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Epigenetic regulation in normal hematopoiesis and its dysfunction in leukemia Lorzadeh, Alireza


Epigenetic modifications including reversible and non-uniform chemical marks to chromatin support activation and silencing of gene transcription. Alterations in normal epigenetic states are associated with transformation across a wide range of cancer types including myeloid malignancies. To understand the role of epigenetic regulation of normal human hematopoietic progenitors and its dysfunction in myeloid transformation, I developed a low-cell input chromatin immunoprecipitation method that, when combined with an analytical framework enables a simultaneous assessment of chromatin accessibility and histone modification state. This method enabled a comparative analysis of the epigenomic states of normal and malignant human blood cell compartments. Application of this methodology to highly purified, phenotypically defined subsets of primitive and terminally differentiating normal human cord blood cells showed that multiple human hematopoietic progenitor phenotypes display a common H3K27me3 signature. This signature includes many large organized H3K27me3 domains co-marked by H3K9me3 also found in the mature lymphoid cells in cord blood (CB) but not in co-isolated monocytes or erythroblasts. These results indicate a marked difference in the epigenomic changes primitive human neonatal hematopoietic cells undergo when they initiate terminal differentiation of the lymphoid and myeloid lineages. Further evidence that this differential H3K27me3 contraction directly impacts hematopoietic differentiation was obtained by manipulating H3K27me3 regulators in cell line models of inducible neutrophil differentiation in vitro. These methodologies were then used to explore epigenomic dysfunction found in the leukemic cells obtained from patients presenting with acute myeloid leukemia (AML) whose blasts differed in their content of neomorphic isocitrate dehydrogenase (IDH) mutations. Comparison of the methylation landscape in the AML cells with and without IDH mutations revealed a higher fractional DNA methylation level at active enhancers in the IDH mutant cells. However, there was no significant difference in global occupancy of histone modifications between the leukemic cells from the two patient groups. Collectively, these findings reveal previously unknown relationships of epigenetic modifications in normal and malignant human blood cells.

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