Defeating Recurrence and resistance in AML:Multigenomic Approaches to analyse heterogeneity
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.
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.
Resistance to treatment might be associated to the selection of rare tumor cells harboring specific DNA mutations (relapse-specific mutations) that cause resistance to drugs. The alternative and/or complementary possibility is that alterations of the “epigenome” (the complex set of proteins that help to package and use DNA within the cell nucleus) are involved in the determination of resistance to drugs. DRAMA aimed to test whether drug resistance in AML is the result of mutations in DNA and/or in the epigenome.
Overall, our results lead us to propose that drug resistance emerges as the consequence of both genetic and epigenetic alterations, and that -though recurrent pathways associated and functionally involved in resistance can be identified- intrinsic features of each individual leukemia shape the molecular path to resistance. Thus, this study has enabled us to identify candidate markers predicting either cure or relapse after treatment, to be tested in clinical trials.
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This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 964264.