in vivo model of childhood ALL. In particular we found that RAD001 increased Beclin 1 expression, the conversion of the soluble form of microtubule-associated protein 1 light chain 3 (LC3) to the autophagic vesicle-associated form LC3-II and the occurence of lysosomes/autophagosomes. Focal degradation of cytoplasmic areas sequestered by autophagic structures was demonstrated by electron microscopy. This effect was associated with massive reduction of leukemic mass and a strong survival advantage for mice treated with RAD001. The discovery of alternative pathways involved in cell death execution and the role that it plays in leukemia suggest mTOR inhibitors should be included in future chemotherapy protocols of ALL.
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PMID:RAD001 (Everolimus) induces autophagy in acute lymphoblastic leukemia. 1936

Glucocorticoids (GCs) are among the most important drugs for acute lymphoblastic leukaemia (ALL), yet despite their clinical importance, the exact mechanisms involved in GC cytotoxicity and the development of resistance remain uncertain. We examined the baseline profile of a panel of T-ALL cell lines to determine factors that contribute to GC resistance without prior drug selection. Transcriptional profiling indicated GC resistance in T-ALL is associated with a proliferative phenotype involving upregulation of glycolysis, oxidative phosphorylation, cholesterol biosynthesis and glutamate metabolism, increased growth rates and activation of PI3K/AKT/mTOR and MYC signalling pathways. Importantly, the presence of these transcriptional signatures in primary ALL specimens significantly predicted patient outcome. We conclude that in lymphocytes the activation of bioenergetic pathways required for proliferation may suppress the apoptotic potential and offset the metabolic crisis initiated by GC signalling. It is likely that the link between GC resistance and proliferation in T-ALL has not been fully appreciated to date because such effects would be masked in the context of current multiagent therapies. The data also provide the first evidence that altered expression of wild-type MLL may contribute to GC-resistant phenotypes. Our findings warrant the continued development of selective metabolic inhibitors for the treatment of ALL.
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PMID:Glucocorticoid resistance in T-lineage acute lymphoblastic leukaemia is associated with a proliferative metabolism. 1943 2

Highly tumorigenic cancer cell (HTC) populations have been identified for a variety of solid tumors and assigned stem cell properties. Strategies for identifying HTCs in solid tumors have been primarily empirical rather than rational, particularly in epithelial tumors, which are responsible for 80% of cancer deaths. We report evidence for a spatially restricted bladder epithelial (urothelial) differentiation program in primary urothelial cancers (UCs) and in UC xenografts. We identified a highly tumorigenic UC cell compartment that resembles benign urothelial stem cells (basal cells), co-expresses the 67-kDa laminin receptor and the basal cell-specific cytokeratin CK17, and lacks the carcinoembryonic antigen family member CEACAM6 (CD66c). This multipotent compartment resides at the tumor-stroma interface, is easily identified on histologic sections, and possesses most, if not all, of the engraftable tumor-forming ability in the parental xenograft. We analyzed differential expression of genes and pathways in basal-like cells versus more differentiated cells. Among these, we found significant enrichment of pathways comprising "hallmarks" of cancer, and pharmacologically targetable signaling pathways, including Janus kinase-signal transducer and activator of transcription, Notch, focal adhesion, mammalian target of rapamycin, epidermal growth factor receptor (erythroblastic leukemia viral oncogene homolog [ErbB]), and wingless-type MMTV integration site family (Wnt). The basal/HTC gene expression signature was essentially invisible within the context of nontumorigenic cell gene expression and overlapped significantly with genes driving progression and death in primary human UC. The spatially restricted epithelial differentiation program described here represents a conceptual advance in understanding cellular heterogeneity of carcinomas and identifies basal-like HTCs as attractive targets for cancer therapy.
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PMID:Differentiation of a highly tumorigenic basal cell compartment in urothelial carcinoma. 1954 56


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