Pretargeted Radioimmunotherapy (PRIT™) Using an Antibody-Streptavidin Fusion Protein in Non-Hodgkin's Lymphoma

2002 ◽  
Vol 43 (10) ◽  
pp. 1971-1973 ◽  
Author(s):  
Paul L. Weiden
Keyword(s):  
Fusion Protein ◽  
Hodgkin’S Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Pretargeted Radioimmunotherapy

scholarly journals Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma-associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis.

1997 ◽  
Vol 17 (4) ◽  
pp. 2312-2325 ◽  
Author(s):  
D Bischof ◽  
K Pulford ◽  
D Y Mason ◽  
S W Morris
Keyword(s):  
Fusion Protein ◽  
Anaplastic Lymphoma Kinase ◽  
Hodgkin’S Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Hybrid Protein ◽  
Anaplastic Lymphoma ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma

The NPM-ALK fusion gene, formed by the t(2;5)(p23;q35) translocation in non-Hodgkin's lymphoma, encodes a 75-kDa hybrid protein that contains the amino-terminal 117 amino acid residues of the nucleolar phosphoprotein nucleophosmin (NPM) joined to the entire cytoplasmic portion of the receptor tyrosine kinase ALK (anaplastic lymphoma kinase). Here, we demonstrate the transforming ability of NPM-ALK and show that oncogenesis by the chimeric protein requires the activation of its kinase function as a result of oligomerization mediated by the NPM segment. Sedimentation gradient experiments revealed that NPM-ALK forms in vivo multimeric complexes of approximately 200 kDa or greater that also contain normal NPM. Cell fractionation studies of the t(2;5) translocation-containing lymphoma cell line SUP-M2 showed NPM-ALK to be localized within both the cytoplasmic and nuclear compartments. Immunostaining performed with both polyclonal and monoclonal anti-ALK antibodies confirmed the dual location of the oncoprotein and also indicated that NPM-ALK is abundant within both the nucleoplasm and the nucleolus. An intact NPM segment is absolutely required for NPM-ALK-mediated oncogenesis, as indicated by our observation that three different NPM-ALK mutant proteins lacking nonoverlapping portions of the NPM segment were each unable to form complexes, lacked kinase activity in vivo, and failed to transform cells. However, NPM could be functionally replaced in the fusion protein with the portion of the unrelated translocated promoter region (TPR) protein that activates the TPR-MET fusion kinase by mediating dimerization through its leucine zipper motif. This engineered TPR-ALK hybrid protein, which transformed cells almost as efficiently as NPM-ALK, was localized solely within the cytoplasm of cells. These data indicate that the nuclear and nucleolar localization of NPM-ALK, which probably occur because of transport via the shuttling activity of NPM, is not required for oncogenesis. Further, the activation of the truncated ALK protein by a completely heterologous oligomerization domain suggests that the functionally important role of the NPM segment of NPM-ALK in transformation is restricted to the formation of kinase-active oligomers and does not involve the alteration of normal NPM functions.

Antiphospholipid Antibodies: Prevalence, Clinical Significance and Correlation to Cytokine Levels in Acute Myeloid Leukemia and Non-Hodgkin’s Lymphoma

1993 ◽  
Vol 70 (04) ◽  
pp. 568-572 ◽  
Author(s):  
Roberto Stasi ◽  
Elisa Stipa ◽  
Mario Masi ◽  
Felicia Oliva ◽  
Alessandro Sciarra ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Clinical Significance ◽  
Antiphospholipid Antibodies ◽  
Myeloid Leukemia ◽  
Hodgkin’S Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Tnf Alpha ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Acute Myeloid

SummaryThis study was designed to explore the prevalence and clinical significance of elevated antiphospholipid antibodies (APA) titres in patients affected by acute myeloid leukemia (AML) and highgrade non-Hodgkin’s lymphoma (NHL). We also analyzed possible correlations with circulating levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and the soluble form of the receptor for interleukin-2 (sIL-2r). Nineteen patients with de novo AML and 14 patients with newly-diagnosed NHL were investigated. Tests for APA included the measurement of anticardiolipin antibodies (ACA) with a solid-phase immunoassay, and the detection of the lupus-like anticoagulant (LA) activity. Five patients with AML (26.3%) and 5 patients with NHL (35.7%) presented elevated APA at diagnosis, as compared to 3 of 174 persons of the control group (p <0.0001). APA titres became normal in all patients responding to treatment, whereas nonresponders retained elevated levels. In addition, 6 patients (4 with AML and 2 with NHL), who had normal APA at diagnosis and were either refractory to treatment or in relapse, subsequently developed LA and/or ACA positivity. At presentation, the mean levels of IgG- and IgM-ACA in patients were not significantly different from Controls, and concordance between ACA and LA results reached just 30%. With regard to the clinical course, we were not able to detect any statistically significant difference between patients with normal and elevated APA. Pretreatment concentrations of IL-6 and TNF-alpha in AML, and sIL-2r in NHL were found significantly elevated compared to Controls (p = 0.003, p = 0.009 and p = 0.024 respectively). In addition, the levels of these cytokines correlated with IgG-ACA at the different times of laboratory investigations. These results demonstrate that APA may have a role as markers of disease activity and progression in some haematological malignancies.

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