scholarly journals NPM-ALK: The Prototypic Member of a Family of Oncogenic Fusion Tyrosine Kinases

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Joel D. Pearson ◽  
Jason K. H. Lee ◽  
Julinor T. C. Bacani ◽  
Raymond Lai ◽  
Robert J. Ingham
Keyword(s):  
Tyrosine Kinases ◽  
Fusion Proteins ◽  
Cell Lymphoma ◽  
Critical Role ◽  
Chromosomal Translocation ◽  
Large Cell ◽  
Signalling Pathways ◽  
Gene Encoding ◽  
Anaplastic Lymphoma ◽  
Constitutively Active

Anaplastic lymphoma kinase (ALK) was first identified in 1994 with the discovery that the gene encoding for this kinase was involved in the t(2;5)(p23;q35) chromosomal translocation observed in a subset of anaplastic large cell lymphoma (ALCL). The NPM-ALK fusion protein generated by this translocation is a constitutively active tyrosine kinase, and much research has focused on characterizing the signalling pathways and cellular activities this oncoprotein regulates in ALCL. We now know about the existence of nearly 20 distinct ALK translocation partners, and the fusion proteins resulting from these translocations play a critical role in the pathogenesis of a variety of cancers including subsets of large B-cell lymphomas, nonsmall cell lung carcinomas, and inflammatory myofibroblastic tumours. Moreover, the inhibition of ALK has been shown to be an effective treatment strategy in some of these malignancies. In this paper we will highlight malignancies where ALK translocations have been identified and discuss why ALK fusion proteins are constitutively active tyrosine kinases. Finally, using ALCL as an example, we will examine three key signalling pathways activated by NPM-ALK that contribute to proliferation and survival in ALCL.

scholarly journals Anaplastic lymphoma kinase in human cancer

2011 ◽  
Vol 47 (1) ◽  
pp. R11-R23 ◽  
Author(s):  
Antonella Barreca ◽  
Elena Lasorsa ◽  
Ludovica Riera ◽  
Rodolfo Machiorlatti ◽  
Roberto Piva ◽  
...  
Keyword(s):  
Anaplastic Lymphoma Kinase ◽  
Tyrosine Kinases ◽  
Fusion Proteins ◽  
Molecular Mechanisms ◽  
Cell Lymphoma ◽  
Human Cancer ◽  
Critical Role ◽  
Large Cell ◽  
Anaplastic Lymphoma ◽  
Alk Positive

The receptor tyrosine kinases (RTKs) play a critical role, controlling cell proliferation, survival, and differentiation of normal cells. Their pivotal function has been firmly established in the pathogenesis of many cancers as well. The anaplastic lymphoma kinase (ALK), a transmembrane RTK, originally identified in the nucleophosmin (NPM)–ALK chimera of anaplastic large cell lymphoma, has emerged as a novel tumorigenic player in several human cancers. In this review, we describe the expression of the ALK–RTK, its related fusion proteins, and their molecular mechanisms of activation. Novel tailored strategies are briefly illustrated for the treatment of ALK-positive neoplasms.

scholarly journals Dependency on the TYK2/STAT1/MCL1 axis in anaplastic large cell lymphoma

Leukemia ◽  
2018 ◽  
Vol 33 (3) ◽  
pp. 696-709 ◽  
Author(s):  
Nicole Prutsch ◽  
Elisabeth Gurnhofer ◽  
Tobias Suske ◽  
Huan Chang Liang ◽  
Michaela Schlederer ◽  
...  
Keyword(s):  
Cell Survival ◽  
Tyrosine Kinases ◽  
Drug Target ◽  
Cell Lymphoma ◽  
Chromosomal Translocation ◽  
Large Cell ◽  
Bcl2 Family ◽  
Anaplastic Lymphoma ◽  
Stat3 Phosphorylation ◽  
Specific Receptors

Abstract TYK2 is a member of the JAK family of tyrosine kinases that is involved in chromosomal translocation-induced fusion proteins found in anaplastic large cell lymphomas (ALCL) that lack rearrangements activating the anaplastic lymphoma kinase (ALK). Here we demonstrate that TYK2 is highly expressed in all cases of human ALCL, and that in a mouse model of NPM-ALK-induced lymphoma, genetic disruption of Tyk2 delays the onset of tumors and prolongs survival of the mice. Lymphomas in this model lacking Tyk2 have reduced STAT1 and STAT3 phosphorylation and reduced expression of Mcl1, a pro-survival member of the BCL2 family. These findings in mice are mirrored in human ALCL cell lines, in which TYK2 is activated by autocrine production of IL-10 and IL-22 and by interaction with specific receptors expressed by the cells. Activated TYK2 leads to STAT1 and STAT3 phosphorylation, activated expression of MCL1 and aberrant ALCL cell survival. Moreover, TYK2 inhibitors are able to induce apoptosis in ALCL cells, regardless of the presence or absence of an ALK-fusion. Thus, TYK2 is a dependency that is required for ALCL cell survival through activation of MCL1 expression. TYK2 represents an attractive drug target due to its essential enzymatic domain, and TYK2-specific inhibitors show promise as novel targeted inhibitors for ALCL.

Identification of Critical Phosporylation Sites within NPM-ALK That Regulate JUNB mRNA Translation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3571-3571
Author(s):  
Claudia Fuchs ◽  
Paul Vesely ◽  
Isabella Bambach ◽  
Silvia Schauer ◽  
Werner Linkesch ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Translational Regulation ◽  
Chromosomal Translocation ◽  
Mrna Translation ◽  
Large Cell ◽  
Wild Type ◽  
Tyrosine Residues ◽  
Anaplastic Lymphoma ◽  
Rps6 Phosphorylation ◽  
Mutant Cells

Abstract Anaplastic large cell lymphoma (ALCL) accounts for approximately 30% of childhood lymphomas and 3% of adult non-Hodgkin lymphomas. The nucleophosmin - anaplastic lymphoma kinase (NPM-ALK) fusion which is the product of a t(2;5)(p23;q35) chromosomal translocation is present in about half of nodal ALCL. Expression of this fusion kinase results in induction of the AP-1 transcription factor JunB and IL-3 independent outgrow of murine hematopoietic Ba/F3 cells. We demonstrated that wild type NPM-ALK increases the amount of ribosomes bound to JUNB mRNA resulting in its more effective translation in large polysomes. The NPM-ALK fusion tyrosine kinase has 20 potential tyrosine residues available for autophosphorylation and phosphorylation by other protein tyrosine kinases. Here we used series of Y-to-F-substituted mutants of NPM-ALK to identify tyrosine residues that are required to regulate the segregation of JUNB mRNAs between polysomes and monosomes as well as ribonucleic particles (RNPs). Neither JUNB transcription nor JunB translation was altered in Ba/F3 cells expressing NPM-ALK mutants Y17F/Y29F/Y67F Y138F/Y152F Y156F/Y191F/Y299F Y378F/Y418F/Y445F and Y646F/Y664F compared to NPM-ALK wild type. Conversely, in NPM-ALK Y567F/Y461F/Y644F mutant cells proliferation was markedly decreased. These cells demonstrated active MEK-ERK pathway, while AKT, mTOR, and rpS6 phosphorylation was impaired. Moreover a shift of JUNB mRNA from the polysomic to the monosomic/mRNP fraction could be observed. In conclusion, we identified specific NPM-ALK phosphorylation sites required to mediate the effect of NPM-ALK on the JUNB translational regulation and therefore provide further insights in the transforming mechanisms of the oncoprotein NPM-ALK.

scholarly journals A novel model of controlling PD-L1 expression in ALK+ anaplastic large cell lymphoma revealed by CRISPR screening

Blood ◽  
2019 ◽  
Vol 134 (2) ◽  
pp. 171-185 ◽  
Author(s):  
Jing-Ping Zhang ◽  
Zhihui Song ◽  
Hong-Bo Wang ◽  
Lang Lang ◽  
Yuan-Zhong Yang ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Anaplastic Large Cell Lymphoma ◽  
Immune Escape ◽  
Cell Lymphoma ◽  
Critical Role ◽  
Large Cell ◽  
Oncogenic Signaling ◽  
Tumor Immune Escape ◽  
Anaplastic Lymphoma ◽  
Large Cell Lymphoma

Abstract The success of programmed cell death protein 1 (PD-1)/PD-L1-based immunotherapy highlights the critical role played by PD-L1 in cancer progression and reveals an urgent need to develop new approaches to attenuate PD-L1 function by gaining insight into how its expression is controlled. Anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALK+ ALCL) expresses a high level of PD-L1 as a result of the constitutive activation of multiple oncogenic signaling pathways downstream of ALK activity, making it an excellent model in which to define the signaling processes responsible for PD-L1 upregulation in tumor cells. Here, using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 library screening, we sought a comprehensive understanding of the molecular effectors required for PD-L1 regulation in ALK+ ALCL. Indeed, we determined that PD-L1 induction is dependent on the nucleophosmin-ALK oncoprotein activation of STAT3, as well as a signalosome containing GRB2/SOS1, which activates the MEK-ERK and PI3K-AKT signaling pathways. These signaling networks, through STAT3 and the GRB2/SOS1, ultimately induce PD-L1 expression through the action of transcription factors IRF4 and BATF3 on the enhancer region of the PD-L1 gene. IRF4 and BATF3 are essential for PD-L1 upregulation, and IRF4 expression is correlated with PD-L1 levels in primary ALK+ ALCL tissues. Targeting this oncogenic signaling pathway in ALK+ ALCL largely inhibited the ability of PD-L1-mediated tumor immune escape when cocultured with PD-1-positive T cells and natural killer cells. Thus, our identification of this previously unrecognized regulatory hub not only accelerates our understanding of the molecular circuitry that drives tumor immune escape but also provides novel opportunities to improve immunotherapeutic intervention strategies.

Oncogenic Anaplastic Lymphoma Kinase Rearrangements in Lymphoma

2009 ◽  
Vol 03 (01) ◽  
pp. 50
Author(s):  
Katrien Van Roosbroeck ◽  
Iwona Wlodarska ◽  
◽  
Keyword(s):  
Anaplastic Lymphoma Kinase ◽  
Tyrosine Kinases ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large Cell ◽  
Null Cell ◽  
Anaplastic Lymphoma ◽  
Large B Cell Lymphoma ◽  
Alk Positive ◽  
Inappropriate Expression

Lymphomas expressing anaplastic lymphoma kinase (ALK) represent two distinct lymphoma entities: ALK-positive T-/null-cell anaplastic large cell lymphoma (ALK+ ALCL) and ALK-positive large B-cell lymphoma (ALK+ LBCL). In both subtypes, the inappropriate expression of ALK is driven by 2p23/ALK-involving chromosomal translocations found to target several partner genes. These translocations lead to constitutively activated and oncogenic ALK fusions, of which nucleophosmin (NPM1)-ALK associated with t(2;5)(p23;q35) is the most common. Recently, various ALK fusions, including those previously described in lymphomas, have been identified in several types of nonhaematological malignancy. Identification of further types of ALK+ tumours is clinically important because in future these patients may benefit from targeted therapy, already applied in neoplasms driven by, for example, the mutated ABL1, KIT and PDGFRA/B tyrosine kinases. In this article, we will focus mainly on oncogenic ALK rearrangements in lymphomas and their molecular consequences.

Correlation of the autoantibody response to the ALK oncoantigen in pediatric anaplastic lymphoma kinase–positive anaplastic large cell lymphoma with tumor dissemination and relapse risk

Blood ◽  
2010 ◽  
Vol 115 (16) ◽  
pp. 3314-3319 ◽  
Author(s):  
Kamel Ait-Tahar ◽  
Christine Damm-Welk ◽  
Birgit Burkhardt ◽  
Martin Zimmermann ◽  
Wolfram Klapper ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Anaplastic Large Cell Lymphoma ◽  
Anaplastic Lymphoma Kinase ◽  
Cell Lymphoma ◽  
Chromosomal Translocation ◽  
Large Cell ◽  
Anaplastic Lymphoma ◽  
Tumor Dissemination ◽  
Large Cell Lymphoma ◽  
Alk Positive

Abstract Anaplastic lymphoma kinase (ALK)–positive anaplastic large cell lymphoma (ALCL) constitutes an ideal model disease to study tumor-specific immune responses. All the tumor cells express oncogenic ALK resulting from a chromosomal translocation involved in lymphomagenesis. Although antibodies and T-cell responses to ALK have previously been detected in ALK-positive ALCL patients, their prognostic significance is unknown. We investigated a large cohort of uniformly treated ALK-positive pediatric ALCL patients to ascertain whether the titers of preexisting ALK autoantibodies correlated with clinical and histologic characteristics, tumor dissemination, and patient outcome. ALK autoantibodies were analyzed in pretherapeutic serum samples from 95 patients enrolled into 2 therapy studies between 1996 and 2007. ALK autoantibodies were detected in 87/95 patients. The titers inversely correlated with stage and amount of circulating tumor cells. High antibody titers correlated with significantly lower cumulative incidence of relapses (CI-R): titers ≥ 1/60 750, n = 29, CI-R 11% ± 6%; titers 1/2025-< 1/60 750, n = 39, CI-R 31% ± 8%; and titers 0-≤ 1/750, n = 27, CI-R of 63% ± 10% (P < .001). Our results provide the first clinical evidence that a robust preexisting immune response to an oncoantigen resulting from an oncogenic chromosomal translocation inhibits lymphoma dissemination and decreases the risk of relapse.

scholarly journals Increased Tenascin C, Osteopontin and HSP90 Levels in Plasmatic Small Extracellular Vesicles of Pediatric ALK-Positive Anaplastic Large Cell Lymphoma: New Prognostic Biomarkers?

Diagnostics ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 253
Author(s):  
Federica Lovisa ◽  
Anna Garbin ◽  
Sara Crotti ◽  
Piero Di Battista ◽  
Ilaria Gallingani ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Enrichment Analysis ◽  
Heat Shock Protein 90 ◽  
Large Cell ◽  
Tenascin C ◽  
Anaplastic Lymphoma ◽  
Large Cell Lymphoma ◽  
Alk Positive

Over the past 15 years, several biological and pathological characteristics proved their significance in pediatric anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALCL) prognostic stratification. However, the identification of new non-invasive disease biomarkers, relying on the most important disease mechanisms, is still necessary. In recent years, plasmatic circulating small extracellular vesicles (S-EVs) gathered great importance both as stable biomarker carriers and active players in tumorigenesis. In the present work, we performed a comprehensive study on the proteomic composition of plasmatic S-EVs of pediatric ALCL patients compared to healthy donors (HDs). By using a mass spectrometry-based proteomics approach, we identified 50 proteins significantly overrepresented in S-EVs of ALCL patients. Gene Ontology enrichment analysis disclosed cellular components and molecular functions connected with S-EV origin and vesicular trafficking, whereas cell adhesion, glycosaminoglycan metabolic process, extracellular matrix organization, collagen fibril organization and acute phase response were the most enriched biological processes. Of importance, consistently with the presence of nucleophosmin (NPM)-ALK fusion protein in ALCL cells, a topological enrichment analysis based on Reactome- and Kyoto Encyclopedia of Genes and Genomes (KEGG)-derived networks highlighted a dramatic increase in proteins of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway in ALCL S-EVs, which included heat shock protein 90-kDa isoform alpha 1 (HSP90AA1), osteopontin (SPP1/OPN) and tenascin C (TNC). These results were validated by Western blotting analysis on a panel of ALCL and HD cases. Further research is warranted to better define the role of these S-EV proteins as diagnostic and, possibly, prognostic parameters at diagnosis and for ALCL disease monitoring.

scholarly journals Analysis with antiidiotype antibody of a patient with chronic lymphocytic leukemia and a large cell lymphoma (Richter's syndrome)

Blood ◽  
1987 ◽  
Vol 70 (1) ◽  
pp. 45-50 ◽  
Author(s):  
LF Bertoli ◽  
H Kubagawa ◽  
GV Borzillo ◽  
M Mayumi ◽  
JT Prchal ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Plasma Cells ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Lymphocytic Leukemia ◽  
Immunoglobulin Gene ◽  
Anaplastic Lymphoma ◽  
Large Cell Lymphoma ◽  
Richter’S Syndrome

Abstract A murine monoclonal antibody made against an idiotypic determinant (Id) of surface IgM/IgD lambda molecules on chronic lymphocytic leukemia (CLL) cells of a 71-year-old woman was used for clonal analysis by two- color immunofluorescence. The anti-Id antibody identified IgM+/IgD+/lambda+ B cells as the predominant cell type of her CLL clone. In addition, substantial proportions of the IgG and IgA B cells and most of the IgM plasma cells in her bone marrow and blood were Id+. Six years after diagnosis, the patient died of respiratory failure due to infiltration of lungs by malignant cells. Autopsy revealed a dramatic change in the tumor cell morphology. The lungs, hilar nodes, and liver were infiltrated by a diffuse large cell lymphoma admixed with the leukemic cells. By immunohistologic staining these anaplastic lymphoma cells were IgM+/IgD-/lambda+ B cells expressing the same Id noted earlier on the CLL cells. The immunoglobulin gene rearrangement pattern on Southern blot analysis was also the same in leukemic blood cells and in the tissues involved by the lymphoma. Thus, the combination of antiidiotype and immunoglobulin gene analyses in this patient with Richter's syndrome revealed that a CLL clone, seemingly “frozen” in differentiation, was actually undergoing isotype switching, differentiation into plasma cells, and evolution into a rapidly growing and fetal lymphoma.

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