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Journal ArticleDOI

Activation of Akt is associated with poor prognosis and chemotherapeutic resistance in pediatric B-precursor acute lymphoblastic leukemia.

TL;DR: This study was undertaken to explore the clinical relevance and molecular mechanisms underlying the activation of Akt (i.e., phosphorylated Akt, P‐Akt) in pediatric B‐pre ALL.
Abstract: Background Activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway, a pro-survival pathway, plays important roles in tumor cell growth. However, the role of Akt in the pathogenesis of pediatric B-precursor acute lymphoblastic leukemia (B-pre ALL) remains to be clarified. This study was undertaken to explore the clinical relevance and molecular mechanisms underlying the activation of Akt (i.e., phosphorylated Akt, P-Akt) in pediatric B-pre ALL. Procedure We evaluated the activation status of Akt in bone marrow samples from 21 children with newly diagnosed B-pre ALL and correlated the expression level of P-Akt with clinicopathologic and prognostic features. Additionally, we transfected the myristoylated Akt cDNA into the B-pre ALL cell line, Nalm-6, and examined the effect, in vitro, of Akt activation on the response to antitumor drugs. Results P-Akt expression in B-pre ALL blast cells at diagnosis was associated significantly with poor response to induction chemotherapy including prednisolone, dexamethasone, vincristine, and adriamycin in B-pre ALL patients. Both overall survival and relapse-free survival in patients with P-Akt expression were reduced significantly more than in patients without P-Akt expression. Activation of Akt reduced the extent of apoptosis induced by the antitumor drugs in Nalm-6 listed above. Activation of Akt did not induce expression of P-glycoprotein, a drug transporter that is capable of conferring multidrug resistance. Conclusion These results support the contention that Akt activation is a mechanism of chemotherapeutic resistance in B-pre ALL and suggest that Akt can be a therapeutic target for the treatment of relapsed or refractory pediatric B-pre ALL. Pediatr Blood Cancer 2012; 59: 83–89. © 2011 Wiley Periodicals, Inc.

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日付
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学総合研究制御科学専攻
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Citations
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Journal ArticleDOI
TL;DR: This study found that GL-V9, a newly synthesized flavonoid compound, had a potent to inhibit the activation of AKT1 and induce the cell apoptosis in T-cell malignancies including cell lines and primary lymphoblastic leukemia.

6 citations

Journal ArticleDOI
TL;DR: This review summarizes the current understanding of cell metabolism dysregulation in childhood acute lymphoblastic leukemia (cALL) and focuses on novel therapeutic approaches emerging from the evolving understanding of the alterations of different metabolic networks in lymphoblasts.
Abstract: The first observations of altered metabolism in malignant cells were made nearly 100 years ago and therapeutic strategies targeting cell metabolism have been in clinical use for several decades. In this review, we summarize our current understanding of cell metabolism dysregulation in childhood acute lymphoblastic leukemia (cALL). Reprogramming of cellular bioenergetic processes can be expected in the three distinct stages of cALL: at diagnosis, during standard chemotherapy, and in cases of relapse. Upregulation of glycolysis, dependency on anaplerotic energy sources, and activation of the electron transport chain have all been observed in cALL. While the current treatment strategies are tackling some of these aberrations, cALL cells are likely to be able to rewire their metabolism in order to escape therapy, which may contribute to a refractory disease and relapse. Finally, here we focus on novel therapeutic approaches emerging from our evolving understanding of the alterations of different metabolic networks in lymphoblasts.

6 citations

Journal ArticleDOI
TL;DR: This study indicated that sLe X involved in the development of MDR of AML cells probably through FUT7 and ST3GAL4 regulating the activity of PI3K/Akt signaling pathway and the expression of P-gp and MRP1.

6 citations

Journal ArticleDOI
02 Feb 2021-Leukemia
TL;DR: In this paper, a dual targeting of mTOR was proposed to reduce the health disparity in high-risk B-cell acute lymphoblastic leukemia (HR B-ALL) among Hispanic/Latino children.
Abstract: Children of Hispanic/Latino ancestry have increased incidence of high-risk B-cell acute lymphoblastic leukemia (HR B-ALL) with poor prognosis This leukemia is characterized by a single-copy deletion of the IKZF1 (IKAROS) tumor suppressor and increased activation of the PI3K/AKT/mTOR pathway This identifies mTOR as an attractive therapeutic target in HR B-ALL Here, we report that IKAROS represses MTOR transcription and IKAROS' ability to repress MTOR in leukemia is impaired by oncogenic CK2 kinase Treatment with the CK2 inhibitor, CX-4945, enhances IKAROS activity as a repressor of MTOR, resulting in reduced expression of MTOR in HR B-ALL Thus, we designed a novel therapeutic approach that implements dual targeting of mTOR: direct inhibition of the mTOR protein (with rapamycin), in combination with IKAROS-mediated transcriptional repression of the MTOR gene (using the CK2 inhibitor, CX-4945) Combination treatment with rapamycin and CX-4945 shows synergistic therapeutic effects in vitro and in patient-derived xenografts from Hispanic/Latino children with HR B-ALL These data suggest that such therapy has the potential to reduce the health disparity in HR B-ALL among Hispanic/Latino children The dual targeting of oncogene transcription, combined with inhibition of the corresponding oncoprotein provides a paradigm for a novel precision medicine approach for treating hematological malignancies

6 citations

01 Jan 2019
TL;DR: Through both genetic and pharmacologic approaches, it is demonstrated that targeted inhibition of cytokine receptor signaling effectively restores GC sensitivity, and the feasibility of this therapeutic approach in two in vivo models of disease is established.
Abstract: Author(s): Meyer, Lauren Kimberly | Advisor(s): Hermiston, Michelle; Shannon, Kevin | Abstract: Glucocorticoids (GCs) are potently immunosuppressive due to their pro-apoptotic effects on lymphoid cells, leading to their utility in a wide range of clinical contexts including autoimmune diseases, hyperinflammatory conditions, and lymphoid malignancies. In addition, GCs are endogenously produced hormones that mediate a wide range of physiologic functions that are essential for life. As a result, cells of the immune system face constant exposure to GCs and therefore require intrinsic mechanisms by which to resist their pro-apoptotic effects under certain developmental and environmental conditions. The retention of these resistance mechanisms in lymphoid-driven diseases thereby poses a challenge to the clinical use of GCs in these contexts. Common -chain cytokines, through activation of the JAK/STAT signal transduction pathway, play essential roles in the differentiation, survival, and function of lymphoid cells. Here, we assess the interplay between GC activity and cytokine-mediated pro-survival signaling in two lymphoid-driven diseases, acute lymphoblastic leukemia and hemophagocytic lymphohistiocytosis, and demonstrate that cytokines are potent mediators of GC resistance. Mechanistically, we show that activation of STAT5 downstream of cytokine receptor signaling is necessary for cytokine-induced GC resistance. STAT5 functions as a transcription factor to upregulate expression of anti-apoptotic mediators, thereby reducing the apoptotic potential and promoting the survival of lymphoid cells. Through both genetic and pharmacologic approaches, we demonstrate that targeted inhibition of cytokine receptor signaling effectively restores GC sensitivity, and we establish the feasibility of this therapeutic approach in two in vivo models of disease.

6 citations


Cites background from "Activation of Akt is associated wit..."

  • ...In another analysis of primary B-ALL samples, patients with increased phosphorylated AKT at diagnosis had a significantly inferior response to steroid-containing induction therapy and had decreased overall and relapse-free survival (115)....

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References
More filters
Journal ArticleDOI
29 Jun 2007-Cell
TL;DR: Those Akt substrates that are most likely to contribute to the diverse cellular roles of Akt, which include cell survival, growth, proliferation, angiogenesis, metabolism, and migration are discussed.

5,505 citations


"Activation of Akt is associated wit..." refers background in this paper

  • ...Akt binds to phosphatidylinositol-3,4,5-triphosphate on the plasma membrane where Akt is activated by phosphorylation at threonine308 (T308) and serine473 (S473) residues....

    [...]

  • ...Antibodies against Akt and PAkt on S473 and HRP-linked secondary antibody were purchased from Cell Signaling Technology Inc. (Irvine, CA) and antibodies against b-actin and Myc tag from Santa Cruz Biotechnology Inc. and Millipore Corp. (Billerica, MA), respectively....

    [...]

  • ...30-Phosphoinositide-dependent kinase 1 phosphorylates the activation loop of Akt at T308, although the mammalian target of rapamycin complex 2 phosphorylates Akt at the hydrophobic motif S473 [7]....

    [...]

Journal ArticleDOI
TL;DR: Akt/PKB plays important roles in the signaling pathways in response to growth factors and other extracellular stimuli to regulate several cellular functions including nutrient metabolism, cell growth, apoptosis and survival.
Abstract: Akt/PKB is a serine/threonine protein kinase that functions as a critical regulator of cell survival and proliferation. Akt/PKB family comprises three highly homologous members known as PKBalpha/Akt1, PKBbeta/Akt2 and PKBgamma/Akt3 in mammalian cells. Similar to many other protein kinases, Akt/PKB contains a conserved domain structure including a specific PH domain, a central kinase domain and a carboxyl-terminal regulatory domain that mediates the interaction between signaling molecules. Akt/PKB plays important roles in the signaling pathways in response to growth factors and other extracellular stimuli to regulate several cellular functions including nutrient metabolism, cell growth, apoptosis and survival. This review surveys recent developments in understanding the molecular mechanisms of Akt/PKB activation and its roles in cell survival in normal and cancer cells.

1,811 citations


"Activation of Akt is associated wit..." refers background in this paper

  • ...We assume that other pathways aside from P-glycoprotein play an important role in MDR in Nalm-6/Akt, such as expression of another ATP-binding cassette transporter, inhibition of BAD, inhibition of Caspase-9, activation of NF-kB, inhibition of p53, and so forth [6,24]....

    [...]

  • ...Activation of the PI3K/Akt pathway induces activation of nuclear factor-kB and Bcl-2 and inhibition of Bcl-2 antagonist of cell death (BAD), Caspase-9 and p53 [6]....

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  • ...The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is a prototypic survival pathway that plays a central role in diverse cellular functions including insulin metabolism, protein synthesis, proliferation, and apoptosis [5,6]....

    [...]

Journal ArticleDOI
20 Oct 2003-Oncogene
TL;DR: A model for how ATP energizes transfer of substrates from these binding sites on P-gp to the outside of the cell is proposed, which accounts for the apparent stoichiometry of two ATPs hydrolysed per molecule of drug transported.
Abstract: Resistance to chemically different natural product anti-cancer drugs (multidrug resistance, or MDR) results from decreased drug accumulation, resulting from expression of one or more ATP-dependent efflux pumps. The first of these to be identified was P-glycoprotein (P-gp), the product of the human MDR1 gene, localized to chromosome 7q21. P-gp is a member of the large ATP-binding cassette (ABC) family of proteins. Although its crystallographic 3-D structure is yet to be determined, sequence analysis and comparison to other ABC family members suggest a structure consisting of two transmembrane (TM) domains, each with six TM segments, and two nucleotide-binding domains. In the epithelial cells of the gastrointestinal tract, liver, and kidney, and capillaries of the brain, testes, and ovaries, P-gp acts as a barrier to the uptake of xenobiotics, and promotes their excretion in the bile and urine. Polymorphisms in the MDR1 gene may affect the pharmacokinetics of many commonly used drugs, including anticancer drugs. Substrate recognition of many different drugs occurs within the TM domains in multiple-overlapping binding sites. We have proposed a model for how ATP energizes transfer of substrates from these binding sites on P-gp to the outside of the cell, which accounts for the apparent stoichiometry of two ATPs hydrolysed per molecule of drug transported. Understanding of the biology, genetics, and biochemistry of P-gp promises to improve the treatment of cancer and explain the pharmacokinetics of many commonly used drugs.

985 citations


"Activation of Akt is associated wit..." refers background in this paper

  • ...P-glycoprotein is a member of ATP-binding cassette transporters that extract antitumor drugs from cytoplasm and which reduce intracellular drug concentrations to sub-lethal levels [20,21]....

    [...]

  • ...The expression of P-glycoprotein, encoded by the MDR1 gene, is often associated with MDR in tumor cells [20,27]....

    [...]

  • ...In patients with leukemias, lymphomas, and multiple myeloma, P-glycoprotein expression, which is very low at presentation, is occasionally enhanced during administration of long-term chemotherapy or when the disease recurs [20]....

    [...]

Journal ArticleDOI
18 Mar 2004-Nature
TL;DR: It is shown that Akt promotes tumorigenesis and drug resistance by disrupting apoptosis, and that disruption of Akt signalling using the mTOR inhibitor rapamycin reverses chemoresistance in lymphomas expressing Akt, but not in those with other apoptotic defects.
Abstract: Evading apoptosis is considered to be a hallmark of cancer, because mutations in apoptotic regulators invariably accompany tumorigenesis. Many chemotherapeutic agents induce apoptosis, and so disruption of apoptosis during tumour evolution can promote drug resistance. For example, Akt is an apoptotic regulator that is activated in many cancers and may promote drug resistance in vitro. Nevertheless, how Akt disables apoptosis and its contribution to clinical drug resistance are unclear. Using a murine lymphoma model, we show that Akt promotes tumorigenesis and drug resistance by disrupting apoptosis, and that disruption of Akt signalling using the mTOR inhibitor rapamycin reverses chemoresistance in lymphomas expressing Akt, but not in those with other apoptotic defects. eIF4E, a translational regulator that acts downstream of Akt and mTOR, recapitulates Akt's action in tumorigenesis and drug resistance, but is unable to confer sensitivity to rapamycin and chemotherapy. These results establish Akt signalling through mTOR and eIF4E as an important mechanism of oncogenesis and drug resistance in vivo, and reveal how targeting apoptotic programmes can restore drug sensitivity in a genotype-dependent manner.

949 citations


"Activation of Akt is associated wit..." refers background in this paper

  • ...Furthermore, murine models of Akt activation have shown that constitutively active Akt causes myeloproliferative disease [30], promotes drug resistance, and shortens tumor-free survival [25]....

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Journal ArticleDOI
TL;DR: Two recent studies used mouse genetics to assess the roles of PTEN and TSC2 in cancer, underscoring the importance of Akt-mTOR interplay for cancer progression and therapy.

767 citations


"Activation of Akt is associated wit..." refers background in this paper

  • ...The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is a prototypic survival pathway that plays a central role in diverse cellular functions including insulin metabolism, protein synthesis, proliferation, and apoptosis [5,6]....

    [...]

  • ...The PI3K/Akt signaling pathway controls the expression and function of many proteins that are necessary for cell survival, growth, and anti-apoptosis [5]....

    [...]

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