The impact of activated p-AKT expression on clinical outcomes in diffuse large B-cell lymphoma: a clinicopathological study of 262 cases

Hong, Jung Yong; Hong, Mineui; Choi, Minsig; Kim, Y.S.; Chang, Wen-Shin; Maeng, Chi Hoon; Park, Seo-Young; Lee, S.J.; Do, In‐Gu; Jo, Jaemin; Jung, Sin‐Ho; Kim, Seung Ju; Ko, Young Hyeh; Kim, W.S.

doi:10.1093/annonc/mdt530

Cited by 27 publications

(21 citation statements)

References 32 publications

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“…DLBCLs are known to be associated with the AKT signaling pathway, which is activated during carcinogenesis (33,34). Furthermore, AKT activation is associated with poor prognosis of DLBCL patients (35). miR-21 activates the phosphoinositide-3 kinase (PI3K)/AKT signaling pathway by directly suppressing forkhead box protein O1 expression and downregulating PTEN expression (36).…”

Section: Mir-21 and Hematological Malignanciesmentioning

confidence: 99%

Emerging role of microRNA-21 in cancer

2016

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Abstract. MicroRNAs (miRs) are a class of single-stranded RNA molecules of 15-27 nucleotides in length that regulate gene expression at the post-translational level. miR-21 is one of the earliest identified cancer-promoting 'oncomiRs', targeting numerous tumor suppressor genes associated with proliferation, apoptosis and invasion. The regulation of miR-21 and its role in carcinogenesis have been extensively investigated. Recent studies have focused on the diagnostic and prognostic value of miR-21 as well as its implication in the drug resistance of human malignancies. The further use of miR-21 as a biomarker and target for cancer treatments is likely to improve the outcome for patients with cancer. The present review highlights recent findings associated with the importance of miR-21 in hematological and non-hematological malignancies. IntroductionMicroRNAs (miRs) are a class of naturally occurring short non-coding RNA molecules of 15-27 nucleotides in length that regulate eukaryotic gene expression at the post-transcriptional level. Almost 2,000 human miRNAs have been identified through cloning and/or sequence analysis (1). They have key regulatory roles in the development, differentiation and apoptosis of normal cells, as well as in the determination of the final phenotype of cancer cells, affecting carcinogenesis and metastatic potential (2). miR-21 is an abundantly expressed miRNA in mammalian cells, whose upregulation is associated with numerous types of cancer (3,4). By generation of a conditional miR-21 knock-in mouse, it was demonstrated that miR-21 functions as an oncogene with its overexpression resulting in malignant B-cell lymphoma (5). Indeed, miR-21 was found to be the only consistently upregulated miRNA in a study that profiled 540 clinical samples from cancer patients (6). The majority of studies on miR-21 have focused on its role in carcinogenesis and its clinical application. miR-21 is also expressed in hematopoietic cells of the immune system, including B/T cells, monocytes, macrophages and dendritic cells. High miR-21 levels are, therefore, considered to be a marker of immune cell activation (7). Regarding pathological necrosis, miR-21 enhances cellular necrosis by negatively regulating tumor suppressor genes associated with the death receptor-mediated intrinsic apoptotic pathway (8). Biological function of miR-21The biological functions of various miRNAs, including miR-21, have been extensively investigated and miR-21 is

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Section: Mir-21 and Hematological Malignanciesmentioning

confidence: 99%

Emerging role of microRNA-21 in cancer

2016

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“…Protein microarray analysis of follicular lymphoma patient samples has revealed a significant increase in Akt (Ser473) phosphorylation (Gulmann et al, 2005, Zha et al, 2004) and the dual PI3K/mTOR inhibitor NVP-BEZ235 inhibits FL cell proliferation and has shown anti-tumor activity in mouse xenograft models (Bhende et al, 2010). Dysregulation of the PI3K/Akt/mTOR signaling pathway was also observed in DLBCL, and patients with high levels of Akt phosphorylation showed decreased survival time (Hong et al, 2014, Hasselblom et al, 2010). Inhibition of the PI3K/Akt/mTOR pathway has been shown to impair proliferation of DLBCL cells (Fang et al, 2013) and several small molecule inhibitors of the PI3K signaling pathways are currently undergoing evaluation in different phases of clinical trials for lymphoma (Majchrzak et al, 2014).…”

Section: Pi3k Mediated Regulation Of Cancer Cell Metabolismmentioning

confidence: 99%

The PI3K pathway in B cell metabolism

Jellusova

Rickert

2016

Critical Reviews in Biochemistry and Molecular Biology

103

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B cell growth and proliferation is tightly regulated by signaling through the B cell receptor and by other membrane bound receptors responding to different cytokines. The PI3K signaling pathway has been shown to play a crucial role in B cell activation, differentiation and survival. Activated B cells undergo metabolic reprogramming in response to changing energetic and biosynthetic demands. B cells also need to be able to coordinate metabolic activity and proliferation with nutrient availability. The PI3K signaling network has been implicated in regulating nutrient acquisition, utilization and biosynthesis, thus integrating receptor mediated signaling with cell metabolism. In this review, we discuss the current knowledge about metabolic changes induced in activated B cells, strategies to adapt to metabolic stress and the role of PI3K signaling in these processes.

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“…Each subtype follows a distinct molecular mechanism and oncogenic signaling pathway and hence, may differ in response to conventional treatment. Chronic active B-cell receptor (BCR) signaling, constitutive myeloid differentiation primary response gene 88 (MYD88) signaling, and subsequent antiapoptotic nuclear factor-kappa B (NF-kappaB) pathway, phosphatidylinositol-3-kinase/serine-threonine kinase (PI3K/Akt/mTOR) pathway, and interferon pathway activation are characteristics of the ABC DLBCL [7,24,32]. On the other hand, BCL6 and EZH2 together are extensively studied in the GCB subtype of DLBCL [33].…”

Section: Biological/molecular Understanding Of Dlbclmentioning

confidence: 99%

“…Abnormally overexpressed phosphorylated AKT (p-AKT) may have poor prognostic impact in DLBCL [32,77,78]. In a clinical trial of 262 DLBCL patients with both GCB and non-GCB subtypes, high p-AKT group had higher proportion of advanced stage disease, two or more extranodal involvement, lactic dehydrogenase elevation, higher international prognostic index (IPI) risk groups, and the presence of B symptoms [32]. The disease deteriorated at a faster rate in high p-AKT group versus the low p-AKT group (median OS, 115.0 months versus not reached, P = 0.004; median PFS, 25.5 versus 105.8 months, P = 0.019).…”

Section: Pi3k/akt/mtor Inhibitorsmentioning

confidence: 99%

Rituximab-Based Therapy in Newly Diagnosed Diffuse Large B-Cell Lymphoma Patients: Individualized Risk-Adapted Therapy Approach Using Molecular Subtypes

Fan

Zhou

et al. 2017

J Hematol

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Rituximab (R) with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) is the current standard of care as first-line treatment for diffuse large B-cell lymphoma (DLBCL), the most common lymphoma subtype. Patients who fail R-CHOP have a poor outcome with relapse or refractory disease resulting in fatality in majority of patients. This review focuses on novel therapies which are currently being assessed as first-line treatment in combination with R-CHOP in patients with DLBCL. Targeted drug development is a possibility with recent developments like gene expression profiling, RNA interference screening, DNA sequencing, identification of new biomarkers and signaling pathways. Newer drugs such as bortezomib, lenalidomide, and ibrutinib are being investigated as first-line therapy in combination with R-CHOP (XR-CHOP) in the activated B-cell (ABC) subtype of DLBCL. Additionally, inhibitors of BCL6, EZH2, and PI3K/Akt/mTOR are being considered for treatment of germinal center B-cell (GCB) subtype of DLBCL in patients with probable survival of less than 5 years. Double-or triple-hit lymphomas and double-expressor lymphomas also have poor prognosis and research to identify effective first-line therapy in these patients remains an unmet need. Presently, individualized approach that includes effective therapeutic combinations with acceptable safety profiles for use in routine practice, especially in patients likely to have poor outcomes such as relapsed/refractory DLBCL remains a distant possibility. Current evidence shows that untreated high risk patients do not have the greater benefit with use of newer drugs compared with R-CHOP. Therefore, R-CHOP remains the first-line treatment for newly diagnosed DLBCL patients.

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The impact of activated p-AKT expression on clinical outcomes in diffuse large B-cell lymphoma: a clinicopathological study of 262 cases

Cited by 27 publications

References 32 publications

Emerging role of microRNA-21 in cancer

Emerging role of microRNA-21 in cancer

The PI3K pathway in B cell metabolism

Rituximab-Based Therapy in Newly Diagnosed Diffuse Large B-Cell Lymphoma Patients: Individualized Risk-Adapted Therapy Approach Using Molecular Subtypes

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