[1382] Epigenetic Mechanisms Underlying the Pathogenesis of Myelodysplastic Syndrome (MDS) and Chronic Myelomonocytic Leukemia (CMML)

Jason X Cheng, John Anastasi, Jeffery Q Shen, Kenneth Watanabe, Edward Grimley, Erica Kleinbrink, Randall Knibbs, Diane Roulston, James W Vardiman. University of Michigan, Ann Arbor, MI; University of Chicago, Chicago, IL; University of Nevada, Las Vegas, NV

Background: CMML is characterized by monocytosis and myelodysplasia. PU.1 is a master regulator of myelopoiesis and monocyte/granulocyte development. Trimethylation of histone 3 lysine 27 (H3K27me3) is critical for modulating hematopoietic stem cell (HSC) differentiation. We recently described a novel epigenetic mechanism involving hyper-H3K27me3 in the PU.1 pathway in Refractory Cytopenia with Multilineage Dysplasia (RCMD), an MDS subtype. However, the role of H3K27me3 and inactivation of PU.1 pathway in the pathogenesis of CMML is unclear.
Design: Pools of CMML, RCMD and normal bone marrow cells with normal karyotypes were used to analyze H3K27me3 status by chromatin immunoprecipitation (ChIP). A group of myeloid determining genes that had hyper-H3K27me3 in RCMD was studied. Quantitative RT-PCR, flow cytometric and immunohistochemical studies were performed. OCI-M2, a MDS-derived cell line and U937, a monocyte line, were also studied.


Results: Different patterns of H3K27me3 and expression of the PU.1 gene were observed in CMML vs. RCMD. A lower level of H3K27me3 at monocytic lineage-determining gene including MAC1, CSF1R and CD11b was observed in CMML as compared to RCMD, but granulocyte-specific genes such as ELA2 had a higher level of H3K27me3 in CMML. The levels of H3K27me3 were inversely related to the levels of gene expression. In vitro experiments showed H3K27me3 inhibitors could effectively inhibit proliferation and induce differentiation in MDS-derived and CMML-derived cell lines.


Conclusions: Hyper-H3K27me3 may play a role in the pathogenesis of MDS and CMML, although different subsets of myelopoiesis-determining genes are likely involved. Our studies suggest new biomarkers to support clinical diagnosis, therapy monitoring and possible new therapy.
Category: Hematopathology

Tuesday, March 20, 2012 2:30 PM

Platform Session: Section G, Tuesday Afternoon

 

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