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Myc-induced Lymphomagenesis: In vivo assessment of downstream pathways
Umeå universitet, Teknisk-naturvetenskaplig fakultet, Molekylärbiologi (Teknisk-naturvetenskaplig fakultet). (Jonas Nilsson)
2010 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)Alternativ titel
Myc-inducerad lymfomutveckling : Utvärdering av målgener in vivo (Svenska)
Abstract [en]

Myc oncogenes encode transcription factors that bind to E-box sequences in DNA, driving the expression of a large number of target genes and are deregulated in approximately 70% of human cancers. Deregulated Myc expression cause enhanced proliferation (which is counteracted by apoptosis), angiogenesis and cancer. Though Myc’s importance in induction of S phase has been established, less is known about its functions in the G2 and M phases of the cell cycle. Paper I addresses the targeting of the Myc targets Aurora kinase A and B that have roles in G2/M transition and provide evidence that pharmaceutical Aurora kinase inhibition causes cell cycle arrest and apoptosis in a Myc-selective manner and is useful in treating Myc-induced lymphomas in vivo.

The assumption that the important target genes responsible for the biological effects of Myc overexpression were those encoding components of the cell cycle machinery lead to little interest in other potentially important groups of target genes. However, recent work challenged this view by indicating that Myc target genes encoding metabolic enzymes may be critical for Myc-induced tumorigenesis. Importantly, the targeting of Myc target genes encoding metabolic enzymes has the potential of providing a new treatment strategy of Myc-induced cancers. Paper II covers the pharmaceutical targeting of the Myc-induced spermidine synthase (Srm) that shows promise as a tool for chemoprevention by affecting proliferation, but not for the treatment of established tumors.

Paper III focuses on the negligible effect an Ldha mutation has on Myc- induced lymphomagenesis. Ldha has long been known to be a Myc target gene and in vitro experiments have recently indicated it to be important for transformation. It seems the negligible effect of the Ldh mutation can be explained by the high frequency of loss of either Arf or p53 in this mouse model, since enforced Ras-Myc oncogenic cooperation in soft agar assays of Ldh mutant MEFs effectively inhibits colony formation, and λ-Myc;Ldh mutant bone marrow infected with oncogenic Ras does not give rise to tumors when transplanted into wild-type mice. A role for Ldh in the ability of tumors to evade the immune system was also indicated in this study. The combined experiences and very different outcome of the three studies included in this thesis draw attention to the value of in vivo assessment of Myc downstream targets in Myc-induced lymphomagenesis.

Ort, förlag, år, upplaga, sidor
2010. , s. 79
Nyckelord [en]
Myc, lymphomagenesis, Aurora kinases, polyamine, glycolysis, targeting, mouse models of cancer
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
molekylärbiologi
Identifikatorer
URN: urn:nbn:se:umu:diva-32093ISBN: 978-91-7264-951-4 (tryckt)OAI: oai:DiVA.org:umu-32093DiVA, id: diva2:300930
Disputation
2010-03-26, Building 6L, Major Groove, Umeå University, Umeå, 10:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2010-03-05 Skapad: 2010-03-01 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
Delarbeten
1. Aurora kinases A and B are Myc targets essential for maintenance of the malignant state
Öppna denna publikation i ny flik eller fönster >>Aurora kinases A and B are Myc targets essential for maintenance of the malignant state
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-32092 (URN)
Tillgänglig från: 2010-03-01 Skapad: 2010-03-01 Senast uppdaterad: 2018-06-08
2. Chemoprevention of B-cell lymphomas by inhibition of the Myc target spermidine synthase
Öppna denna publikation i ny flik eller fönster >>Chemoprevention of B-cell lymphomas by inhibition of the Myc target spermidine synthase
2010 (Engelska)Ingår i: Cancer Prevention Research, ISSN 1940-6207, E-ISSN 1940-6215, Vol. 3, nr 2, s. 140-147Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The oncogenic transcription factor c-Myc (Myc) is frequently overexpressed in human cancers. Myc is known to induce or repress a large set of genes involved in cell growth and proliferation, explaining the selection for mutations in cancer that deregulate Myc expression. Inhibition of ornithine decarboxylase, an enzyme of the polyamine biosynthetic pathway and a Myc target, has been shown to be chemopreventive. In the present study, we have dissected the role of another enzyme in the polyamine biosynthetic pathway, spermidine synthase (Srm), in Myc-induced cancer. We find that Srm is encoded by a Myc target gene containing perfect E-boxes and that it is induced by Myc in a direct manner. RNA interference against Srm shows that it is important for Myc-induced proliferation of mouse fibroblasts but to a lesser extent for transformation. Using the compound trans-4-methylcyclohexylamine, we show that Srm inhibition can delay the onset of B-cell lymphoma development in λ-Myc transgenic mice. We therefore suggest that inhibition of Srm is an additional chemopreventive strategy that warrants further consideration.

Ort, förlag, år, upplaga, sidor
Philadelphia, PA: American Association for Cancer Research, 2010
Nyckelord
Myc, Srm, Odc, polyamines, lymphomagenesis
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-32085 (URN)10.1158/1940-6207.CAPR-09-0166 (DOI)000274247000005 ()2-s2.0-77949715975 (Scopus ID)
Tillgänglig från: 2010-03-01 Skapad: 2010-03-01 Senast uppdaterad: 2023-03-24Bibliografiskt granskad
3. Differential requirement of Ldha in Myc-induced tumorigenesis based on cooperating oncogenic lesion and tumor immunogenicity
Öppna denna publikation i ny flik eller fönster >>Differential requirement of Ldha in Myc-induced tumorigenesis based on cooperating oncogenic lesion and tumor immunogenicity
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-32091 (URN)
Tillgänglig från: 2010-03-01 Skapad: 2010-03-01 Senast uppdaterad: 2018-06-08Bibliografiskt granskad

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