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Role of Heterochromatin Epigenetic Factors in CML

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Final rept. 1 Mar 2006-28 Jul 2008

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The main goal of this work was to test and further develop a hypothesis that structural modifications andor interference between two heterochromatin proteins MNEI and HP1 lead to abnormal gene regulation and impaired myeloid differentiation CML acceleration blast crises andor secondary acute leukemia. In specific aim 1 we separated monomeric and high molecular forms of MNEI by chromatography and gel electrophoresis and probed their primary structure by mass spectroscopy and Western blotting indicating the presence of MNEI-elastase complex also containing an unmodified peptide specific for the high molecular form. We raised antibodies against 3 distinct high molecular forms of MNEI. We found that these antibodies recognize elevated levels of high molecular MNEI co-expressed with HP1 in a subset of CML cases including blastic form of CML. In specific Aim 2 we constructed cell lines derived from a blastic CML cell model K562 expressing MNEI and HP1. We showed that expression of MNEI did not interfere with constitutive heterochromatin but significantly inhibited cell proliferation. Using high throughput gene expression analysis and chromatin immunoprecipitation we found that HP1 and MNEI similarly target multiple chromosomal loci. Our results suggest that MNEI interacts with chromosomal loci vacated by HP1 during normal myeloid differentiation and that association with the same set of gene targets with HP1 may impair gene regulation in cases where both MNEI isoforms and HP1 are expressed.

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  • Medicine and Medical Research

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