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doi:10.1038/sj/leu/2401467

Cited by 10 publications

(3 citation statements)

References 23 publications

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“…Specific hematopoietic tumors are frequently characterized by the discrete activation of specific oncogenes such as MYC 5–7 . BCL2 8,9 and BCR-ABL 10–13 . Targeted inactivation of oncoproteins is emerging as a specific and effective therapy for cancer 14,15 .…”

Section: Introductionmentioning

confidence: 99%

“…Imatinib treatment results in tumor cell signaling changes in vitro , leading to cell death 19,20 . In general, the ability to detect specific oncoproteins and their activation state is likely to be highly useful towards the development of new therapeutics as well as monitoring the effectiveness of these treatments, and evaluating apparent therapeutic resistance 13,21 .…”

Section: Introductionmentioning

confidence: 99%

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Nanofluidic proteomic assay for serial analysis of oncoprotein activation in clinical specimens

Fan

Deb-Basu²,

Orban

et al. 2009

Nat Med

103

125

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Current methods of protein detection are insensitive to detecting subtle changes in oncoprotein activation that underlie critical cancer signaling processes. The requirement for large numbers of cells precludes serial tumor sampling for assessing a response to therapeutics. Therefore, we have developed a nano-fluidic proteomic immunoassay (NIA) to quantify total and low abundance protein isoforms in 4 nanoliters of lysate. Our method could quantify levels of MYC and BCL2 proteins in Burkitt’s versus follicular lymphoma; identify changes in activation of ERK1/2, MEK1, STAT3/5, JNK and caspase 3 in imatinib-treated chronic myelogeneous leukemia (CML) cells; measure a novel change in phosphorylation of an ERK2 isomer in CML patients who responded to imatinib; and detect a decrease in STAT3/5 phosphorylation in lymphoma patients treated with atorvastatin. Therefore, we have described a novel and highly sensitive method for interrogating oncoprotein expression and phosphorylation in clinical specimens for the development of new therapeutics for cancer.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nanofluidic proteomic assay for serial analysis of oncoprotein activation in clinical specimens

Fan

Deb-Basu²,

Orban

et al. 2009

Nat Med

103

125

View full text Add to dashboard Cite

show abstract

“…The BCR-ABL transcript was shown to contain the first 13 to 14 BCR exons and exons 1 or 2 through 11 of ABL, generating a large mRNA product that, after splicing, encoded an 8.5 kB BCR-ABL chimeric transcript 3. The fusion of BCR to ABL during translocation increases the tyrosine kinase activity of ABL, and brings new regulatory domains/motifs to ABL, such as the growth factor receptor-bound protein 2 SH2-binding sites 4–6…”

Section: Introductionmentioning

confidence: 99%

Omacetaxine mepesuccinate in the treatment of intractable chronic myeloid leukemia

Chen¹,

Li²

2014

OTT

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In a significant proportion of patients with chronic myeloid leukemia, resistance to BCR-ABL tyrosine kinase inhibitors develops due to acquisition of BCR-ABL kinase domain mutations and insensitivity of leukemia stem cells to tyrosine kinase inhibitors. Omacetaxine mepesuccinate (formerly called homoharringtonine) is a natural alkaloid that inhibits protein synthesis and induces cell death. Omacetaxine mepesuccinate has been recently approved by the US Food and Drug Administration to treat patients with chronic myeloid leukemia who failed to respond to multiple tyrosine kinase inhibitors and/or acquired the BCR-ABL-T315I mutation. In this review, we discuss the use and effectiveness of omacetaxine mepesuccinate in the treatment of chronic myeloid leukemia, with coverage of its pharmacology, mode of action, and pharmacokinetics. We believe that omacetaxine mepesuccinate will be beneficial to many patients with chronic myeloid leukemia who do not respond well to tyrosine kinase inhibitors.

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ROS-mediated amplification of AKT/mTOR signalling pathway leads to myeloproliferative syndrome in Foxo3−/− mice

Yalçın

Marinković

Mungamuri

et al. 2010

EMBO J

133

161

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Reactive oxygen species (ROS) participate in normal intracellular signalling and in many diseases including cancer and aging, although the associated mechanisms are not fully understood. Forkhead Box O (FoxO) 3 transcription factor regulates levels of ROS concentrations, and is essential for maintenance of hematopoietic stem cells. Here, we show that loss of Foxo3 causes a myeloproliferative syndrome with splenomegaly and increased hematopoietic progenitors (HPs) that are hypersensitive to cytokines. These mutant HPs contain increased ROS, overactive intracellular signalling through the AKT/mammalian target of rapamycin signalling pathway and relative deficiency of Lnk, a negative regulator of cytokine receptor signalling. In vivo treatment with ROS scavenger N-acetyl-cysteine corrects these biochemical abnormalities and relieves the myeloproliferation. Moreover, enforced expression of Lnk by retroviral transfer corrects the abnormal expansion of Foxo3 À/À HPs in vivo. Our combined results show that loss of Foxo3 causes increased ROS accumulation in HPs. In turn, this inhibits Lnk expression that contributes to exaggerated cytokine responses that lead to myeloproliferation. Our findings could explain the mechanisms by which mutations that alter Foxo3 function induce malignancy. More generally, the work illustrates how deregulated ROS may contribute to malignant progression.

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Cited by 10 publications

References 23 publications

Nanofluidic proteomic assay for serial analysis of oncoprotein activation in clinical specimens

Nanofluidic proteomic assay for serial analysis of oncoprotein activation in clinical specimens

Omacetaxine mepesuccinate in the treatment of intractable chronic myeloid leukemia

ROS-mediated amplification of AKT/mTOR signalling pathway leads to myeloproliferative syndrome in Foxo3−/− mice

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