Research Projects

An epigenomic approach to study resistance and recurrence in acute myeloid leukemia

IEO — European Institute of Oncology

Milan

Italy

12/13

Supervision

Saverio Minucci
IEO, 1st Supervisor

Genevieve Almouzni
Institut Curie, 2nd Supervisor

Objectives

Although standard chemotherapy induces disease remission in the majority of Acute Myeloid Leukemia (AML) patients, most of them relapse and eventually die since they do not respond to therapy anymore. Therefore, there is an urgent medical need to identify disease markers predicting relapse or response to treatment.
Currently, resistance to treatment is associated mainly to the selection of rare tumor cells harboring specific DNA mutations (relapse-specific mutations) that cause resistance to drugs. More recently, however, a complementary possibility emerged, that envisions alterations of the “epigenome” as involved in the determination of resistance to drugs. Initial findings hint at the possibility that those alterations exist, and they affect the genome architecture both locally and at a more global level.
This project aims to explore drug resistance in AML as the result of functional alterations in the epigenome, and to analyze both local and global changes in the epigenome. The initial discovery phase will be followed by a validation phase to assess the functional significance of the epigenetic alterations identified. This study will enable identifying markers predicting cure or relapse after treatment, ready to be tested in clinical trials.

Methodology

Expected Results

Identification of drug resistance associated epigenetic alterations in AMLs

Planned Secondments

CRG, Spain (2x 1 month):
Computational analyses and functional studies.
CURIE, France (1 month):
Preliminary characterisation of histone H3.3 spatial organisation in AML samples.
ELISAVA, Spain (2 weeks):
Learning new design features to represent AM drug resistance.

Enrolment in doctoral programs

PhD in Systems Medicine (curriculum of Molecular Oncology) from University of Milan

References

Santoro F, Botrugno OA, Dal Zuffo R, Pallavicini I, Matthews GM, Cluse L, Barozzi I, Senese S, Fornasari L, Moretti S, Altucci S, Pelicci PG, Chiocca S, Johnstone RW, Minucci S (2013). A dual role for Hdac1: oncosuppressor in tumorigenesis, oncogene in tumor maintenance. Blood. 2013 Apr 25; vol. 121(17): p. 3459-3468. doi: 10.1182/blood-2012-10-461988. Epub 2013 Feb 25.

Magnani L, Frigè G, Gadaleta RM, Corleone G, Fabris S, Kempe H, Verschure PJ, Barozzi I, Vircillo V, Hong SP, Perone Y, Saini M, Trumpp A, Viale G, Neri A, Ali S, Colleoni MA, Pruneri G, Minucci S. Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ERα metastatic breast cancer. Nat Genet. 2017 Mar;49(3):444-450. doi: 10.1038/ng.3773. Epub 2017 Jan 23.

Helin K and Minucci S. The Role of Chromatin-Associated Proteins in Cancer. Annual Review of Cancer Biology Vol. 1:355-377 (Volume publication date March 2017) doi: 10.1146/annurev-cancerbio-050216-034422.