Targeting the NF-κB signaling pathway in Notch1-induced T-cell leukemia

Vilimas, Tomas; Mascarenhas, Joaquina; Palomero, Teresa; Mandal, Malay; Buonamici, Silvia; Meng, Fanyong; Thompson, Benjamin J.; Spaulding, Christina; Macaroun, Sami; Alegre, Maria‐Luisa; Kee, Barbara L.; Ferrando, Adolfo A.; Miele, Lucio; Aifantis, Iannis

doi:10.1038/nm1524

Cited by 312 publications

(281 citation statements)

References 44 publications

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“…41,42 Significant associations were also found between lower bax/bcl-2 ratio and UM-IGHV or TP53 mutations (P<0.0001) ( Table 1), thus confirming that biological mechanisms related to defective apoptosis play a pivotal role both in the chemoresistance and in the unfavorable clinical course of these patient subgroups.…”

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confidence: 59%

Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia

Principe

Bittolo

et al. 2015

Haematologica

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In chronic lymphocytic leukemia the balance between the pro-apoptotic and anti-apoptotic members of the bcl-2 family is involved in the pathogenesis, chemorefractoriness and clinical outcome. Moreover, the recently proposed anti-bcl-2 molecules, such as ABT-199, have emphasized the potential role of of bcl-2 family proteins in the context of target therapies. We investigated bax/bcl-2 ratio by flow cytometry in 502 patients and identified a cut off of 1.50 to correlate bax/bcl-2 ratio with well-established clinical and biological prognosticators. Bax/bcl-2 was 1.50 or over in 263 patients (52%) with chronic lymphocytic leukemia. Higher bax/bcl-2 was associated with low Rai stage, lymphocyte doubling time over 12 months, beta-2 microglobulin less than 2.2 mg/dL, soluble CD23 less than 70 U/mL and a low risk cytogenetic profile (P<0.0001). On the other hand, lower bax/bcl-2 was correlated with unmutated IGHV (P<0.0001), mutated NOTCH1 (P<0.0001) and mutated TP53 (P=0.00007). Significant shorter progression-free survival and overall survival were observed in patients with lower bax/bcl-2 (P<0.0001). Moreover, within IGHV unmutated (168 patients) and TP53 mutated (37 patients) subgroups, higher bax/bcl-2 identified cases with significant longer PFS (P=0.00002 and P=0.039). In multivariate analysis of progression-free survival and overall survival, bax/bcl-2 was an independent prognostic factor (P=0.0002 and P=0.002). In conclusion, we defined the prognostic power of bax/bcl-2 ratio, as determined by a flow cytometric approach, and highlighted a correlation with chemoresistance and outcome in chronic lymphocytic leukemia. Finally, the recently proposed new therapies employing bcl-2 inhibitors prompted the potential use of bax/bcl-2 ratio to identify patients putatively resistant to these molecules. ABSTRACT

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confidence: 59%

Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia

Principe

Bittolo

et al. 2015

Haematologica

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“…Several groups have reported that activation of the NF-nB pathway enhances tumor development and may act primarily in the late stages of tumorigenesis in mouse models of intestinal, liver, and mammary cancer. Inhibition of NF-nB signaling uniformly suppressed tumor development but, depending on the model studied, this salutary effect was attributed to an increase in tumor cell apoptosis, reduced expression of tumor cell growth factors supplied by surrounding stromal cells, or abrogation of a tumor cell dedifferentiation program that is critical for tumor invasion/metastasis (33)(34)(35)(36)(37)(38)(39)(40). The demonstration that pNP73-102 inhibited activation of NF-nB and that NF-nB activation was reduced in the lungs of NPRA À/À mice could represent another additional mechanism underlying its anticancer activity.…”

Section: Discussionmentioning

confidence: 99%

Natriuretic Peptide Receptor A as a Novel Anticancer Target

Kong¹,

Wang

et al. 2008

Cancer Research

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The receptor for atrial natriuretic peptide (ANP), natriuretic peptide receptor A (NPRA), is expressed in cancer cells, and natriuretic peptides have been implicated in cancers. However, the direct role of NPRA signaling in tumorigenesis remains elusive. Here, we report that NPRA expression and signaling is important for tumor growth. NPRA-deficient mice showed significantly reduced antigen-induced pulmonary inflammation. NPRA deficiency also substantially protected C57BL/6 mice from lung, skin, and ovarian cancers. Furthermore, a nanoparticle-formulated interfering RNA for NPRA attenuated B16 melanoma tumors in mice. Ectopic expression of a plasmid encoding NP73-102, the NH 2 -terminal peptide of the ANP prohormone, which down-regulates NPRA expression, also suppressed lung metastasis of A549 cells in nude mice and tumorigenesis of Line 1 cells in immunocompetent BALB/c mice. The antitumor activity of NP73-102 was in part attributed to apoptosis of tumor cells. Western blot and immunohistochemistry staining indicated that the transcription factor, nuclear factor-KB, was inactivated, whereas the level of tumor suppressor retinoblastoma protein was upregulated in the lungs of NPRA-deficient mice. Furthermore, expression of vascular endothelial growth factor was downregulated in the lungs of NPRA-deficient mice compared with that in wild-type mice. These results suggest that NPRA is involved in tumor angiogenesis and represents a new target for cancer therapy. [Cancer Res 2008;68(1):249-56]

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“…Even in the same cell type, Notch activation can signal via different pathways [28,29]. In addition to the "classical" downstream targets such as Deltex [13], Hes1 and Hes5 [30,31], Pre-T-α [31,32], p21 [28,33], important cancer-related downstream targets and signaling pathways including c-Myc [12,34], NF-κB [35,36], and PTEN/AKT-PI3K [37] have been identified more recently.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Notch signaling by γ-secretase inhibition can abrogate chemotherapy-induced apoptosis in T-ALL cell lines

Liu¹,

Breit²,

Danckwardt³

et al. 2008

Ann Hematol

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Activation of Notch1 signaling plays an important role in the pathogenesis of precursor T-cell lymphoblastic leukemia (T-ALL). The Notch1 receptor is cleaved and activated via the γ-secretase complex. Downregulation of Notch1 signaling by γ-secretase inhibitors (GSIs) thus represents a potential novel therapeutic approach. In this study, we analyzed the response of four T-ALL cell lines to compound E, a potent γ-secretase inhibitor, and to the combination of compound E with vincristine, daunorubicin, L-asparaginase (L-ASP), and dexamethasone (DEX). We identified two distinct types of responses: In type 1 cell lines, represented by TALL1 and HSB2, GSI-induced apoptosis followed cell cycle arrest and enhanced the induction of apoptosis caused by DEX and L-ASP. In type 2 cell lines, represented by CEM and Jurkat J6, GSI caused neither cell cycle block nor cell death. Notably, the combination of GSI with chemotherapy-induced resistance by decreasing apoptosis. In type 2 cells, GSI induced the upregulation of Bcl-xl mRNA and protein, which was thus identified as a candidate mechanism for the inhibition of apoptosis. In conclusion, the data presented here caution against clinical use of a combination treatment of GSI and chemotherapy in T-ALL.

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Targeting the NF-κB signaling pathway in Notch1-induced T-cell leukemia

Cited by 312 publications

References 44 publications

Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia

Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia

Natriuretic Peptide Receptor A as a Novel Anticancer Target

Downregulation of Notch signaling by γ-secretase inhibition can abrogate chemotherapy-induced apoptosis in T-ALL cell lines

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