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Myc sensitizes p53-deficient cancer cells to the DNA-damaging effects of the DNA methyltransferase inhibitor decitabine
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).
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
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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. Vol. 113, no 18, 4281-4288 p.
Keyword [en]
Myc
National Category
Cell and Molecular Biology
Research subject
Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-44268DOI: 10.1182/blood-2008-10-183475OAI: oai:DiVA.org:umu-44268DiVA: diva2:419836
Available from: 2011-05-30 Created: 2011-05-30 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Regulation of DNA damage responses by the Myc oncogene: implications for future anti-cancer therapies
Open this publication in new window or tab >>Regulation of DNA damage responses by the Myc oncogene: implications for future anti-cancer therapies
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Myc is a transcription factor frequently found deregulated in human cancer. Cells with deregulated expression of Myc carry a selective advantage against its neighbours due to the fact that Myc-mediated transcription governs crucial cellular events such as proliferation and growth. In addition, Myc has been implicated in several other aspects of tumour biology like cellular immortality, the formation of new blood vessels and the colonization of distant tissues through the process of metastasis. Therapy aimed at disrupting essential pathways regulated by Myc is important because of the many different types of cancers that depend on continued signalling along these pathways.  This thesis describes new treatment opportunities for cancers with a high Myc signature. In Paper Ι, we describe a new role for the DNA methyltransferase inhibitor Decitabine in the treatment of Myc transformed tumours cells. We show that the therapeutic potential of Decitabine in the treatment of Burkitt Lymphoma relies not only on its ability to cause reactivation of silenced genes such as pro-apoptotic PUMA, but also on the DNA damage that this drug induces. In vivo, Decitabine delays disease progression of transplanted lymphoma cells. In Paper ΙΙ, we identify the DNA damage checkpoint kinase Chk1 as a therapeutic target in Myc overexpressing cancers. We show that targeting Chk1 with shRNA or with a novel small molecule inhibitor cause a delay in disease progression of transplanted lymphoma cells in vivo. In Paper ΙΙΙ, the Chk1-related kinase Chk2 is evaluated as a therapeutic target in Myc overexpressing cancers. Myc overexpressing cells are not dependent on Chk2 but we show that Chk2 abrogation using shRNA causes polyploidization and protection against DNA damage. However, Chk2-targeted therapy elicits a synergistic lethal response in combination with inhibition of the DNA repair associated protein PARP. In conclusion, this thesis shows the potential of targeting the DNA damage machinery and the functional hubs important for maintenance of genomic stability in tumours with a deregulated expression of Myc.

Place, publisher, year, edition, pages
Umeå: Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet), Umeå universitet, 2011. 96 p.
Keyword
Myc, DNA damage, Decitabine, Chk1, Chk2
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-44284 (URN)978-91-7459-231-3 (ISBN)
Public defence
2011-09-09, Norrlands universitetssjukhus, våning 9,sal 933, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2011-05-30 Created: 2011-05-30 Last updated: 2011-05-30Bibliographically approved
2. 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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Höglund, AndreasNilsson, Lisa M.Plym Forshell, LinusNilsson, Jonas A.
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