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Dissecting the role of histone deacetylases 1, 2, and 6 in Eμ-myc driven B cell lymphoma

Pillonel, Vincent. Dissecting the role of histone deacetylases 1, 2, and 6 in Eμ-myc driven B cell lymphoma. 2016, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_11979

Abstract

Histone deacetylases (Hdacs) belong to a family of 18 enzymes which removes acetylation marks on lysine residues of histone and non-histone proteins (Reichert et al.,2012). Hdacs were shown to play an important roles in cancer and are attractive pharmacological targets for cancer therapy(Haery et al., 2015). HDAC inhibitors (HDACis) have potent antitumor activity in hematological and solid malignancies, mainly by inducing apoptosis, inhibiting cell cycle progression and cellular differentiation (Falkenberg and Johnstone, 2014; West and Johnstone,2014). Previous works on classI Hdac1 and Hdac2, as well as classII Hdac6, showed that they play important roles in several cancer settings, including B cell malignancies (Haery et al., 2015; Seidel et al., 2015). However, Hdac1 and Hdac2 (Santoro et al., 2013), but also Hdac6 (Seidel et al., 2015), were shown to have contradicting tumor promoting and tumor suppressive roles in cancer. Despite improved knowledge in Hdac cancer research, the exact role of Hdac1, Hdac2, and Hdac6 in cancer remain largely unexplored. During my PhD thesis I investigated the functional role of Hdac1, Hdac2, and Hdac6 in the Eμ-myc model of B cell lymphoma.
The first, and main part of my thesis work is the study of the functional role of classII Hdac1 and Hdac2 in the Eμ-myc mouse model of B cell lymphoma. We found, that Hdac1 and Hdac2 have a pro-oncogenic roles in both, Eμ-myc tumorigenesis and tumor maintenance. In this study, we reveal for the first time in the Eμ-myc model, that Hdac1 and Hdac2 promote tumorigenesis in a gene dose-dependent manner, with a dominant function of Hdac1. Our findings raise the prospect of using selective HDAC1 (and HDAC2) inhibitors in clinics for the treatment of BL and other B cell lymphomas with Myc deregulation. The results of this work are presented in the form of a publication manuscript: “Histone deacetylase 1 plays a predominant role in Eμ-myc driven B cell lymphoma” (Pillonel et al., Accepted for publication in Scientific Reports).
The second part of my thesis adresses the functional role of Hdac1 and Hdac2 in B cell development. This work was done in collaboration with R.M. Heideman. We could confirm our previous findings that Hdac1 and Hdac2 regulate B cell development in a gene dose-dependent manner, with a dominant function of Hdac1. We show, that Hdac1Δ/Δ;Hdac2Δ/+ mice have abnormal early B cell development. Further preliminary findings provide an insight into the role of Hdac1 and Hdac2 in B cell development, and suggests possible defects in V(D)J recombination.
In the last part of my thesis, I focus on the cytoplasmic classII Hdac6. We dissected the role of Hdac6 in Eμ-myc driven B cell lymphoma. We found, that Hdac6 overexpression accelerates lymphomagenesis, whereas Hdac6 knockout in the germ line may delay tumor development in Eμ-myc mice.
Advisors:Matthias, Patrick and Schwaller, Jürg
Faculties and Departments:09 Associated Institutions > Friedrich Miescher Institut FMI > Transcriptional and epigenetic networks and function of histone deacetylases in mammals (Matthias)
Item Type:Thesis
Thesis no:11979
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (250 Seiten)
Language:English
Identification Number:
Last Modified:28 Dec 2016 11:57
Deposited On:28 Dec 2016 11:56

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