Translocations involving anaplastic lymphoma kinase (ALK)

Duyster, Justus; Bai, Ren Yuan; Morris, Stephan W.

doi:10.1038/sj.onc.1204594

Cited by 258 publications

(211 citation statements)

References 122 publications

(116 reference statements)

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“…pp60 c-src is not a physical intermediate of Vav3 and NPM-ALK association since mutation of its binding site (Y418F) had no effect on the association. Interestingly, assessment of the intrinsic tyrosine kinase activity of NPM-ALK with the anti-pNPM-ALK(Y664) antibody confirmed that three of the mutants, namely, Y338F, Y342F and Y343F, had reduced kinase activity (Duyster et al, 2001).The fact that two of them are still capable of binding Vav3 indicates that Y343 is probably phosphorylated by another kinase still to identify.…”

Section: Role Of Gtpases In Npm-alk( þ ) Alclsmentioning

confidence: 98%

“…Cells were lysed 48 h post nucleofection. pcDNA3 containing wild-type NPM-ALK or the Y338F, Y342F, Y343F, Y418F and Y664F mutants were already described (Duyster et al, 2001;Cussac et al, 2004). pcDNA3-EGFP-Rac1T17N was a generous gift from Dr K Hahn (University of North Carolina, Chapel Hill, NC, USA).…”

Section: Reagents and Antibodiesmentioning

confidence: 99%

“…Anaplastic large cell lymphomas (ALCLs), a subtype of high-grade non-Hodgkin's lymphomas of T or null phenotype, are characterized by the aberrant expression of the oncogenic fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) in 75% of cases (Lamant et al, 1996;Duyster et al, 2001;Falini, 2001). The constitutive tyrosine kinase activity of NPM-ALK is responsible for malignant transformation of fibroblasts and lymphoid cells and was shown to induce Band T-cell lymphomas in transgenic mice (Chiarle et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas

et al. 2007

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The majority of anaplastic large cell lymphomas (ALCLs) express the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion protein, which is oncogenic due to its constitutive tyrosine kinase activity. Transformation by NPM-ALK not only increases proliferation, but also modifies cell shape and motility in both lymphoid and fibroblastic cells. We report that the Rac1 GTPase, a known cytoskeletal regulator, is activated by NPM-ALK in ALCL cell lines (Karpas 299 and Cost) and transfected cells (lymphoid Ba/F3 cells, NIH-3T3 fibroblasts). We have identified Vav3 as one of the exchange factors involved in Rac1 activation. Stimulation of Vav3 and Rac1 by NPM-ALK is under the control of Src kinases. It involves formation of a signaling complex between NPM-ALK, pp60 c-src , Lyn and Vav3, in which Vav3 associates with tyrosine 343 of NPM-ALK via its SH2 domain. Moreover, Vav3 is phosphorylated in NPM-ALK positive biopsies from patients suffering from ALCL, demonstrating the pathological relevance of this observation. The use of Vav3-specific shRNA and a dominant negative Rac1 mutant demonstrates the central role of GTPases in NPM-ALK elicited motility and invasion.

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Section: Role Of Gtpases In Npm-alk( þ ) Alclsmentioning

confidence: 98%

Section: Reagents and Antibodiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas

et al. 2007

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“…14 Previous in vitro studies have demonstrated that NPM-ALK is capable of activating the phosphatidylinositol 3-kinase (PI3K)-Akt/PKB pathway. 15,16 Activation of this pathway results in phosphorylation of the BCL-2 family protein BAD, preventing BAD from binding to the antiapoptotic proteins BCL-2 and BCL-XL and inhibiting their function.…”

mentioning

confidence: 99%

Caspase-3 activation in systemic anaplastic large-cell lymphoma

et al. 2004

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Anaplastic large-cell lymphoma (ALCL), as currently defined, includes a subset of tumors that have abnormalities of chromosome 2p23 (alk gene) resulting in overexpression of anaplastic lymphoma kinase (ALK). We have previously shown differences in apoptotic rate and expression of apoptosis-related proteins between ALK-positive and ALK-negative ALCL. In this study, we assessed for activated caspase-3 (aC-3), an executioner of apoptotic cell death, in ALCL cell lines and tumors. We used the Karpas 299 and SU-DHL-1 cell lines, and the caspase inhibitors Boc-D-FMK and DEVD-FMK to investigate the role of caspase-3 activation in tumor cell death after treatment with doxorubicin. Cell viability and apoptosis were assessed by trypan blue and Annexin-V methods. A caspase-3 assay was used to evaluate caspase-3 enzymatic activity. Caspase-3 activity was significantly increased in Karpas-299 and SU-DHL-1 cells treated with doxorubicin, but remained as low as control levels with addition of Boc-D-FMK or DEVD-FMK. Expression of aC-3 was also assessed immunohistochemically in 57 ALCL tumors. The mean percentage of aC-3 positive tumor cells was 3.2% in ALK-positive ALCL compared with 1.2% in ALK-negative ALCL (P ¼ 0.0003, Mann-Whitney test), and inversely correlated with BCL-2 expression (P ¼ 0.01, Mann-Whitney test). aC-3 expression did not correlate with patient outcome in either the ALK-positive or ALK-negative ALCL groups. In conclusion, doxorubicin-induced cell death of ALK-positive ALCL cells involves caspase-3 activation in vitro. aC-3 levels correlate with ALK expression in ALCL tumors.

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“…Cytogenetically, the 2p23 locus is translocated frequently with 5q35, and less frequently with 1p25, 3q21 or 2q35. (34) In 1994, Morris et al showed that the t(2;5) translocation fused the NPM1 gene on 5q35 to a previously unidentified protein tyrosine kinase gene, ALK, on 2p23. (35) In the NPM-ALK chimeric kinase, the N-terminus of NPM (amino acids 1-117) is fused to the catalytic domain of ALK (amino acids 1058-1620).…”

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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Translocations involving anaplastic lymphoma kinase (ALK)

Cited by 258 publications

References 122 publications

Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas

Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas

Caspase-3 activation in systemic anaplastic large-cell lymphoma

Nucleophosmin: A versatile molecule associated with hematological malignancies

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