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Hallberg, Bengt
Publications (10 of 42) Show all publications
Fransson, S., Hansson, M., Ruuth, K., Djos, A., Berbegall, A., Javanmardi, N., . . . Martinsson, T. (2015). Intragenic Anaplastic Lymphoma Kinase (ALK) Rearrangements: Translocations as a Novel Mechanism of ALK Activation in Neuroblastoma Tumors. Genes, Chromosomes and Cancer, 54(2), 99-109
Open this publication in new window or tab >>Intragenic Anaplastic Lymphoma Kinase (ALK) Rearrangements: Translocations as a Novel Mechanism of ALK Activation in Neuroblastoma Tumors
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2015 (English)In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 54, no 2, p. 99-109Article in journal (Refereed) Published
Abstract [en]

Anaplastic lymphoma kinase (ALK) has been demonstrated to be deregulated in sporadic as well as in familiar cases of neuroblastoma (NB). Whereas ALK-fusion proteins are common in lymphoma and lung cancer, there are few reports of ALK rearrangements in NB indicating that ALK mainly exerts its oncogenic capacity via activating mutations and/or overexpression in this tumor type. In this study, 332 NB tumors and 13 cell lines were screened by high resolution single nucleotide polymorphism microarray. Gain of 2p was detected in 23% (60/332) of primary tumors and 46% (6/13) of cell lines, while breakpoints at the ALK locus were detected in four primary tumors and two cell lines. These were further analyzed by next generation sequencing and a targeted enrichment approach. Samples with both ALK and MYCN amplification displayed complex genomic rearrangements with multiple breakpoints within the amplicon. None of the translocations characterized in primary NB tumors are likely to result in a chimeric protein. However, immunohistochemical analysis reveals high levels of phosphorylated ALK in these samples despite lack of initial exons, possibly due to alternative transcription initiation sites. Both ALK proteins predicted to arise from such alterations and from the abnormal ALK exon 4-11 deletion observed in the CLB-BAR cell line show strong activation of downstream targets STAT3 and extracellular signal-regulated kinase (ERK) when expressed in PC12 cells. Taken together, our data indicate a novel, although rare, mechanism of ALK activation with implications for NB tumorigenesis. 

National Category
Cancer and Oncology Medical Genetics
Identifiers
urn:nbn:se:umu:diva-99211 (URN)10.1002/gcc.22223 (DOI)000346348600005 ()
Available from: 2015-04-22 Created: 2015-02-04 Last updated: 2018-06-07Bibliographically approved
Velghe, A., Van Cauwenberghe, S., Polyansky, A. A., Chand, D., Montano-Almendras, C., Charni, S., . . . Demoulin, J. (2014). PDGFRA alterations in cancer: characterization of a gain-of-function V536E transmembrane mutant as well as loss-of-function and passenger mutations. Oncogene, 33(20), 2568-2576
Open this publication in new window or tab >>PDGFRA alterations in cancer: characterization of a gain-of-function V536E transmembrane mutant as well as loss-of-function and passenger mutations
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2014 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 33, no 20, p. 2568-2576Article in journal (Refereed) Published
Abstract [en]

Activating mutations in the platelet-derived growth factor (PDGF) receptor alpha (PDGFRA) have been described in patients with gastrointestinal stromal tumors or myeloid malignancies associated with hypereosinophilia. These patients respond well to imatinib mesylate, raising the question as to whether patients with a PDGF receptor mutation in other tumor types should receive a tyrosine kinase inhibitor treatment. We characterized 10 novel somatic point mutations in PDGFRA that have been reported in isolated cases of glioblastoma, melanoma, acute myeloid leukemia, peripheral nerve sheath tumors and neuroendocrine carcinoma. The PDGFRA transmembrane domain mutation V536E stimulated Ba/F3 cell growth and signaling via ERK and STAT5 in the absence of ligand. This mutant, identified in glioblastoma, was strongly inhibited by imatinib. Modeling suggested that the mutation modulates the packing of the transmembrane domain helices in the receptor dimer. By contrast, two mutations in highly conserved residues affected the receptor traffic to the cell surface or kinase activity, thereby preventing the response to PDGF. The other mutations had no significant impact on the receptor activity. This functional analysis matched the predictions of SIFT and PolyPhen for only five mutations and these algorithms do not discriminate gain from loss of function. Finally, an E996K variant that had been identified in a melanoma cell line was not expressed in these cells. Altogether, several newly identified PDGFRA mutations do not activate the receptor and may therefore represent passenger mutations. Our results also underline the importance of characterizing novel kinase alterations in cancer patients.

Place, publisher, year, edition, pages
Nature Publishing Group, 2014
Keywords
PDGF receptor, tyrosine kinase inhibitors, glioblastoma, leukemia, GIST
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-81142 (URN)10.1038/onc.2013.218 (DOI)000336502700003 ()
Available from: 2013-10-02 Created: 2013-10-02 Last updated: 2018-06-08Bibliographically approved
Chand, D., Yamazaki, Y., Ruuth, K., Schönherr, C., Martinsson, T., Kogner, P., . . . Hallberg, B. (2013). Cell culture and Drosophila model systems define three classes of anaplastic lymphoma kinase mutations in neuroblastoma. Disease Models and Mechanisms, 6(2), 373-382
Open this publication in new window or tab >>Cell culture and Drosophila model systems define three classes of anaplastic lymphoma kinase mutations in neuroblastoma
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2013 (English)In: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 6, no 2, p. 373-382Article in journal (Refereed) Published
Abstract [en]

Neuroblastoma is a childhood extracranial solid tumor which is associated with a number of genetic changes. Included in these genetic alterations are mutations in the kinase domain of the Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase (RTK), which have been found in both somatic and familial neuroblastoma. In order to treat patients accordingly required characterisation of these mutations in terms of their response to ALK tyrosine kinase inhibitors (TKIs). Here, we report the identification and characterisation of two novel neuroblastoma ALK mutations (A1099T and 1464STOP) which we have investigated together with several previously reported but uncharacterised ALK mutations (T1087I, D1091N, T1151M, M1166R, F1174I and A1234T). In order to understand the potential role of these ALK mutations in neuroblastoma progression we have employed cell culture based systems together with the model organism Drosophila as a readout for ligand-independent activity. Mutation of ALK at position F1174I generates a gain-of-function receptor capable of activating intracellular targets, such as ERK (extracellular signal regulated kinase) and STAT3 (signal transducer and activator of transcription 3) in a ligand independent manner. Analysis of these previously uncharacterised ALK mutants and comparison with ALK(F1174) mutants suggests that ALK mutations observed in neuroblastoma fall into three classes. These are: (i) gain-of-function ligand independent mutations such as ALK(F1174), (ii) kinase-dead ALK mutants, e.g. ALK(I1250T)(Schonherr et al 2011a) or (iii) ALK mutations which are ligand-dependent in nature. Irrespective of the nature of the observed ALK mutants, in every case the activity of the mutant ALK receptors could be abrogated by the ALK inhibitor crizotinib (PF-02341066, Xalkori), albeit with differing levels of sensitivity.

Place, publisher, year, edition, pages
Cambridge, UK: The Company of Biologists Ltd, 2013
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-61265 (URN)10.1242/dmm.010348 (DOI)000317266500009 ()23104988 (PubMedID)
Available from: 2012-11-07 Created: 2012-11-07 Last updated: 2018-06-08Bibliographically approved
Yamazaki, Y., Schönherr, C., Varshney, G. K., Dogru, M., Hallberg, B. & Palmer, R. H. (2013). Goliath family E3 ligases regulate the recycling endosome pathway via VAMP3 ubiquitylation. EMBO Journal, 32(4), 524-537
Open this publication in new window or tab >>Goliath family E3 ligases regulate the recycling endosome pathway via VAMP3 ubiquitylation
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2013 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 32, no 4, p. 524-537Article in journal (Refereed) Published
Abstract [en]

Diverse cellular processes depend on endocytosis, intracellular vesicle trafficking, sorting and exocytosis, processes regulated post-transcriptionally by modifications such as phosphorylation and ubiquitylation. In addition to sorting to the lysosome, cargo is recycled to the plasma membrane via recycling endosomes. Here, we describe a role of the goliath gene family of protease-associated (PA) domain E3 ligases in regulating recycling endosome trafficking. The two Drosophila members of this family-Goliath and Godzilla(CG10277) - are located on endosomes, and both ectopic expression and loss-of-function lead to the accumulation of Rab5-positive giant endosomes. Furthermore, the human homologue RNF167 exhibits similar behaviour. We show that the soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE) protein VAMP3 is a target of these ubiquitin ligases, and that recycling endosome trafficking is abrogated in response to their activity. Furthermore, mutation of the Godzilla ubiquitylation target lysines on VAMP3 abrogates the formation of enlarged endosomes induced by either Godzilla or RNF167. Thus, Goliath ubiquitin ligases play a novel role in regulating recycling endosome trafficking via ubiquitylation of the VAMP3 SNARE protein.

Place, publisher, year, edition, pages
Nature Publishing Group, 2013
Keywords
E3 ubiquitin ligase, goliath, RING domain, SNARE, VAMP3
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-68487 (URN)10.1038/emboj.2013.1 (DOI)000316467200006 ()
Available from: 2013-04-26 Created: 2013-04-22 Last updated: 2018-06-08Bibliographically approved
Popichenko, D., Hugosson, F., Sjögren, C., Dogru, M., Yamazaki, Y., Wolfstetter, G., . . . Palmer, R. H. (2013). Jeb/Alk signalling regulates the Lame duck GLI family transcription factor in the Drosophila visceral mesoderm. Development, 140(15), 3156-3166
Open this publication in new window or tab >>Jeb/Alk signalling regulates the Lame duck GLI family transcription factor in the Drosophila visceral mesoderm
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2013 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 140, no 15, p. 3156-3166Article in journal (Refereed) Published
Abstract [en]

The Jelly belly (Jeb)/Anaplastic Lymphoma Kinase (Alk) signalling pathway regulates myoblast fusion in the circular visceral mesoderm (VM) of Drosophila embryos via specification of founder cells. However, only a limited number of target molecules for this pathway are described. We have investigated the role of the Lame Duck (Lmd) transcription factor in VM development in relationship to Jeb/Alk signal transduction. We show that Alk signalling negatively regulates Lmd activity post-transcriptionally through the MEK/MAPK (ERK) cascade resulting in a relocalisation of Lmd protein from the nucleus to cytoplasm. It has previously been shown that downregulation of Lmd protein is necessary for the correct specification of founder cells. In the visceral mesoderm of lmd mutant embryos, fusion-competent myoblasts seem to be converted to 'founder-like' cells that are still able to build a gut musculature even in the absence of fusion. The ability of Alk signalling to downregulate Lmd protein requires the N-terminal 140 amino acids, as a Lmd(141-866) mutant remains nuclear in the presence of active ALK and is able to drive robust expression of the Lmd downstream target Vrp1 in the developing VM. Our results suggest that Lmd is a target of Jeb/Alk signalling in the VM of Drosophila embryos.

Keywords
Lmd, Alk, Jeb, Drosophila, Visceral muscle, Founder cell, Fusion competent myoblast
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-79229 (URN)10.1242/dev.094466 (DOI)000321864900009 ()
Available from: 2013-09-16 Created: 2013-08-13 Last updated: 2018-06-08Bibliographically approved
Hallberg, B. & Palmer, R. H. (2013). Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology. Nature Reviews. Cancer, 13(10), 685-700
Open this publication in new window or tab >>Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology
2013 (English)In: Nature Reviews. Cancer, ISSN 1474-175X, E-ISSN 1474-1768, ISSN 1474-1768, Vol. 13, no 10, p. 685-700Article in journal (Refereed) Published
Abstract [en]

The burgeoning field of anaplastic lymphoma kinase (ALK) in cancer encompasses many cancer types, from very rare cancers to the more prevalent non-small-cell lung cancer (NSCLC). The common activation of ALK has led to the use of the ALK tyrosine kinase inhibitor (TKI) crizotinib in a range of patient populations and to the rapid development of second-generation drugs targeting ALK. In this Review, we discuss our current understanding of ALK function in human cancer and the implications for tumour treatment.

Place, publisher, year, edition, pages
Nature Publishing Group, 2013
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-81089 (URN)10.1038/nrc3580 (DOI)000324866100008 ()24060861 (PubMedID)
Funder
Swedish Cancer Society, 12-0722, 12-0796Swedish Research Council, 621-2011-5181, 521-2012-2831
Available from: 2013-10-02 Created: 2013-10-02 Last updated: 2018-06-08Bibliographically approved
Sattu, K., Hochgräfe, F., Wu, J., Umapathy, G., Schönherr, C., Ruuth, K., . . . Hallberg, B. (2013). Phosphoproteomic analysis of anaplastic lymphoma kinase (ALK) downstream signaling pathways identifies signal transducer and activator of transcription 3 as a functional target of activated ALK in neuroblastoma cells. Paper presented at 6th Garvan Signalling Symposium, 2012. The FEBS Journal, 280(21), 5269-5282
Open this publication in new window or tab >>Phosphoproteomic analysis of anaplastic lymphoma kinase (ALK) downstream signaling pathways identifies signal transducer and activator of transcription 3 as a functional target of activated ALK in neuroblastoma cells
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2013 (English)In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 280, no 21, p. 5269-5282Article in journal (Refereed) Published
Abstract [en]

Activation of the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is a key oncogenic mechanism in a growing number of tumor types. In the majority of cases, ALK is activated by fusion with a dimerizing partner protein as a result of chromosomal translocation events, most studied in the case of the nucleophosmin-ALK and echinoderm microtubule-associated protein-like 4-ALK oncoproteins. It is now also appreciated that the full-length ALK receptor can be activated by point mutations and by deletions within the extracellular domain, such as those observed in neuroblastoma. Several studies have employed phosphoproteomics approaches to find substrates of ALK fusion proteins. In this study, we used MS-based phosphotyrosine profiling to characterize phosphotyrosine signaling events associated with the full-length ALK receptor. A number of previously identified and novel targets were identified. One of these, signal transducer and activator of transcription 3 (STAT3), has previously been observed to be activated in response to oncogenic ALK signaling, but the significance of this in signaling from the full-length ALK receptor has not been explored further. We show here that activated ALK robustly activates STAT3 on Tyr705 in a number of independent neuroblastoma cell lines. Furthermore, knockdown of STAT3 by RNA interference resulted in a reduction in myelocytomatosis neuroblastom (MYCN) protein levels downstream of ALK signaling. These observations, together with a decreased level of MYCN and inhibition of neuroblastoma cell growth in the presence of STAT3 inhibitors, suggest that activation of STAT3 is important for ALK signaling activity in neuroblastoma.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2013
Keywords
anaplastic lymphoma kinase, cancer, neuroblastoma, SHP-2, signal transducer and activator of transcription 3 (STAT3)
National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-81092 (URN)10.1111/febs.12453 (DOI)000328622200027 ()23889739 (PubMedID)
Conference
6th Garvan Signalling Symposium, 2012
Funder
Swedish Cancer Society, 12-0722, 120796Swedish Research Council, 621-2011-5181, 521-2012-2831
Note

Special Issue: Frontiers in Cell Signalling, and Ca2+-Signalling and Transport in Health and Disease

Available from: 2013-10-02 Created: 2013-10-02 Last updated: 2018-06-08Bibliographically approved
Palmer, R., Johansson, M. & Hallberg, B. (2012). ALK inblandad i många cancerformer. Onkologi i Sverige : tidningen för svensk cancervård (2), 70-78
Open this publication in new window or tab >>ALK inblandad i många cancerformer
2012 (Swedish)In: Onkologi i Sverige : tidningen för svensk cancervård, ISSN 1653-1582, no 2, p. 70-78Article in journal (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-55797 (URN)
Available from: 2012-11-07 Created: 2012-05-31 Last updated: 2018-06-08Bibliographically approved
Schönherr, C., Ruuth, K., Kamaraj, S., Wang, C.-L., Yang, H.-L., Combaret, V., . . . Hallberg, B. (2012). Anaplastic Lymphoma Kinase (ALK) regulates initiation of transcription of MYCN in neuroblastoma cells. Oncogene, 31(50), 5193-5200
Open this publication in new window or tab >>Anaplastic Lymphoma Kinase (ALK) regulates initiation of transcription of MYCN in neuroblastoma cells
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2012 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 31, no 50, p. 5193-5200Article in journal (Refereed) Published
Abstract [en]

Neuroblastoma is a neural crest-derived embryonal tumour of the postganglionic sympathetic nervous system and a disease with several different chromosomal gains and losses, which include MYCN-amplified neuroblastoma on chromosome 2, deletions of parts of the chromosomes 1p and 11q, gain of parts of 17q and triploidy. Recently, activating mutations of the ALK (Anaplastic Lymphoma Kinase) RTK (Receptor Tyrosine Kinase) gene have been described in neuroblastoma. A meta-analysis of neuroblastoma cases revealed that ALK mutations (49 of 709 cases) in relation to genomic subtype were most frequently observed in MYCN amplified tumours (8.9%), correlating with a poor clinical outcome. MYCN proteins target proliferation and apoptotic pathways, and have an important role in the progression of neuroblastoma. Here, we show that both wild-type and gain-of-function mutants in ALK are able to stimulate transcription at the MYCN promoter and initiate mRNA transcription of the MYCN gene in both neuronal and neuroblastoma cell lines. Further, this stimulation of MYCN gene transcription and de novo MYCN protein expression is abrogated by specific ALK inhibitors, such as crizotinib (PF-2341066), NVP-TAE684, and by small interfering RNA to ALK resulting in a decrease in proliferation rate. Finally, co-transfection of ALK gain-of-function mutations together with MYCN leads to an increase in transformation potential. Taken together, our results indicate that ALK signalling regulates initiation of transcription of the MYCN gene providing a possible explanation for the poor clinical outcome observed when MYCN is amplified together with activated ALK.Oncogene advance online publication, 30 January 2012; doi:10.1038/onc.2012.12.

National Category
Cell and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-53961 (URN)10.1038/onc.2012.12 (DOI)22286764 (PubMedID)
Available from: 2012-04-10 Created: 2012-04-10 Last updated: 2018-06-08Bibliographically approved
Schonherr, C., Hallberg, B. & Palmer, R. (2012). Anaplastic lymphoma kinase in human cancer. Critical reviews in oncogenesis, 17(2), 123-143
Open this publication in new window or tab >>Anaplastic lymphoma kinase in human cancer
2012 (English)In: Critical reviews in oncogenesis, ISSN 0893-9675, E-ISSN 2162-6448, Vol. 17, no 2, p. 123-143Article in journal (Refereed) Published
Abstract [en]

The anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is now implicated in a wide range of human cancers. Results from recent clinical trials with ALK inhibitors provide promise for patients harboring oncogenic ALK lesions. This review will discuss our current understanding of ALK in human cancer and the implication of recent results for treatment.

Keywords
ALK, NSCLC, neuroblastoma, inhibitors, receptor tyrosine kinases, oncogene
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-55158 (URN)22471704 (PubMedID)
Available from: 2012-06-01 Created: 2012-05-09 Last updated: 2018-06-08Bibliographically approved
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