The Role of Cyclin E in Myelodysplastic Syndrome
EJ Duncavage, SR Tripp, ME Salama. University of Utah, Salt Lake City, UT
Background: Cyclin E is a key protein in the G1 to S cell cycle transition. Cyclin E levels are up-regulated by Retinoblastoma-mediated release of E2F1 during S phase entry. Cyclin E then complexes with CDK2, which acts to increase levels of Cyclin D, pushing the cell into S phase. A recent study has shown that Cyclin E knock-in mice lacking a key domain required for normal degradation develop a myelodysplastic syndrome (MDS) phenotype with erythroid dysplasia, anemia, and impaired differentiation as a result of increased Cyclin E levels (PMID: 18559482). Extrapolating from this model, we aimed to uncover the relationship between Cyclin E expression and human MDS.
Design: We identified a set of 51 cases of MDS for which adequate clinical data and formalin-fixed paraffin-embedded bone marrow cores were available. Using a phospo-specific antibody targeted at the activated, threonine 62 phosphorylated, form of Cyclin E (pCyclin E), immunohistochemistry was performed on core biopsy material using an automated stainer. Normal breast was used as a positive staining control. Slides were then scanned at 20X resolution and staining quantitated by image analysis software. The percentage of cells expressing a 3+ nuclear staining pattern was recorded, and significance of expression differences determined using the Mann-Whitney U-test. An additional set of normal, non-MDS bone marrow cores were similarly stained and analyzed for comparison.
Results: We found that pCyclinE levels are significantly decreased in MDS compared to normal controls (p<0.005). However, within MDS cases, no significant correlations were found between blast percentage, lineage specific dysplasia, age, white cell count, hemoglobin, diagnosis, or overall survival and pCyclin E levels.
Conclusions: pCyclin E levels are significantly reduced in MDS, arguing that the normal cyclin E regulatory system is intact in MDS. MDS generally presents with an abnormal proliferation of erythroid progenitors that have escaped cell cycle checkpoints by clonal selection and expansion of cells with deleterious mutations. The remaining, intact cell regulatory machinery tends to counteract these oncogenic stimuli by reducing levels of proteins required for cell division. Our findings are consistent with an intact Cyclin E regulatory mechanism, with down-regulation resulting as a normal, protective response to unchecked cell division. We conclude that while increased levels of cyclin E are capable of producing murine MDS, cyclin E likely does not play a role in the pathogenesis of human MDS.
Tuesday, March 23, 2010 1:00 PM
Poster Session IV # 171, Tuesday Afternoon