Date of Award

Spring 5-17-2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

Ellen Pure

Abstract

Fatty acid metabolism governs critical cellular processes in multiple cell types. The goal of my dissertation was to investigate the intersection between fatty acid metabolism and hematopoiesis. Although fatty acid metabolism has been extensively studied in mature hematopoietic subsets during inflammation, in developing hematopoietic cells the role of fatty acid metabolism, in particular by 12/15-Lipoxygenase (12/15-LOX), was unknown. The observation that 12/15-LOX-deficient (Alox15) mice developed a myeloid leukemia instigated my studies since leukemias are often a consequence of dysregulated hematopoiesis. This observation lead to the central hypothesis of this dissertation which is that polyunsaturated fatty acid metabolism mediated by 12/15-LOX participates in hematopoietic development. Using genetic mouse models and in vitro and in vivo cell development assays, I found that 12/15-LOX indeed regulates multiple stages of hematopoiesis including the function of hematopoietic stem cells (HSC) and the differentiation of B cells, T cells, basophils, granulocytes and monocytes. Within hematopoietic development, I concentrated on the mechanisms that underlie the defects in HSC function and monocyte development since these defects likely contribute to the myeloid leukemogenesis in Alox15 mice. Interestingly, I determined that 12/15-LOX promotes HSC self-renewal and quiescence, which is associated with the activation of canonical Wnt signaling. Moreover, my studies demonstrate that 12/15-LOX-mediated redox signaling of SHP-2 and the transcription factor ICSBP/IRF-8 promotes monocyte development while inhibiting granulocyte development. This pathway is also conserved in IL-12p40 expression in macrophages. Therefore, I establish 12/15- LOX as a critical regulator of hematopoiesis and provide insight into novel mechanisms whereby HSC function and monocyte cell fate decisions are regulated. These findings have implications for leukemogenesis and immunity.

Files over 3MB may be slow to open. For best results, right-click and select "save as..."

Share

COinS