Biology of acute myeloid leukemia stem cells

Acute myeloid leukemia (AML) is a form of blood cancer that affects the myeloid lineage of blood cells and is characterized by the accumulation of immature myeloid blasts in the bone marrow. The prognosis for patients with AML is currently still rather poor, mainly due to disease relapse. Whereas current standard chemotherapy strategies lead to an initial reduction of leukemic blasts in the majority of patients, a small cell population persists and is apparently not efficiently targeted, leading to recurrence of the disease. Evidence exists that relapse is initiated by leukemia stem cells (LSCs), and analysis of the molecular mechanisms that drive their stemness- and drug-resistant- properties is necessary to improve AML therapy.  The maintenance of hematopoietic stem cells and their differentiation into mature blood cells is regulated by a complex network of different proteins, including the in AML frequently deregulated proteins CITED2 and PU.1.  The first part of this thesis focuses on analyzing the role of CITED2 and PU.1 in AML cell survival and stem cell maintenance, as well as in processes preceding malignant transformation.  Reduction of CITED2 levels in AML cells is highlighted as a potential therapy strategy.The second part of this thesis aims to analyze metabolic properties of LSCs and demonstrates that AML cells with low mitochondrial activity have a high expression of genes linked to stem cell maintenance and chemotherapy resistance, and therefore likely coincide with the LSCs. It is demonstrated that these cells can be efficiently targeted by inhibition of the mitochondrial regulator BCL2.

Dissertation: http://hdl.handle.net/11370/5b7f5445-6ab3-4f58-841e-893124a8d536