Dissecting mechanisms of tumorigenic chromosome translocations
1 PhD project offered in the IPP summer call 2019
Chromosome fusions are hallmark of cancer cells and often play direct roles in the initial steps of tumorigenesis. Since the discovery of the Philadelphia chromosome (the BCR-ABL fusion) as the prototypical rearrangement directly leading to carcinogenesis, several hundreds of different oncogenic fusions have been identified. Although the pathological relevance of these translocations in cancer is now well established, how these translocations form in the context of the intact cell nucleus is only poorly understood. In our lab we are interested to understand which the molecular features that define recurrent chromosome breakpoints are and to shed light to the DNA repair mechanisms that mediate the chromosome fusions. We are also interested to identify novel factors that favor interchromosomal fusions (translocations) over intrachromosomal repair. We are employing a combination of molecular biology techniques, genetics, high-throughput imaging and sequencing approaches to address these questions.
PhD Project proposal: Elucidating mechanisms of oncogenic therapy-related translocations
A major problem in chemotherapy today is the occurrence of second primary cancers which arise as response to treatment for a primary tumor. Therapy-induced acute myeloid leukemias (t-AML) develop after treatment of primary cancers with topoisomerase-inhibitors and are often characterized by only one chromosome abnormality involving a translocation of the mixed lineage leukemia locus (MLL). Recurrent MLL translocation hot spots fuse with several different genes and patients carrying these translocations develop acute myeloid leukemia (AML) with very short latency and poor prognosis.
Due to difficulties in modeling the formation of these translocations in vivo very little is known about the molecular mechanisms governing the formation of these cancerous translocations. We have recently established in the lab an imaging-based approach to probe and quantify the formation of these rare events in response to treatment with topoisomerase inhibitors. We are currently using this methodology in combination with high-throughput sequencing techniques to shed light to the molecular pathways that contribute to the formation of these translocations in vivo. We would like to understand (1) what determines the localization of the recurrent breakpoints found in patients with t-AML, (2) which is the molecular basis of the different localization compared to de novo, non-therapy related MLL translocations, (3) which is the role of the various topoisomerase isoforms as well as the potential role of transcription & replication in MLL susceptibility to breakage and translocation formation and (4) which DNA repair pathways are involved in the formation of these translocations. Understanding the molecular mechanisms that facilitate the formation of these specific translocations has a great potential for identification of drugs that minimize their occurrence.
Publications relevant to this project:
Piccino R, Cipinska M and Roukos V. Studies of the DNA damage response by using the Lac operator/repressor (LacO/LacR) tethering system. Methods Mol Biol, in press
Roukos V#, Pegoraro G, Voss TC and Misteli T# (2015). Cell-cycle staging of individual cells by fluorescence microscopy. Nat Protoc, 10: 334-348
Roukos V# and Misteli T# (2014). The biogenesis of chromosome translocations. Nat Cell Biol, 4: 293-300
Roukos V, Voss TC, Schmidt CK, Lee S, Wangsa D and Misteli T (2013). Spatial dynamics of chromosome translocations in living cells. Science, 341: 660-664
(# indicates joint correspodance)