Abstract A33: Towards validation of three-dimensional nuclear telomeric profiles as a biomarker of myelodysplastic syndromes and acute myeloid leukemias in a mouse model
Authors: Gadji Macoura , Rodrigues Prerana , Mai Sabine 
Published: May 2015

Introduction: Myelodysplastic Syndromes (MDS) are a group of disorders characterized by cytopenias, with a propensity for evolution into Acute Myeloid Leukemias (AML). However, the cellular and molecular mechanisms causing the transition of MDS to AML remain unknown.

Method: Following our published data in human MDS and AML samples1, we are studying the three-dimensional nuclear telomeric profiles based on telomere numbers, telomeric aggregates, telomere signal intensities, nuclear volumes, and nuclear telomere distribution in a unique mouse model that shows progression from MDS to AML “C57BL/6-Tg(Vava1-NUP98/HOXD13)G2Apla/J”2. These hemizygote mice develop MDS with peripheral blood cytopenia and dysplasia and normocellular to hypercellular bone marrow. By 14 months of age, a subset of hemizygotes succumbs to malignant AML or severe anemia and leucopenia. In the last few months, we set up a colony of these mice at MICB/CCMB. The transgenic mice have been bred with C57BL/6NCrL mice. All mice were genotyped and the wild-type littermates are being used as controls.

Results: We have started to sample the mice for this study. In total, we are observing 75 C57BL/6-Tg(Vava1-NUP98/HOXD13)G2Apla/J and 75 C57BL/6NCrL mice. The extra 20 mice (10 C57BL/6-Tg(Vava1-NUP98/HOXD13)G2Apla/J mice and 10 C57BL/6NCrL) will be used as a back – up for replacement of the sudden death of mice over the time of this project. The time points of harvesting are at 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14 months. We already harvested 21 transgenic mice prematurely (outside this harvesting scheme) due to signs of illness at different ages. All these 21 mice developed MDS and just transformed to AML confirmed by cytological analyzes of the mouse bone marrow showed increasing numbers of blast cells characteristic to AML status. Their 3D telomere profiles were done comparatively to sex and age matched-control ones. We found a trend of chronological telomere dysfunction in mice that is similar to the human condition. Finally, the two-telomere pathways of progression from MDS to AML already defined with human samples appear to be confirmed by the mouse samples.

Conclusion(s): This mutant mouse strain is useful to examine our 3D nuclear telomeric profiling of both diseases. Since transgenic mice/non transgenic littermate mice share the same genetic background, except the transgene, the 3D profiles and any genetic abnormalities found will be a resultant of the disease initiation and/or progression

Outcome / Impact: We will gain a better understanding of the nuclear processes leading to this transition between MDS and AML that will provide a new basis for new molecular therapeutic strategies aimed at improving the dire prognosis of MDS, AML/MDS and AML. This will, in the future, aid in individualized (personalized) patient management.

References:

1. Gadji M, Adebayo Awe J, Rodrigues P, et al. Profiling three-dimensional nuclear telomeric architecture of myelodysplastic syndromes and acute myeloid leukemia defines patient subgroups. Clin Cancer Res. 2012;18:3293-3304.

2. Lin YW, Slape C, Zhang Z, Aplan PD. NUP98-HOXD13 transgenic mice develop a highly penetrant, severe myelodysplastic syndrome that progresses to acute leukemia. Blood. 2005;106:287-295.

Citation Format: Macoura Gadji, Prerana Rodrigues, Sabine Mai. Towards validation of three-dimensional nuclear telomeric profiles as a biomarker of myelodysplastic syndromes and acute myeloid leukemias in a mouse model. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A33.