Ludwig DPhil Studentship - Molecular mechanisms of action and basis of resistance to hypomethylating agents in cancer
A DPhil project available with Stefan Constantinescu and Skirmantas Kriaucionis, Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford
The student will be supervised by two supervisors. Prof Skirmantas Kriaucionis’ research group aims to elucidate the molecular function of DNA modifications in normal cells, leading to the understanding of how defective pathways contribute to neoplasia. Prof Constantinescu’s group at Ludwig Oxford studies the link between signalling, epigenetic regulators, chromatin dynamics and differentiation in myeloid blood cancers.
Secondary acute myeloid leukemia (AML) is a very severe malignant condition with negative prognosis at the moment. It is defined as AML occurring in patients that previously suffered from chronic blood cancers such as myeloproliferative neoplasms or myelodysplastic syndromes, and overlaps with aged individuals’ AML and AML occurring in patients previously treated with chemotherapy or radiation for other cancers. Many (30%) of such secondary AMLs carry mutations in TP53, and others overexpress proteins that inhibit p53 function. Classical chemotherapy used in de novo AML fails to induce remission and recently it has been shown that hypomethylating agents such as 5-azacytidine or decitabine can induce remissions but the overall survival is reduced due to relapse 5-7 months after treatment.
In this project cell lines and model organisms will be used to dissect the mode of action and especially resistance mechanisms to hypomethylating agents currently employed in the clinic. The student will be trained in modern techniques to map methylated cytosines using massively parallel sequencing (TAPS); cell culture techniques; gene expression interrogation using RNA-seq; working with model organisms and hematopoietic cell lines; and small molecule mass-spectrometry.
- Distinct contributions of DNA methylation and histone acetylation to the genomic occupancy of transcription factors. Cusack M, King HW, Spingardi P, Kessler BM, Klose RJ, Kriaucionis S. Genome Res. 2020 Oct;30(10):1393-1406. doi: 10.1101/gr.257576.119.
- The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Kriaucionis S, Heintz N. Science. 2009 May 15;324(5929):929-30. doi: 10.1126/science.1169786. Epub 2009 Apr 16.
- Orientation-specific signalling by thrombopoietin receptor dimers. Staerk J, Defour JP, Pecquet C, Leroy E, Antoine-Poirel H, Brett I, Itaya M, Smith SO, Vainchenker W, Constantinescu SN.EMBO J. 2011 Sep 2;30(21):4398-413. doi: 10.1038/emboj.2011.315.
- Persistent STAT5 activation in myeloid neoplasms recruits p53 into gene regulation. Girardot M, Pecquet C, Chachoua I, Van Hees J, Guibert S, Ferrant A, Knoops L, Baxter EJ, Beer PA, Giraudier S, Moriggl R, Vainchenker W, Green AR, Constantinescu SN.Oncogene. 2015 Mar 5;34(10):1323-32. doi: 10.1038/onc.2014.60. Epub 2014 Mar 31.
- Mechanisms of progression of myeloid preleukemia to transformed myeloid leukemia in children with down syndrome. Labuhn M, Perkins K, Matzk S, Varghese L, Garnett C, Papaemmanuil E, Metzner M, Kennedy A, Amstislavskiy V, Risch T, Bhayadia R, Samulowski D, Hernandez DC, Stoilova B, Iotchkova V, Oppermann U, Scheer C, Yoshida K, Schwarzer A, Taub JW, Crispino JD, Weiss MJ, Hayashi Y, Taga T, Ito E, Ogawa S, Reinhardt D, Yaspo ML, Campbell PJ, Roberts I, Constantinescu SN, Vyas P, Heckl D, Klusmann JH.Cancer Cell. 2019 Aug 12;36(2):123-138.e10. doi: 10.1016/j.ccell.2019.06.007. Epub 2019 Jul 11.