Separase activity in myelodysplastic syndrome and secondary acute myeloid leukemia correlates with disease malignancy and transformation process Separase-Aktivität beim myelodysplastischen Syndrom und der akuten myeloischen Leukämie korreliert mit Malignität der Erkrankung und dem Transformationsprozess Sabrina Ruppenthal1, Helga Kleiner1, Daniel Nowak1, Florian Nolte1, Wolf-Karsten Hofmann1, Alice Fabarius1, Wolfgang Seifarth1 1
Department of Hematology and Oncology, Mannheim Medical Center, Heidelberg University, 68167 Mannheim, Germany
[email protected] Introduction Missegregation of chromosomes and resulting aneuploidy leads to genetic instability. Separase is a key player for centrosome duplication and sister chromatid separation in mitotic anaphase. Aberrant expression and altered separase activity have been associated with centrosome aberrations (CA), chromosomal missegregation and aneuploidy. Thus, increased separase activity in a small subpopulation of tumor cells may serve as a driver of tumor heterogeneity and clonal evolution in hematopoietic disorders. No data are currently available on separase activity in myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (sAML). Therefore we set out to measure separase activity in respective clinical samples and correlate the activity with CA and clinical data in terms of disease malignancy and transformation process. Methods Mononuclear cells from bone marrow (BM) specimen of 67 patients (pts) were analyzed by fluorescence-activated cell sorting (FACS). The number of separase-active cells and the intercellular separase activity distribution (expressed as SAD) were calculated. 37 pts with MDS (median age 69, range 28-88), 9 pts with de novo AML (median age 57, range 25-82) and 8 pts with sAML (median age 70, range 45-80) were included. FACS, karyotype, mutation analysis and centrosome staining were performed with samples from patients either at the time of initial diagnosis and/or during follow up. Pts treated at time point of sample collection were excluded. 7 healthy donors (median age 65, range 24-86) served as controls. Results A higher number of CA was found in sAML (12%) compared to MDS (7%, p=0.0441) and controls (4%, p
