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A novel transgenic mouse model for somatic gene delivery to B lymphocytes
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). (Jonas Nilsson)
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). (Jonas Nilsson)
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). (Jonas Nilsson)
(English)Manuscript (preprint) (Other academic)
Keyword [en]
Transgenic mouse model
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-46529OAI: oai:DiVA.org:umu-46529DiVA: diva2:438695
Available from: 2011-09-05 Created: 2011-09-05 Last updated: 2011-09-06Bibliographically approved
In thesis
1. Assessment of therapeutic targets in experimental models of Myc-induced lymphoma
Open this publication in new window or tab >>Assessment of therapeutic targets in experimental models of Myc-induced lymphoma
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The Myc transcription factor activates expression of genes that promote cellular functions such as proliferation and cell growth. The deregulated Myc expression, characteristic for the tumor cell, also activates apoptosis, which selects for additional genetic changes deactivating the induced cell death. However, the continuous overexpression of Myc can also be a liability for a tumor, which can be taken advantage of in cancer treatment.  In Paper I, we describe a new way of using the DNA methyltransferase inhibitor Decitabine, in treating Myc overexpressing tumors. We show that Decitabine treatment activates cell death by reactivating silenced tumor suppressors such as Puma, but also by inducing DNA damage. Decitabine treatment of Myc driven lymphomas is also shown to prolong disease free survival in mouse models. Myc driven transformation requires a collaborative deregulation of genes. The family of Pim kinases has been shown to collaborate with Myc in tumorigenesis. In Paper II, we show that the Pim-3 kinase protein is highly expressed in many Myc overexpressing lymphomas from Myc transgenic mice as well as human Burkitt Lymphoma samples. The Pim-3 locus is shown to interact with the Myc protein and be a direct target for Myc activated transcription. Additionally, we demonstrate that the Pim kinase inhibitor, Pimi, targeting the Pim kinase family (Pim-1, Pim-2 and Pim-3), induce a cell death that is mediated by, but not dependent on caspase activity. The Pimi induced cell death was potentiated when combined with RNAi knockdown of the casein kinase II (CK2) protein.  In paper III, we describe the development of a somatic mouse model for lymphomagenesis, utilizing the RCAS-tva technology. We show that primary B cells from these mice are transducible and transformed when infected with a combination of RCAS- HA tagged Myc, KRasV12D and human Bcl-XL virus. In conclusion, we show that the labile milieu created by the deregulated expression of Myc facilitates new approaches in treatment of Myc overexpressing tumors. Also, our new tva mouse model show promise in modeling lymphomagenesis.

Place, publisher, year, edition, pages
Umeå: Umeå University, Department of Molecular Biology, 2011. 123 p.
Keyword
Cancer, Myc, Decitabine, Pim kinase, RCAS-tva
National Category
Neurosciences
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-46534 (URN)978-91-7459-283-2 (ISBN)
Public defence
2011-09-28, Major Groove, Building 6L, Umeå University, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2011-09-07 Created: 2011-09-05 Last updated: 2011-09-26Bibliographically approved

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CiteExportLink to record
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Citation style
  • apa
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  • Other style
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