The molecular processes that drive leukemogenesis from senescent bone marrow are largely unknown. The aim of this thesis is to understand the molecular basis of BM senescence in response to DNA damage, and how these steps subsequently contribute to leukemogenesis. Ercc1 deficient mice are deficient in both NER and ICL repair and display signs of premature aging in the BM. Because Ercc1 is involved in the FA pathway of ICL repair we used this model to investigate the molecular mechanisms of BM failure and subsequent leukemogenesis as seen in FA. Important questions in this respect are: (i) Is BM failure specifi c to defective ICL repair, or to the overall aging phenotype (Chapter 2), (ii) what is the influence of Ercc1 levels on senescence in the hematopoietic system (Chapter 3), (iii) which tumor suppressor mechanisms are responsible for BM failure as seen in Ercc1 deficient mice (Chapter 4), and (iv) is the poor response to Epo specific to the lack of Fanconi proteins or secondary to senescence (Chapter 5). Finally, we investigated whether activation of p53 counteracts Wnt signaling (Chapter 6). In order to address these questions we analyzed FA deficient erythroblasts isolated from fetal liver (Chapter 5), compared the phenotypes of Ercc1-/-, Ercc1-/d and Ercc1d/d mice (Chapter 3), generated double knockout mice which lack either the tumor suppressor gene Cdkn2A (p16INK4A/p19Arf) or p53 in an Ercc1 hypomorph background (Chapter 4) and analyzed the effect of the Wnt signaling pathway in primary erythroblasts derived from fetal livers (Chapter 6).

DNA damage, bone marrow failure, hematopoiesis, leukemia
I.P. Touw (Ivo)
Erasmus University Rotterdam
This work was funded by Grant EMCR 2005-3314 from the Dutch Cancer Society “Koningin Wilhelmina Fonds”. Financial support for printing this thesis was kindly given by the Dutch Cancer Society “Koningin Wilhelmina Fonds”, J.E. Jurriaanse Stichting, CaseMaster:EDC – Innovative EDC/eCRF Solutions and Erasmus MC University.
978-94-91602-06-1
hdl.handle.net/1765/38928
Erasmus MC: University Medical Center Rotterdam

Verhagen-Oldenampsen, J.H.E. (2013, February 26). Consequences of Interstrand Crosslinks in Hematopoiesis: Tipping the balance between senescence and proliferation. Erasmus University Rotterdam. Retrieved from http://hdl.handle.net/1765/38928