Page 132 - CIBERER-2015-eng

Research Groups
Group U749
Programme: Inherited Cancer, Haematological & Dermatological Diseases Lead Researcher: Fernández Piqueras, José
Group members
STAFF MEMBERS: Cobos Fernández, María de los Ángeles | González Sánchez, Laura. ASSOCIATED MEMBERS: Santos Hernández, Javier | Villa Morales, María.
Main lines of research
An integrated genomic and epigenomic view of intra- tumor heterogeneity during the evolution of precursor T-cell lymphoblastic neoplasms in the context of a precision and individualized medicine
Precursor T-cell lymphoblastic neoplasms are aggres- sive haematological malignancies, which mainly de- velop in children but can also affect adults. Most often they manifest with extensive marrow and blood affec- tation (acute T-cell lymphoblastic leukaemia, T-ALL), and less commonly as a mass lesion in the thymus/ anterior mediastinum or in lymph nodes, with less than 25% marrow blasts (T-cell lymphoblastic lympho- ma, T-LBL). As any type of cancer, T-cell lymphoblas- tic neoplasms consist of a very heterogeneous group of diseases characterized by the joint occurrence of genetic and epigenetic alterations, which evolve from the time of diagnosis in the context of intratu- moral heterogeneity as an unavoidable consequence of genetic instability, and may be deeply modified in relapses. In view of this background, our first aim is to assess for intratumoral heterogeneity in selected
series of human T-cell lymphoblastic neoplasms us- ing next generation sequencing (tailored genomic and transcriptomic analyses) and epigenomic approach- es in paired samples at diagnosis and relapse. Since preliminary results evidenced overexpression of sev- eral deaminases of the ADAR and APOBEC families, we are comparing genomic and transcriptomic se- quences to assess for DNA and/or RNA editing. An- other goal is to explain aberrant expression of critical genes. Epigenetic changes at critical regulatory re- gions and deregulation of specific microRNAs may be instrumental in resolving this complex puzzle. Finally, we are performing in vitro and in vivo (with xenotrans- planted mice) preclinical assays in order to reappraise clinical therapeutic strategies.
KEY WORDS: Precursor T-cell lymphoblastic neo- plasms (T-ALL/TLBL). Individualized precision medi- cine. Next-generation sequencing. Intratumoral heter- ogeneity. RNA editing. MicroRNAs. Cancer exosomes. Epigenomic analyses. Signaling pathways. Critical mutations. Aberrant expression.
132 I Annual report 2015 I CIBERER