Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Specific inhibitors of PI3K isoforms are currently evaluated for their therapeutic potential in leukemia. We found that BCR/ABL(+) human leukemic cells express PI3Kdelta and therefore explored its impact on leukemia development. Using PI3Kdelta-deficient mice, we define a dual role of PI3Kdelta in leukemia. We observed a growth-promoting effect in tumor cells and an essential function in natural killer (NK) cell-mediated tumor surveillance: Abelson-transformed PI3Kdelta-deficient cells induced leukemia in RAG2-deficient mice with an increased latency, indicating that PI3Kdelta accelerated leukemia progression in vivo. However, the absence of PI3Kdelta also affected NK cell-mediated tumor surveillance. PI3Kdelta-deficient NK cells failed to lyse a large variety of target cells because of defective degranulation, as also documented by capacitance recordings. Accordingly, transplanted leukemic cells killed PI3Kdelta-deficient animals more rapidly. As a net effect, no difference in disease latency in vivo was detected if both leukemic cells and NK cells lack PI3Kdelta. Other tumor models confirmed that PI3Kdelta-deficient mice succumbed more rapidly when challenged with T- or B-lymphoid leukemic or B16 melanoma cells. Thus, the action of PI3Kdelta in the NK compartment is as relevant to survival of the mice as the delayed tumor progression. This dual function must be taken into account when using PI3Kdelta inhibitors as antileukemic agents in clinical trials.
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PMID:Leukemic challenge unmasks a requirement for PI3Kdelta in NK cell-mediated tumor surveillance. 1902 50

This study investigated whether advanced glycation end products (AGE) and RAGE (receptor for AGE) are involved in the proliferation of leukemia cells. AGE strongly induced the proliferation of primary acute myeloid leukemia (AML) cells and cell lines. MAP kinase, PI3K and JAK/STAT pathways were involved in cellular proliferation of HEL cells by AGE. RAGE antisense S-ODN effectively inhibited cell growth, induced apoptosis and reversed AGE-induced expression of targeting molecules in HEL cells. The study demonstrated for the first time that AGE directly induced human AML cell proliferation via the MAPK, PI3K and JAK/STAT pathways.
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PMID:Advanced glycation end product (AGE)-induced proliferation of HEL cells via receptor for AGE-related signal pathways. 1869 78

Some cases of pre-B cell acute lymphoblastic leukemia (pre-B-ALL) are caused by the Philadelphia (Ph) chromosome-encoded BCR-ABL oncogene, and these tend to have a poor prognosis. Inhibitors of the PI3K/AKT pathway reduce BCR-ABL-mediated transformation in vitro; however, the specific PI3K isoforms involved are poorly defined. Using a murine model of Ph+ pre-B-ALL, we found that deletion of both Pik3r1 and Pik3r2, genes encoding class IA PI3K regulatory isoforms, severely impaired transformation. BCR-ABL-dependent pre/pro-B cell lines could be established at low frequency from progenitors that lacked these genes, but the cells were smaller, proliferated more slowly, and failed to cause leukemia in vivo. These cell lines displayed nearly undetectable PI3K signaling function and were resistant to the PI3K inhibitor wortmannin. However, they maintained activation of mammalian target of rapamycin (mTOR) and were more sensitive to rapamycin. Treatment with rapamycin caused feedback activation of AKT in WT cell lines but not PI3K-deficient lines. A dual inhibitor of PI3K and mTOR, PI-103, was more effective than rapamycin at suppressing proliferation of mouse pre-B-ALL and human CD19+CD34+)Ph+ ALL leukemia cells treated with the ABL kinase inhibitor imatinib. Our findings provide mechanistic insights into PI3K dependency in oncogenic networks and provide a rationale for targeting class IA PI3K, alone or together with mTOR, in the treatment of Ph+ ALL.
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PMID:Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells. 2856 34

Since the discovery of leukemic stem cells (LSCs) over a decade ago, many of their critical biological properties have been elucidated, including their distinct replicative properties, cell surface phenotypes, their increased resistance to chemotherapeutic drugs and the involvement of growth-promoting chromosomal translocations. Of particular importance is their ability to transfer malignancy to non-obese diabetic-severe combined immunodeficient (NOD-SCID) mice. Furthermore, numerous studies demonstrate that acute myeloid leukemia arises from mutations at the level of stem cell, and chronic myeloid leukemia is also a stem cell disease. In this review, we will evaluate the main characteristics of LSCs elucidated in several well-documented leukemias. In addition, we will discuss points of therapeutic intervention. Promising therapeutic approaches include the targeting of key signal transduction pathways (for example, PI3K, Rac and Wnt) with small-molecule inhibitors and specific cell surface molecules (for example, CD33, CD44 and CD123), with effective cytotoxic antibodies. Also, statins, which are already widely therapeutically used for a variety of diseases, show potential in targeting LSCs. In addition, drugs that inhibit ATP-binding cassette transporter proteins are being extensively studied, as they are important in drug resistance-a frequent characteristic of LSCs. Although the specific targeting of LSCs is a relatively new field, it is a highly promising battleground that may reveal the Holy Grail of cancer therapy.
Leukemia 2009 Jan
PMID:Targeting the leukemic stem cell: the Holy Grail of leukemia therapy. 1880 Jan 46

Transient leukemia (TL) has been observed in approximately 10% of newborn infants with Down syndrome (DS). Although treatment with cytarabine is effective in high-risk TL cases, approximately 20% of severe patients still suffer early death. In this study, we demonstrate abundant KIT expression in all 13 patients with GATA1 mutations, although no significant difference in expression levels was observed between TL and acute myeloid leukemia. Stem cell factor (SCF) stimulated the proliferation of the TL cells from five patients and treatment with the tyrosine kinase inhibitor imatinib suppressed the proliferation effectively in vitro. To investigate the signal cascade, we established the first SCF-dependent, DS-related acute megakaryoblastic leukemia cell line, KPAM1. Withdrawal of SCF or treatment with imatinib induced apoptosis of KPAM1 cells. SCF activated the RAS/MAPK and PI3K/AKT pathways, followed by downregulation of the pro-apoptotic factor BIM and upregulation of the anti-apoptotic factor MCL1. Although we found novel missense mutations of KIT in 2 of 14 TL patients, neither mutation led to KIT activation and neither reduced the cytotoxic effects of imatinib. These results suggest the essential role of SCF/KIT signaling in the proliferation of DS-related leukemia and the possibility of therapeutic benefits of imatinib for TL patients.
Leukemia 2009 Jan
PMID:The key role of stem cell factor/KIT signaling in the proliferation of blast cells from Down syndrome-related leukemia. 1883 Feb 55

The development of multiple myeloma (MM) is a complex multi-step process involving both early and late genetic changes in the tumor cell as well as selective supportive conditions by the bone marrow (BM) microenvironment. Indeed, it is now well established that MM cell-induced disruption of the BM homeostasis between the highly organized cellular and extracellular compartments supports MM cell proliferation, survival, migration and drug resistance through activation of various signaling (for example, PI3K/Akt, JAK/Stat-, Raf/MEK/MAPK-, NFkappaB- and Wnt-) pathways. Based on our enhanced understanding of the functional importance of the MM BM microenvironment and its inter-relation with the MM cell resulting in homing, seeding, proliferation and survival, new molecular targets have been identified and derived treatment regimens in MM have already changed fundamentally during recent years. These agents include thalidomide, its immunomodulatory derivative lenalidomide and the proteasome inhibitor bortezomib, which mediate tumor cytotoxicity in the BM milieu. Ongoing studies are further delineating MM pathogenesis in the BM to enhance cytotoxicity, avoid drug resistance and improve patient outcome.
Leukemia 2009 Jan
PMID:Bone marrow microenvironment and the identification of new targets for myeloma therapy. 1884 84

T cell large granular lymphocyte (T-LGL) leukemia features a clonal expansion of antigen-primed, competent, cytotoxic T lymphocytes (CTL). To systematically understand signaling components that determine the survival of CTL in T-LGL leukemia, we constructed a T-LGL survival signaling network by integrating the signaling pathways involved in normal CTL activation and the known deregulations of survival signaling in leukemic T-LGL. This network was subsequently translated into a predictive, discrete, dynamic model. Our model suggests that the persistence of IL-15 and PDGF is sufficient to reproduce all known deregulations in leukemic T-LGL. This finding leads to the following predictions: (i) Inhibiting PDGF signaling induces apoptosis in leukemic T-LGL. (ii) Sphingosine kinase 1 and NFkappaB are essential for the long-term survival of CTL in T-LGL leukemia. (iii) NFkappaB functions downstream of PI3K and prevents apoptosis through maintaining the expression of myeloid cell leukemia sequence 1. (iv) T box expressed in T cells (T-bet) should be constitutively activated concurrently with NFkappaB activation to reproduce the leukemic T-LGL phenotype. We validated these predictions experimentally. Our study provides a model describing the signaling network involved in maintaining the long-term survival of competent CTL in humans. The model will be useful in identifying potential therapeutic targets for T-LGL leukemia and generating long-term competent CTL necessary for tumor and cancer vaccine development.
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PMID:Network model of survival signaling in large granular lymphocyte leukemia. 1885 69

Toll-like receptors (TLRs) act to sense the environment for microbial products and submit danger signals to antigen-presenting cells (APCs) resulting in activation of complex immune responses. In this study, we analyzed the function of human monocyte-derived APCs generated in vitro in the presence of interleukin (IL)-10 upon activation by TLR ligands. Exposure of these APCs to IL-10 resulted in a skewed phenotypic maturation in response to stimuli provided by the TLR ligands, a reduced cytokine production, such as IL-12, IL-6 or tumor necrosis factor-alpha, and impaired capacity to stimulate T-cell activation. Furthermore, CCR7 upregulation in APCs exposed to TLR stimulation as well as migration towards CCL19/MIP-3beta were strongly reduced. IL-10 was found to downregulate MyD88, IRAK1 (IL-1 receptor-associated kinase) and tumor necrosis factor receptor-associated factor 6, essential adaptor molecules for TLR signaling, and to decrease TLR-induced nuclear expression of the nuclear factor-kappaB transcription factors c-Rel and Rel-B as well as interferon regulatory factor (IRF)-3 and IRF-8. This was not due to the inhibition of the mitogen-activated protein kinase pathway, but was rather mediated by the blockage of the PI3K signaling cascade. Interestingly, the inhibition of proteins involved in TLR signaling, such as MyD88, IRAK1 and mammalian target of rapamycin, was due to a selective post-transcriptional regulation.
Leukemia 2009 Mar
PMID:Post-transcriptional regulation of adapter molecules by IL-10 inhibits TLR-mediated activation of antigen-presenting cells. 1900 81

Casticin, a component from Vitex rotundifolia, widely used as an anti-inflammatory agent in Chinese traditional medicine, was reported to have anti-tumor activities. This study aims to examine the anti-leukemic activity of casticin on leukemia cells and its molecular mechanism. Cell viability was measured by MTT method; apoptosis and cell cycle arrest were determined by flow cytometry, AV-PI assay, and DNA fragmentation assay. Western blot were performed to measure the protein expression level. The cell morphology alteration was detected with immunofluorescent analysis and DAPI nuclear staining. Our results showed that the proliferation of leukemia cells, including K562, Kasumi-1, and HL-60, were inhibited by casticin in a time- and dose-dependent manner. The IC50, determined after 48 h incubation, was 5.95 microM, 4.82 microM, and 15.56 microM for K562, HL-60, and Kasumi-1, respectively. The cell cycle analysis demonstrated casticin treatment resulted in a significant G2/M accumulation, concomitant with upregulation of P21waf1 and P27kip1. The percentage of cells in G2/M increased with time of exposure and reached to its climax (75.3%) at 12 h after casticin treatment, and subsequently declined to 27% at 48 h. We found that casticin treatment induced remarkable apoptosis, evidenced by increased percentage of AV-positive PI-negative cells as well as the cleavage of PARP and caspase 3. In addition, DNA fragmentation assay showed the typical apoptotic DNA ladder in casticin-treated K562 cells. Mitotic catastrophe and decreased polymeric tubulin can also be observed in casticin-treated K562 cells. In addition, we found that PI3K/AKT pathway was activated; Ly294002, a PI3K/AKT specific inhibitor, can enhance the anti-leukemic effect of casticin. Taken together, these results demonstrated that casticin induced leukemic cell death via apoptosis and mitotic catastrophe, and could synergize with PI3K/AKT inhibitor, suggesting that casticin could be a promising therapeutic agent against leukemia.
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PMID:Casticin induces leukemic cell death through apoptosis and mitotic catastrophe. 1913 93

Kaempferol (3,4',5,7-tetrahydroxyflavone) is a flavonoid with anti- and pro-oxidant activity present in various natural sources. Kaempferol has been shown to posses anticancer properties through the induction of the apoptotic program. Here we report that treatment of the chronic myelogenous leukemia cell line K562 and promyelocitic human leukemia U937 with 50 microM kaempferol resulted in an increase of the antioxidant enzymes Mn and Cu/Zn superoxide dismutase (SOD). Kaempferol treatment induced apoptosis by decreasing the expression of Bcl-2 and increasing the expressions of Bax. There were also induction of mitochondrial release of cytochrome c into cytosol and significant activation of caspase-3, and -9 with PARP cleavage. Kaempferol treatment increased the expression and the mitochondria localization of the NAD-dependent deacetylase SIRT3. K562 cells stably overexpressing SIRT3 were more sensitive to kaempferol, whereas SIRT3 silencing did not increase the resistance of K562 cells to kaempferol. Inhibition of PI3K and de-phosphorylation of Akt at Ser473 and Thr308 was also observed after treating both K562 and U937 cells with kaempferol. In conclusion our study shows that the oxidative stress induced by kaempferol in K562 and U937 cell lines causes the inactivation of Akt and the activation of the mitochondrial phase of the apoptotic program with an increase of Bax and SIRT3, decrease of Bcl-2, release of cytochrome c, caspase-3 activation, and cell death.
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PMID:Kaempferol induces apoptosis in two different cell lines via Akt inactivation, Bax and SIRT3 activation, and mitochondrial dysfunction. 1916 Apr 23


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