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Molecular and Cellular Biology

Abstract 2044: Three-dimensional nuclear telomeric architecture defines cytopenias of myelodysplastic syndrome and its transformation to acute myeloid leukemia

Macoura Gadji, Julius Adebayo Awe, Prerana Rodriguez, Ludger Klewes, Rajat Kumar, Donald S. Houston, Roberto Passetto Falcão, Fábio Morato de Oliveira and Sabine Mai
Macoura Gadji
1The University of Manitoba, Winnipeg, Manitoba, Canada
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Julius Adebayo Awe
1The University of Manitoba, Winnipeg, Manitoba, Canada
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Prerana Rodriguez
1The University of Manitoba, Winnipeg, Manitoba, Canada
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Ludger Klewes
1The University of Manitoba, Winnipeg, Manitoba, Canada
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Rajat Kumar
1The University of Manitoba, Winnipeg, Manitoba, Canada
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Donald S. Houston
1The University of Manitoba, Winnipeg, Manitoba, Canada
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Roberto Passetto Falcão
2University of São Paulo, São Paulo, Brazil
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Fábio Morato de Oliveira
2University of São Paulo, São Paulo, Brazil
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Sabine Mai
1The University of Manitoba, Winnipeg, Manitoba, Canada
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DOI: 10.1158/1538-7445.AM2012-2044 Published April 2012
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Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL

Abstract

Background Myelodysplastic Syndromes (MDS) are a group of disorders characterized by cytopenias, with a propensity for evolution into Acute Myeloid Leukemias (AML). This transformation is governed by acquisition of additional mutations, which in turn 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 from MDS to AML. Methods We undertook a prospective pilot study of 95 patients to investigate the nuclear telomere organization in MDS (57 patients) and AML (38 patients). Three-dimensional (3D) quantitative fluorescent in situ hybridization was performed to label telomeres of bone marrow samples. Nuclear telomere organization was analyzed using TeloViewTM and TeloScanTM. Findings Our cohort was composed of 57 cases of MDS and 38 AML. MDS cohort was constituted of Refractory Anaemia with Multilineage Dysplasia (RCMD = 32 cases), Refractory Anaemia (RA = 12 cases), Refractory Anaemia with Excess of Blasts 1 and 2 (RAEB-1 = 8 cases; RAEB-2 =1 case), Refractory Anaemia with Ring Sideroblasts (RARS = 2 cases), MDS associated with isolated del(5q) (1 case), and MDS unclassified (MDS-U = 1 case). AML were composed of AML-M4 (12 cases), AML-M2 (10 cases), AML-M5 (5 cases), AML-M0 (5 cases), AML-M1 (2 cases), AML-M4eo (1 case), and AML with multidysplasia related changes (1 case). We analyzed the 3D nuclear telomeric architecture, and determined the telomere numbers, presence of telomere aggregates, telomere signal intensities, nuclear volume, and telomere distribution. From these parameters we constructed 3D telomeric profiles, and we were able to subdivide the MDS patients into 9 subgroups and the AML patients into 6 subgroups. Each of the quantitative telomere parameters showed significant difference between MDS and AML. Furthermore, statistical analyses combining all the telomere parameters displayed significant difference between all subgroups. These profiles were linked to the evolution of telomere dysfunction in these subgroups allowing us to define a model of progression of MDS to AML. Our 3D telomeres profiling reflect better genomic abnormalities in MDS and AML than the cytogenetic categorisations. Telomere profiles seem to be a potential biomarker, which will improve the clinical management of these patients combined to other indexes such as IPSS and WPSS in MDS, and the cytogenetic risk factor classifications of AML. Interpretation Our results define for the first time the chronological and evolutionary process of telomere dysfunction in MDS and AML. These results are consistent with the hypothesis that telomere dysfunction generates genomic instability, leading to worsening cytopenias and to the transformation of MDS to AML.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2044. doi:1538-7445.AM2012-2044

  • ©2012 American Association for Cancer Research
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Cancer Research: 72 (8 Supplement)
April 2012
Volume 72, Issue 8 Supplement
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Abstract 2044: Three-dimensional nuclear telomeric architecture defines cytopenias of myelodysplastic syndrome and its transformation to acute myeloid leukemia
Macoura Gadji, Julius Adebayo Awe, Prerana Rodriguez, Ludger Klewes, Rajat Kumar, Donald S. Houston, Roberto Passetto Falcão, Fábio Morato de Oliveira and Sabine Mai
Cancer Res April 15 2012 (72) (8 Supplement) 2044; DOI: 10.1158/1538-7445.AM2012-2044

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Abstract 2044: Three-dimensional nuclear telomeric architecture defines cytopenias of myelodysplastic syndrome and its transformation to acute myeloid leukemia
Macoura Gadji, Julius Adebayo Awe, Prerana Rodriguez, Ludger Klewes, Rajat Kumar, Donald S. Houston, Roberto Passetto Falcão, Fábio Morato de Oliveira and Sabine Mai
Cancer Res April 15 2012 (72) (8 Supplement) 2044; DOI: 10.1158/1538-7445.AM2012-2044
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Cancer Research Online ISSN: 1538-7445
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