The NPM-ALK oncoprotein abrogates CD30 signaling and constitutive NF-κB activation in anaplastic large cell lymphoma

Horie, Ryouichi; Watanabe, Miki; Ishida, Takeshi; Koiwa, Tsukasa; Aizawa, Shojiro; Itoh, Kengo; Higashihara, Masaaki; Kadin, Marshall E.; Watanabe, Toshiki

doi:10.1016/s1535-6108(04)00084-4

Cited by 70 publications

(74 citation statements)

References 52 publications

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“…17 Doublestranded oligonucleotide probes containing the mouse immunoglobulin kappa (Igk) light-chain NF-kB consensus site and Oct-1 were purchased from Promega (Madison, WI, USA). Antibodies used for super-shift assays were as follows: NF-kB p50 (C-19) goat polyclonal antibody, RelB (C-19) rabbit polyclonal antibody and mouse antibodies for NF-kB p65 (C-20), NF-kB p52 (C-5) and c-Rel (B-6) (all from Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA).…”

Section: Electrophoretic Mobility Shift Analysismentioning

confidence: 99%

“…17 Briefly, 2 mg of poly(A)-selected RNA was sizefractionated on 1% formalin agarose gel electrophoresis and subsequently blotted onto Hybond-C extra-nitrocellulose membranes (Amersham Bioscience Corp.). Filters were hybridized in 4 Â SSC, 1 Â Denhardts, 0.5% SDS, 0.1 M NaPO 4 (pH 7.0), 10% Dextran-Na at 651C with 1.0 Â 10 6 cpm/ml of random prime-labeled probes.…”

Section: Northern Blottingmentioning

confidence: 99%

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IκBα independent induction of NF-κB and its inhibition by DHMEQ in Hodgkin/Reed-Sternberg cells

Watanabe

Dewan

Taira

et al. 2007

Laboratory Investigation

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Constitutive nuclear factor kB (NF-kB) activation characterizes Hodgkin/Reed-Sternberg (H-RS) cells. Blocking constitutive NF-kB has been shown to be a potential strategy to treat Hodgkin lymphoma (HL). Here, for the first time we show that although constitutive NF-kB level of H-RS cell lines is very high, topoisomerase inhibitors further enhance NF-kB activation through IkB kinase activation in not only H-RS cell lines with wild-type IkBa, but also in those with IkBa mutations and lacking wild-type IkBa. Thus, both constitutive and inducible NF-kB are potential targets to treat HL. We also present the data that indicate the involvement of IkBb in NF-kB induction by topoisomerase inhibitors. A new NF-kB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ) inhibited constitutive NF-kB activity and induced apoptosis of H-RS cell lines. DHMEQ also inhibited the growth of H-RS cells without significant systemic toxicity in a NOD/SCID/gc null (NOG) mice model. DHMEQ and topoisomerase inhibitors revealed enhancement of apoptosis of H-RS cells by blocking inducible NFkB. Results of this study suggest that both constitutive and inducible NF-kB are molecular targets of DHMEQ in the treatment of HL. The results also indicate that IkBb is involved in NF-kB activation in H-RS cells and IkBb substitutes for IkBa in H-RS cells lacking wild-type IkBa.

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Section: Electrophoretic Mobility Shift Analysismentioning

confidence: 99%

Section: Northern Blottingmentioning

confidence: 99%

IκBα independent induction of NF-κB and its inhibition by DHMEQ in Hodgkin/Reed-Sternberg cells

Watanabe

Dewan

Taira

et al. 2007

Laboratory Investigation

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“…In addition, NPM-ALK impedes CD30 signalling and NFkB activation by a mechanism dependent on interaction between the N-terminal NPM domain of NPM-ALK with endogenous NPM. 29 It is therefore possible that a 50% reduction in endogenous NPM expression might subvert this process. If either of these roles for endogenous NPM proves to be important in the transforming process, or in determining the phenotype of the transformed lineage, then possible oncogenic roles for other ALK fusion partners may need to be considered.…”

Section: Transgenic Mouse Modelsmentioning

confidence: 99%

What have we learnt from mouse models of NPM-ALK-induced lymphomagenesis?

Turner

Alexander

2005

Leukemia

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The nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is generated as a t(2;5) chromosomal breakpoint product, typically in CD30 þ anaplastic large cell lymphomas. Activation of the NPM-ALK tyrosine kinase by NPM dimerisation causes autophosphorylation at multiple tyrosine residues and the consequent recruitment of a 'signalosome' that couples the fusion protein to pathways regulating mitogenesis and apoptosis. This review focuses on recent advances in our understanding of the transforming signals induced by this fusion protein in mouse models.

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“…(41) In contrast, Horie et al clarified that NPM-ALK disrupts CD30 signaling and constitutive NF-κB activation in ALCL. (42) TRAF2/5 was shown to be bound with NPM-ALK on both the kinase domain of ALK and the N-terminal domain of NPM. In the same study, wild-type NPM was shown to be tyrosine-phosphorylated by NPM-ALK, although the significance remains unclear.…”

Section: Npm-alk Chimeric Kinase In Alclmentioning

confidence: 99%

Nucleophosmin: A versatile molecule associated with hematological malignancies

Naoe

Suzuki

Kiyoi³

et al. 2006

Cancer Science

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Nucleophosmin (NPM) is a nucleolar phosphoprotein that plays multiple roles in ribosome assembly and transport, cytoplasmicnuclear trafficking, centrosome duplication and regulation of p53. In hematological malignancies, the NPM1 gene is frequently involved in chromosomal translocation, mutation and deletion. The NPM1 gene on 5q35 is translocated with the anaplastic lymphoma kinase (ALK) gene in anaplastic large cell lymphoma with t(2;5). The MLF1 and RARA genes are fused with NPM1 in myelodysplastic syndrome and acute myeloid leukemia (AML) with t(3;5) and acute promyelocytic leukemia with t(5;17), respectively. In each fused protein, the Nterminal NPM portion is associated with oligomerization of a partner protein leading to altered signal transduction or transcription. Recently, mutations of exon 12 have been found in a significant proportion of de novo AML, especially in those with a normal karyotype. Mutant NPM is localized aberrantly in the cytoplasm, but the molecular mechanisms for leukemia remain to be studied. N ucleophosmin (NPM), also called B23, numatrin or NO38, was isolated as an abundant nucleolar phosphoprotein, whose expression level is increased significantly by several kinds of stimulation and transformation. (1,2) In 1989, a human NPM cDNA encoding a 294-amino-acid protein was cloned. (3) In 2002, a shorter isoform encoding a 259-amino acid protein that differs at the C-terminus was also isolated. (4) The NPM1 gene spans 25 kb, contains 12 exons and maps to chromosome 5q35. (4,5) Exon 8 is frequently skipped, and exon 10 is used only for the short isoform. Although the biological significance of the short isoform remains unclear, its expression is increased in radiation-insensitive cell lines and the product is localized in the cytoplasm as well as in the nucleus. (4,6) The structural features of NPM consist of an oligomerization domain, a metalbinding motif, a bipartite nuclear localization signal, two Asp/ Glu-rich domains, phosphorylation sites for CDK2 and a nucleor localization signal. (6,7) NPM1 has been recognized by oncologists as a partner gene for various chromosomal translocations: NPM-anaplastic lymphoma kinase (ALK) in anaplastic large cell lymphoma (ALCL) with t(3;5), NPM-RARA in acute promyelocytic leukemia (APL) with t(5;17), and NPM-MLF1 in acute myeloid leukemia (AML)/ myelodysplastic syndrome (MDS) with t(3;5). (8)(9)(10) (Fig. 1, 2) In each chimeric gene product, the N-terminal NPM portion is thought to act as the interface for oligomerization and oncogenic conversion of the C-terminal functional domain such as a kinase or transcription factor. Recently, NPM was associated with centrosome duplication and the regulation of p53, (11,12) and might have a role as a tumor suppressor. Expression and function of NPMNucleophosmin is an abundant and ubiquitously expressed phosphoprotein. It is located mainly in the nucleolus and shuttles between the nucleus and cytoplasm. (13,14) NPM has been proposed to be associated with the synthesis and processing of ribosomal RNA (rRNA), regu...

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The NPM-ALK oncoprotein abrogates CD30 signaling and constitutive NF-κB activation in anaplastic large cell lymphoma

Cited by 70 publications

References 52 publications

IκBα independent induction of NF-κB and its inhibition by DHMEQ in Hodgkin/Reed-Sternberg cells

IκBα independent induction of NF-κB and its inhibition by DHMEQ in Hodgkin/Reed-Sternberg cells

What have we learnt from mouse models of NPM-ALK-induced lymphomagenesis?

Nucleophosmin: A versatile molecule associated with hematological malignancies

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