Abstract 4206: Impact of nuclear telomere architecture in the transition of myelodysplastic syndromes to acute myeloid leukemias.

Abstract

Abstract Myelodysplastic Syndromes (MDS) are a group of disorders characterized by cytopenias, with a propensity for evolution into Acute Myeloid Leukemias (AML). This transformation is driven by genomic instability and epigenetic events. However, how genomic instability occurs in this disease remains unknown. Telomere dysfunction might be the generator of genomic instability leading to cytopenias and disease progression. Despite several studies demonstrating the role of telomere dysfunction in the occurrence of hematopoietic malignancies, little is known about their role in the evolution of MDS to AML/MDS. Our preliminary data allowed us to define three-dimensional nuclear telomeric profiles on the basis of telomere numbers, telomeric aggregates, telomere signal intensities, nuclear volumes, and nuclear telomere distribution. Using these parameters, we blindly subdivided the MDS patients into nine subgroups and the AML patients into six subgroups. We showed distinct telomeric profiles specific to patients with MDS, AML, and suggested for the first time a chronological and evolutionary process of telomere dysfunction in both diseases and the transformation of MDS to AML. To validate the clinical significance of 3D telomere profiling of MDS-patients and AML-patients, we are studying new patient cohorts and patients progressing from MDS to AML over time. Such a longitudinal study will allow for precise 3D telomeric profiling during disease progression. Since transformation of MDS to AML can occur over a long period of time, we are also studying disease progression from MDS to AML using a mouse model (C57BL/6-Tg(Vava1-NUP98/HOXD13)G2Apla/J). These mice will transform their MDS-disease to AML disease in a time period of in between 4-14 months. Therefore, we are following the mice monthly up to 14 months. Our study will allow us to gain an understanding of the 3D telomeric signatures that predict and accompany the transition of MDS to AML. In addition, we will define the molecular profiles at disease transition to improve, once validated, treatment strategies for patients with MDS/AML. Citation Format: Macoura Gadji, Fábio Morato de Oliveira, Sabine Mai. Impact of nuclear telomere architecture in the transition of myelodysplastic syndromes to acute myeloid leukemias. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4206. doi:10.1158/1538-7445.AM2013-4206