Exploring the role of epigenetic alterations in myeloid malignancies with focus on drug response

Abstract

The production of blood cells (hematopoiesis), where the hematopoietic stem cell (HSC) is the cell of origin of all blood cells, is regulated by a complex network of intrinsic and extrinsic signals. Dysregulation of hematopoiesis, including somatic heterozygous mutations, cytogenetic aberrations, or epigenetic aberrations, are found in hematological malignancies. Advances in the technical field have lead to identification of many genetic and epigenetic alterations in myeloid malignancies. However, their exact role in disease pathogenesis and prognosis remains unclear. The main purpose of this thesis was to explore the role of epigenetic alterations in the myeloid malignancies systemic mastocytosis (SM), the myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML).

In study I, we investigated the overall effect on the epigenome caused by Azacitidine in primary MDS bone marrow CD34+ cells. We observed an increase in genes important for the immune system, ERVs, however with no clear correlation with the changes in the epigenome. In study II, four different HDACi were found to dose dependently kill KIT D816V mutated mast cells. Primary patient mast cells were selectively targeted compared to healthy mast cells, and the more aggressive disease, the more sensitive to HDACi mediated killing. In study III, we examined the epigenetic effects of Selenium compounds in AML cell line K562 as well as primary patient AML cells, and found that MSA treatment affected the adhesion capacity of AML cells, which may implicate MSA as a complement to chemotherapy to better target leukemic cells in the bone marrow niche. In study IV, we further investigated the mechanism of action of the findings in study II, delineating the effects of HDACi treatment on mast cell epigenome and transcriptome. We demonstrate a direct effect of HDACi on KIT as well as KIT downstream signaling in D816V KIT mutated cells.

In conclusion, this thesis provides insight of the mechanism of action of epigenetically active drugs used in the clinic today, findings that may have direct consequences for improved treatment strategies in myeloid malignancies.