Kranc, Kamil

Forrester, Lesley

Sepúlveda, Catarina

Medical Research Council (MRC)

2018-02-12T16:02:22Z

2018-02-12T16:02:22Z

2017-07-08

The finely tuned regulation of haematopoietic stem and progenitor cells (HSPCs) is crucial to sustain normal haematopoiesis. The disruption of the balance between the quiescence state of haematopoietic stem cells (HSCs) and the proliferation/differentiation programs that are necessary to meet daily haematopoietic demands and respond to external insults, can lead to malignant transformation, such as acute myeloid leukaemia (AML). Therefore, it is essential to investigate the players that are responsible to maintain haematopoietic homeostasis, so that novel therapeutic targets can be identified. HSCs reside in a hypoxic environment that is crucial for their maintenance, as it protects them from over-proliferation and exhaustion. The response to a limited availability of oxygen is critically mediated by a transcription factor - hypoxia inducible factor (HIF). HIF is predominantly regulated by prolyl hydroxylases (PHDs) that are 2-oxoglutarate (2OG) dependent oxygenases. This superfamily of oxygen-sensing enzymes has been assigned important roles ranging from hypoxia signaling, DNA repair, chromatin modifications and oncogenesis Following the data published by our group attesting that HIF is dispensable for HSC survival and maintenance, we focused our investigation on HIF-independent pathways. This manuscript describes the study of the role of an oxygen-sensor enzyme, member of the 2OG oxygenases and HIF negative regulator, jumonji domain-containing protein 6 (Jmjd6), in normal and malignant haematopoiesis. Our knockout studies deleting Jmjd6 specifically within the haematopoietic system (Jmjd6fl/fl;Vav-iCre) demonstrate that the homeostasis of HSPC pool was compromised and lymphopoiesis was attenuated in Jmjd6-deficient cohorts. Upon transplantation, HSCs lacking Jmjd6 exhibited a defective chimerism and impaired capacity to fully reconstitute haematopoiesis of recipient mice. Thus, Jmjd6 is essential for HSC self-renewal and maintenance. Our assessment of the impact of Jmjd6 deletion in the context of inflammatory response and recovery from treatment with a myelotoxic agent treatment revealed that Jmjd6 is a positive regulator of HSC homeostasis and recovery from cytotoxic stress. There are accumulating data on the importance of epigenetics in the development of haematological malignancies. Being an epigenetic regulator, clearly involved in RNA splicing, we investigated Jmjd6 as possible player in leukaemogenesis. The results from our leukaemic studies unravelled a new biological function for Jmjd6 as a tumour suppressor in Meis1/Hoxa9 murine model. Altogether, our findings offer important novel insights into the biological functions of Jmjd6 and pave the way for further studies to discover on the mechanism of action of this complex enzyme. Our observations add value to the idea that Jmjd6 might constitute a good candidate for cancer diagnosis, that can be use to ameliorate patient’s prognosis and that it can be used to help patient prognosis in the future.

http://hdl.handle.net/1842/28742

en

The University of Edinburgh

Vukovic M., Sepulveda C., Subramani C., Guitart A. V., Mohr J., Allen L., Panagopoulou T. I., Paris J., Lawson H., Villacreces A., Armesilla-Diaz A., Gezer D., Holyoake T. L., Ratcliffe P. J. and Kranc K. R. (2016). Adult hematopoietic stem cells lacking Hif-1α self-renew normally. Blood, 127(23), 2841–2846.

Vukovic M., Guitar A. V., Sepulveda C., Villacreces A., O’Duibhir E., Panagopoulou T. I., Alasdair I., Menendez-Gonzalez J., Iglesias J. M., Allen L., Glykofrydis F., Subramani C., Armesilla-Diaz A., Post A. E. M., Schaak K., Gezer D., So C. W. E., Holyoake T. L., Wood A., O’Carroll D., Ratcliffe P. J. and Kranc K. R. (2015). Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance. The Journal of Experimental Medicine, 212(13), 2223–2234.

Guitart, A. V., Subramani, C., Armesilla-Diaz, A., Smith, G., Sepulveda, C., Gezer, D., Vukovic M., Dunn K., Pollard P., Holyoake T. L., Ratcliffe P. J. and Kranc K. R. (2013). Hif-2α is not essential for cell-autonomous hematopoietic stem cell maintenance. Blood, 122(10), 1741–1745.

2027-03-14

Jmjd6

normal haematopoiesis

acute myeloid leukaemia

Role of Jmjd6 in normal and malignant haematopoiesis

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy

Restricted Access