umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Assessment of therapeutic targets in experimental models of Myc-induced lymphoma
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). (Jonas Nilsson)
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 [en]
Cancer, Myc, Decitabine, Pim kinase, RCAS-tva
National Category
Neurosciences
Research subject
Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-46534ISBN: 978-91-7459-283-2 (print)OAI: oai:DiVA.org:umu-46534DiVA: diva2:438885
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
List of papers
1. Myc sensitizes p53-deficient cancer cells to the DNA-damaging effects of the DNA methyltransferase inhibitor decitabine
Open this publication in new window or tab >>Myc sensitizes p53-deficient cancer cells to the DNA-damaging effects of the DNA methyltransferase inhibitor decitabine
Show others...
2009 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 113, no 18, 4281-4288 p.Article in journal (Refereed) Published
Abstract [en]

Decitabine (also referred to as 5-aza-2'-deoxycytidine) is a drug that has recently been approved by the Food and Drug Administration (FDA) for the treatment of myelodysplastic syndrome (MDS). The mechanism of action is believed to be the blocking of DNA methylation and thereby reactivating silenced genes involved in harnessing MDS. When analyzing reactivation of genes involved in Burkitt lymphoma (BL), we discovered that decitabine also sensitizes tumor cells by inducing DNA damage. This sensitization is grossly augmented by the MYC oncogene, which is overexpressed in BL, and occurs in cells lacking a functional p53 tumor suppressor pathway. In p53-deficient BL cells and p53(-/-) mouse embryo fibroblasts, Myc overrides a transient G2-block exerted by decitabine via activation of Chk1. This triggers aneuploidy and cell death that correlates with, but can occur in the absence of, Epstein-Barr virus (EBV) reactivation, caspase activation, and/or expression of the BH3-only protein Puma. In vivo modeling of Myc-induced lymphoma suggests that decitabine constitutes a potential new drug against lymphoma that would selectively sensitize tumor cells but spare normal tissue.

Place, publisher, year, edition, pages
The American Society of Hematology, 2009
Keyword
Myc
National Category
Cell and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-44268 (URN)10.1182/blood-2008-10-183475 (DOI)
Available from: 2011-05-30 Created: 2011-05-30 Last updated: 2017-12-11Bibliographically approved
2. The direct Myc target Pim3 cooperates with other Pim kinases in supporting viability of Myc-induced B-cell lymphomas
Open this publication in new window or tab >>The direct Myc target Pim3 cooperates with other Pim kinases in supporting viability of Myc-induced B-cell lymphomas
Show others...
2011 (English)In: Oncotarget, ISSN 1949-2553, Vol. 2, no 6, 448-460 p.Article in journal (Refereed) Published
Abstract [en]

The Pim kinases are weak oncogenes. However, when co-expressed with a strong oncogene, such as c-Myc, Pim kinases potentiate the oncogenic effect resulting in an acceleration of tumorigenesis. In this study we show that the least studied Pim kinase, Pim-3, is encoded by a gene directly regulated by c-Myc via binding to one of the conserved E-boxes within the Pim3 gene. Accordingly, lymphomas arising in Myc-transgenic mice and Burkitt lymphoma cell lines exhibit elevated levels of Pim-3. Interestingly, inhibition of Pim kinases by a novel pan-Pim kinase inhibitor, Pimi, in Myc-induced lymphoma results in cell death that appears independent of caspases. The data indicate that Pim kinase inhibition could be a viable treatment strategy in certain human lymphomas that rely on Pim-3 kinase expression.

Place, publisher, year, edition, pages
Albany, N.Y.: Impact Journals, 2011
National Category
Biochemistry 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-46326 (URN)10.18632/oncotarget.283 (DOI)000293510200005 ()21646687 (PubMedID)
Available from: 2011-08-30 Created: 2011-08-30 Last updated: 2017-01-17Bibliographically approved
3. A novel transgenic mouse model for somatic gene delivery to B lymphocytes
Open this publication in new window or tab >>A novel transgenic mouse model for somatic gene delivery to B lymphocytes
(English)Manuscript (preprint) (Other academic)
Keyword
Transgenic mouse model
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-46529 (URN)
Available from: 2011-09-05 Created: 2011-09-05 Last updated: 2011-09-06Bibliographically approved

Open Access in DiVA

Doctoral thesis L Plym Forshell(2083 kB)796 downloads
File information
File name FULLTEXT01.pdfFile size 2083 kBChecksum SHA-512
568ffcebef5d3253cba7994e49c16a100108eac7164b7c39ea6ce9e60a9ca9465ae0249a654feb68009ecd03b5acf86f263db7a843b647dd3bdc3aed8a31a31a
Type fulltextMimetype application/pdf

Search in DiVA

By author/editor
Plym Forshell, Linus
By organisation
Department of Molecular Biology (Faculty of Science and Technology)
Neurosciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 796 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 187 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf