Project: Defeating Recurrence and resistance in AML: Multigenomic Approaches to analyse heterogeneity

Acronym	DRAMA (Reference Number: TRS-2015-00000048)
Duration	01/07/2016 - 01/07/2019
Project Topic	Standard chemotherapy induces disease remission in the majority of Acute Myeloid Leukemia (AML) patients, but most of them relapse within 3-5 years and eventually succumb to the disease. Relapse is assumed to result from residual chemoresistant leukemic cells, and there is a strong medical need to identify disease markers that predict relapse or response to treatment. Next generation sequencing (NGS) studies have started to explore intrinsic and therapy-driven genetic heterogeneity in tumors. These studies have revealed that, in some AML patients, tumor regrowth after chemotherapy is associated with the selection, during treatment, of rare tumor subclones harboring specific DNA mutations (relapse-specific mutations), likely within the rare leukemia stem cell population. Alternatively, chemoresistance might be supported by changes in the structure of chromatin (epimutations), which are either selected (clonal selection) or acquired (adaptive response) during chemotherapy: indeed, recent studies suggest that drug-tolerant states might be partly reversible due to epigenetic alterations in resistant cells. We will test the hypotheses that chemoresistance in AML is the consequence of the selection of rare tumor subclones harboring specific DNA mutations or epimutations, and/or the consequence of epigenome-mediated adaptation of leukemic cells to therapy, aiming at identifying genetic and epigenetic markers that are predictive of cure or relapse after standard treatment. The experimental plan includes: i) combined genomic/epigenomic analyses of pairs of primary/relapsed AML samples to identify a relapse-specific molecular signature and assess its frequency at disease onset (Discovery Phase); ii) validation of the identified molecular signature in a large cohort of primary AMLs patients who have received comparable treatment regimens and careful clinical follow-up (Validation Phase); iii) identification and functional validation of chemoresistance associated gene networks in relapsed AMLs. Key and innovative aspects of this research plan include: i) the design and implementation of NGS and digital PCR- based strategies for the identification of rare mutations and epimutations in primary AMLs; ii) validation pipelines for the assessment of their functional significance/predictive value. This work will culminate –by the end of the proposed Project- in the design of a clinical study aimed at validating our findings in AML patients, and at providing a new approach for the treatment of recurrent and resistant AMLs.
Network	TRANSCAN-2
Call	Joint Transnational Call for Proposals (JTC 2014)

Project partner

Number	Name	Role	Country
1	Istituto Europeo di Oncologia	Coordinator	Italy
2	Istituto Europeo di Oncologia	Partner	Italy
3	Radboud University Nijmegen	Partner	Netherlands
4	Fundacion para la Investigacion del Hospital Universitario La Fe de la Comunidad Valenciana	Partner	Spain
5	INSERM U944, CNRS/UPD UMR 7212,	Partner	France
6	University Hospital Ulm	Partner	Germany